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Introduction

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective treatment for a number of hematologic malignancies and non-malignant disorders, but it is associated with significant non-relapse mortality (NRM). Recently, a number of studies emphasized the role of endothelial dysfunction in such life-threatening complications of alloHSCT as graft-versus-host disease (GVHD) and veno-occlussive disease (VOD). The concept of endothelial injury in alloHSCT is not new, in 1996 Testa S et al., reported association between level of thrombomodulin, an endothelial damage marker, and GVHD, VOD and septicemia [30]. Since then the role of endothelium in acute alloHSCT complications were predicted to be more complex. On the one hand, neovascularization of bone marrow, skin and gastrointestinal tract is presiding event to acute GVHD, and it is associated with increased level of vascular endothelial growth factor (VEGF) [13,17,21]. On the other hand, endothelium is damaged by conditioning and calcineurin inhibitors, which leads to increased incidence of microvascular complications, infections and non-relapse mortality [8]. Also it was proposed that not the overwhelming T-cell alloreactive cytotoxicity, but severe endothelial dysfunction is responsible for steroid-refractory form of acute GVHD [14]. These multiple roles of endothelium in complications of alloHSCT make endothelial damage markers an attractive tool to predict prognosis.

Furthermore, neovasculogenesis and its key regulator VEGF were found to play an important role in pathogenesis of hematologic malignancies. VEGF A expression was associated with altered morphology and increased vascularization of the bone marrow in myeloproliferative disorders [2,10]. Also it was demonstrated that increased level of VEGF A is associated with worse outcome of chemotherapy in patients with acute myeloid leukemia [1], chronic myeloid leukemia [34], acute lymphoblastic leukemia [5], myelodysplastic syndrome [33] and different types of lymphoproliferation [6, 11, 25]. Apart from VEGF, level of circulating endothelial cells (CEC) was also found to predict prognosis in patients treated with chemotherapy for acute myeloid leukemia [35]. The significance of this negative prognostic factor was not established in recipients of alloHSCT.

A number of endothelial damage was studied in alloHSCT patients. The principal groups are adhesion molecules (ICAM, VCAM etc.), VEGF, CEC, von Willebrand factor, thrombomodulin and anti-coagulants, which are rapidly depleted in cases of extensive endothelial injury (protein C, antithrombin III etc) [8]. Among all these markers for the present study we selected VEGF A and CECs, because they are increased both in situation of endothelial injury and tumor-associated neovasculogenesis, and thus, may have a prognostic significance for both early complications after alloHSCT and relapse of the underlying hematologic malignancy.

Previously, we have reported a predictive value of VEGF A for early non-relapse mortality and relapses after alloHSCT [20] and a diagnostic significance of CEC level for VOD [19].

In the present study we evaluated predictive significance of VEGF and CECs for short- and long-term outcomes of alloHSCT and association between these two endothelial damage markers.

Patients and methods

Patients

The study was based on the blood samples and hospital records of 91 consecutive adult patients with hematologic malignancies undergoing HSCT in R.M. Gorbacheva Memorial Institute of Children Hematology and Transplantation. Samples for the study were collected prospectively between 2010 and 2012. The study was approved by the Ethical Committee of I.P. Pavlov State Medical University and informed consent was received from all patients for blood collection.

73% of patients had acute leukemia, 10% chronic myeloid leukemia, 8% myelodysplastic syndrome and 9% other hematologic malignancies. Median age was 38 years (range 18-60), median performance score and modified EBMT risk score [12, 29] ² and 8 mg/kg busulfan or 140 mg/m² melphalan in case of previous busulfan-based conditioning or anamnesis of neurological disorders. Acute GVHD prophylaxis consisted of calcineurin inhibitor (tacrolimus in 81% of patients) and short-course methotrexate. Antilymphocyte globulin (Atgam, Pfizer, NY, USA) 60 mg/kg was used for unrelated grafts. All but two patients received single allogeneic graft. Ten patients had previous autologous transplantation. Detailed patient characteristics are given in table 1. VOD prophylaxis with fixed-dose heparin was performed in all patients.

The staging and grading of acute GVHD were performed using the modified Glucksberg consensus criteria [24] and occurred at the time of initiation of treatment. VOD was diagnosed clinically according to the modified Seattle criteria extended until day +30 after HSCT, which required the presence of at least two of the following three clinical findings: jaundice with bilirubin>34 µmol/l, painful hepatomegaly and fluid retention >5% of the body weight. VOD was classified as severe in presence of multi-organ failure.

Laboratory methods

Venous blood was collected using EDTA anticoagulant from the central venous catheter before the start of conditioning, on the day of SCT (day 0) before graft transfusion, on the day of engraftment and additionally on the day of VOD diagnosis.

For VEGF A analysis, the blood samples were centrifuged for 15 minutes at 1000 g and the plasma aliquots were stored in polypropylene tubes at -80ºC until the day of the assay. Measurement of VEGF A concentrations in plasma samples was performed by enzyme-linked immunosorbent assays (ELISA) using commercially available kits (eBioscience, CA, USA) according to the instructions of the manufacturer. The detection limit was 7.9 to 1000 pg/ml. Concentrations were determined without knowledge of clinical data.

Measurement of CEC was performed within 2 hours from the blood collection. Peripheral blood samples were processed by lysing buffer (BD Pharm Lyse, BD Biosciences). Cell-surface triple staining was performed with fluorochrome-labeled monoclonal anti-human mouse antibodies incubated for 20 minutes at room temperature. The following antibody combination was used: CD31-FITC, CD146-PE, and CD45-PerCP (Becton Dickinson, San Jose, CA,USA). Data acquisition and analysis were performed by using BD FACSAria II flow cytometer and BD FACSDiva software (Becton Dickinson). For CECs measurement at least 1 million events was acquired. To exclude platelets, dead cells, and microparticles, the FSC/SSC plot was used. CECs were identified as CD45-negative CD31-bright positive CD146-bright positive (CD45-/CD31bright/ CD146bright) [16].

Statistical analysis

Experimental and clinical data were analyzed using SPSS Version 17.0. Chi-square and Wilcoxon criteria were used for univariate non-parametric analysis. Kruskal-Wallis test was used to determine the effect of pre-transplant therapy on the level of endothelial damage markers before conditioning. Kaplan–Meier survival analysis and Log Rank test were used for univariate survival, transplant-related mortality and cumulative incidence of relapse comparisons. Multivariate analysis was performed using Cox regression. Multivariate models were built with the use of stepwise forward selection, using a p-value ≤0.01 to include variables in the model. Proportional-hazards assumption was tested for each variable individually, all variables met this assumption. Separate models were created for assessment of CEC predictive value, since they were measured only in 55 consecutive patients. Cut-off levels of VEGF for survival analysis were determined based on ROC curves. Results of VEGF measurement at different time points were selected for Kaplan–Meier analysis and Cox regression if ROC area under the curve (AUC) for this time point was ≥0.5, and the time point with the highest value was selected.

Laboratory samples were collected within 30 days after transplantation and then patients were followed-up for survival and relapse. Median follow-up was 895 days (range 135-1364). NRM was defined as the cumulative incidence of death from the date of transplant not related to the relapse and its subsequent treatment. Even-free survival (EFS) was defined as the time from the date of transplantation to the documented event (relapse or death).

Results

Clinical outcomes

Engraftment was achieved in 90% of patients, 10% had either primary graft failure and/or progressive disease. Three-year overall survival (OS), EFS and NRM in the whole group were 44%, 35% and 34% respectively. Three -year cumulative incidence of relapse was 31%. VOD was diagnosed in 14% (n=13) of patients, severe VOD- in 10%. Median day of VOD diagnosis was 13 (range 6-21). Acute GVHD grade 1-4 was diagnosed in 54.4% of patients, grade 3-4 GVHD in 20.9%.

Selection of the optimal time points and cut-offs

The ROC curve analysis was performed to determine the time points of alloHSCT with highest predictive value for NRM and RR. The analysis separated early events (within 1 year after alloHSCT) and late events (after 1 year). The analysis for late relapses was not performed since there was only single such event in the study group. The results for VEGF A and CEC are presented in table 1.

Time point	Before conditioning	Day 0	Upon engraftment
VEGF A
1-year relapse incidence	0.62	0.53	0.50
1-year non-relapse mortality	0.46	0.67	0.57
Relapse incidence after one year	n.a	n.a	n.a
Non-relapse mortality after one year	0.40	0.36	0.46
Circulating endothelial cells
1-year relapse incidence	0.55	0.62	0.62
1-year non-relapse mortality	0.66	0.50	0.54
Relapse incidence after one year	n.a	n.a	n.a
Non-relapse mortality after one year	0.54	0.35	0.00

n.a.= not applicable

Table 1. ROC areas under the curves for predictive value of VEGF A and CECs

VEGF A before conditioning was found to have the highest predictive value for 1-year relapse (AUC=0.62). The ROC determined cut-off for relapse was 37 pg/ml. An additional analysis was performed to exclude the effect of pre-transplant chemotherapy on the level of VEGF A before conditioning. Neither time from diagnosis to HSCT (p=0.83), number of previous chemotherapy courses (p=0.12), number of high-dose chemotherapy courses (p=0.82), previous HSCT (p=0.11) or time from the last chemotherapy course (p=0.28) significantly effected the level of VEGF A.

Early NRM was best predicted by VEGF A level after conditioning (AUC=0.67). The determined cut-off value was the limit of quantification (<7.8 pg/ml). On the contrary, late NRM was not predicted by VEGF A concentrations with AUC<0.5 at all time points.

For CECs, early relapse was best predicted by level after conditioning ( AUC=0.62) with a cut-off 87 cells/ml. Level of CECs before conditioning was both predictive for 1-year (AUC=0.66) and late NRM (AUC=0.54) with a cut-off value of 38 cells/ml. As with VEGF time from diagnosis to HSCT (p=0.34), number of previous chemotherapy courses (p=0.40), number of high-dose chemotherapy courses (p=0.58) or time from the last chemotherapy course (p=0.25) were not significantly effecting the pre-transplant level of CECs.

As based on these results, we selected pre-transplant VEGF A level and day 0 CEC level to be tested in Kaplan–Meier survival analysis of relapse incidence, and day 0 VEGF along with pre-transplant CEC levels for NRM analysis.

Predictive value of VEGF for
relapse and non-relapse mortality

Patients with pre-conditioning level of VEGF A >37 pg/ml had significantly higher 1-year relapse incidence (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40, figure 1). Also patients VEGF A after conditioning <7.8 pg/ml demonstrated a trend to lower non-relapse mortality (17% vs 35%, p=0.10, Fig. 1). In a multivariate analysis VEGF A >37 pg/ml was a significant factor associated with relapse (HR 3.15, 95%CI 1.34-7.40, p=0.009, table 2). Moreover, when corrected for confounding factors in multivariate regression VEGF A after conditioning <7.8 pg/ml was a significant predictor of NRM (HR 0.15, 95%CI 0.03-0.69, p=0.015, table 2). Surprisingly, 3-year overall survival (OS) was not different in patients with high and low VEGF concentrations (50% vs 42% respectively, p=0.60), as majority of patients in high VEGF group responded to salvage therapy after relapse.

Figure 1. 1-year relapse incidence and non-relapse mortality according to VEGF level

Factor	Multivariate, p-value	HR	HR 95% CI
1-year cumulative relapse rate
Unrelated vs related donor	0.232
Active disease at the time of HSCT	0.002	4.05	1.68-9.79
MAC vs RIC conditioning	0.461
Acute GVHD, grade 1-4	0.002	0.26	0.11-0.61
Chronic GVHD	0.003	0.19	0.06-0.55
VEGF A before conditioning > 37 pg/ml	0.009	3.15	1.34-7.40
1-year non-relapse mortality
Active disease at the time of HSCT	0.027	4.67	1.19-18.30
Age	0.70
Unrelated vs related donor	0.022	6.64	1.32-33.40
MAC vs RIC conditioning	0.32
Acute GVHD, grade 3-4	0.024	4.87	1.24-19.14
VEGF A on day 0 < 7.8 pg/ml	0.015	0.15	0.03-0.69

Table 2. Multivariate analysis of relapse incidence and non-relapse mortality (whole group)

Predictive value of CECs for
relapse and non-relapse mortality

Univariate analysis with previously determined cut-off value showed patients with CEC level after conditioning >87 cells/ml had higher relapse incidence (60% vs 21%, p<0.001), but in multivariate analysis it was not a significant factor (p=0.09, table 3). So CECs was not an independent predictive marker of relapse, but rather demonstration the increased endothelial damage in patients with high-risk disease. This was confirmed by the fact that level >87 cells/ml was significantly more often observed in patients with active disease at the time of the alloHSCT (80% vs 20%, p=0.032).

Univariate analysis of NRM confirmed that patients with pre-conditioning level of CECs >71 had increased risk of transplant-related death during the first year (69% vs 20%, p=0.001), while the incidence of late NRM was not significantly different (0% vs 5%, p=0.70). Nevertheless, in multivariate analysis the differences in 1-year NRM were also not significant (95%CI 0.84-5.76, p=0.102, table 3). Regarding results of multivariate analysis of CEC as the predictive marker, the statistical power of the models was relatively low due to small number of patients with CEC measured, so with a larger group of patients, the CECs as the covariate might reach the significant level.

Factor	Multivariate, p-value	HR	HR 95% CI
1-year cumulative relapse rate
Active disease at the time of HSCT	0.82
MAC vs RIC conditioning	0.148
Acute GVHD, grade 1-4	0.035	0.24	0.07-0.91
Chronic GVHD	0.019	0.08	0.01-0.66
CEC after conditioning>87 cells/ml	0.086
1-year non-relapse mortality
Active disease at the time of HSCT	0.050	3.05	1.00-9.31
Acute GVHD, grade 3-4	0.040	2.98	1.05-8.45
CEC before conditioning>71 cells/ml	0.102

Table 3. Multivariate analysis of relapse incidence and non-relapse mortality (only patients with measured level of CECs)

Association between level
of VEGF A and CECs

The interesting result of the analysis was that there was no correlation between pre-transplant level of CECs and VEGF (p=0.81), as well as for after conditioning (p=0.74) and engraftment levels (p=0.59). But when the cut-off levels of CEC (>71 cells/ml) and VEGF (<7.8 pg/ml) that predicted NRM were tested, in patients with high CEC level pre-conditioning VEGF was significantly more frequently elevated on day 0 (83% vs 51%, p=0.036).

Discussion

In this study we confirmed the prognostic significance of endothelial damage markers for non-relapse mortality. As expected, these markers allow to predict only early, but not late mortality. This is due to the fact that late NRM is mostly associated with chronic GVHD or infections related to impaired immune system [26]. The factors that influence development of chronic GVHD and immune reconstitution are mostly immunologic and are associated with patient-donor major or minor HLA-antigen disparity and trigger these events in the late post-transplant period [3, 24]. On the contrary, in an early post-transplant period endothelial dysfunction plays a role in a number of acute complications. In our study due to small number of patients it was impossible to establish relationship between endothelial damage and all of the complications, but as we previously reported elevation of VEGF and CEC levels was closely related to development of VOD [19, 20]. Likewise, a number of studies demonstrated association between endothelial damage and acute GVHD [14, 15, 18],

In this study we found out that VEGF is predictive for NRM after conditioning, while CEC – when measured before conditioning. So different endothelial damage markers may represent different aspects of endothelial damage and are elevated variable time after a damage occurs. This was confirmed in our study by absence of correlation between VEGF and CEC, and only more sophisticated methods revealed association between these two biomarkers. So VEGF A is secreted a large variety of cells, including endothelial and blood mononuclears. It is eliminated via cleavage with serum proteases and binding to either soluble or cellular VEGF receptors. But also a large proportion of VEGF is bound to extracellular matrix (ECM) heparin sulfate proteoglycans. In response to endothelial and tissue damage ECM-bound VEGF is cleaved from proteoglycan complex and released into circulation to facilitate reparation. What is important is that activity of serum proteases in terms of VEGF elimination is insufficient to decrease its level in situations of its extensive release from ECM. But its levels in plasma return to normal values very rapidly, within hours, if there are no continuous stimuli [9, 28, 32]. Hence, VEGF A level in plasma represent the acute phase of endothelial damage, that is why the time-point post-conditioning is of highest predictive value. CEC levels, on the other hand, represent chronic endothelial damage and are present in circulation for a longer period of time than VEGF. That is why it is a valuable tool to predict complications in diabetes and cardiovascular disorders [3, 7]. Marginally significant predictive value of CEC in multivariate analysis may not indicate that this is less valuable prognostic marker, but may be a result of a smaller number of patients in whom it as measured. In summary, different endothelial damage markers complement each other and in further clinical research should be used in combination.

Another aspect of our study was a dual role of VEGF. Besides its role as endothelial damage biomarker, it is also a disease risk factor in hematologic malignancies [1, 5, 6, 11, 33, 34]. We have demonstrated that it is also a factor of adverse disease prognosis in HSCT, but it is important that there were no differences in OS respective to pre-transplant VEGF level. Successful salvage post-transplant chemotherapy and donor lymphocyte infusions, at least in some patients from the high-VEGF A group, demonstrates a potential utility of graft-versus-leukemia effect to overcome this factor of resistance. Allogeneic HSCT is considered a treatment of choice for high-risk disease in patients with acute leukemias, myelodysplastic syndrome, chronic myeloid leukemia and lymphomas [23, 36]. As standard therapy outcome for these malignancies was reported to be negatively influenced by VEGF A overexpression, further studies are required to determine whether patients with high level of this factor should be candidates for HSCT. Due to very low incidence of late relapses in the study group we failed to demonstrate if there was any influence of VEGF expression on late disease recurrence, so larger studies are required to test this, but given very high incidence of early relapses in our study in the high VEGF group, early post-transplant therapy should be considered for these patients.

Recently, a number of clinical scoring systems were validated to predict risk of alloHSCT, like EBMT risk score [12, 29] or Seattle PAM score [27]. The results of this study show that the endothelial damage markers are of distinct predictive value, irrelevant of clinical parameters. Therefore, further studies are required to evaluate if they could be incorporated into the risk assessment models. In conclusion, peripheral CECs and plasma VEGF levels represent a useful prognostic tool to predict the risk of alloHSCT and disease relapse.

Conflict of interests

No conflict interest is reported.

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Introduction

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective treatment for a number of hematologic malignancies and non-malignant disorders, but it is associated with significant non-relapse mortality (NRM). Recently, a number of studies emphasized the role of endothelial dysfunction in such life-threatening complications of alloHSCT as graft-versus-host disease (GVHD) and veno-occlussive disease (VOD). The concept of endothelial injury in alloHSCT is not new, in 1996 Testa S et al., reported association between level of thrombomodulin, an endothelial damage marker, and GVHD, VOD and septicemia [30]. Since then the role of endothelium in acute alloHSCT complications were predicted to be more complex. On the one hand, neovascularization of bone marrow, skin and gastrointestinal tract is presiding event to acute GVHD, and it is associated with increased level of vascular endothelial growth factor (VEGF) [13,17,21]. On the other hand, endothelium is damaged by conditioning and calcineurin inhibitors, which leads to increased incidence of microvascular complications, infections and non-relapse mortality [8]. Also it was proposed that not the overwhelming T-cell alloreactive cytotoxicity, but severe endothelial dysfunction is responsible for steroid-refractory form of acute GVHD [14]. These multiple roles of endothelium in complications of alloHSCT make endothelial damage markers an attractive tool to predict prognosis.

Furthermore, neovasculogenesis and its key regulator VEGF were found to play an important role in pathogenesis of hematologic malignancies. VEGF A expression was associated with altered morphology and increased vascularization of the bone marrow in myeloproliferative disorders [2,10]. Also it was demonstrated that increased level of VEGF A is associated with worse outcome of chemotherapy in patients with acute myeloid leukemia [1], chronic myeloid leukemia [34], acute lymphoblastic leukemia [5], myelodysplastic syndrome [33] and different types of lymphoproliferation [6, 11, 25]. Apart from VEGF, level of circulating endothelial cells (CEC) was also found to predict prognosis in patients treated with chemotherapy for acute myeloid leukemia [35]. The significance of this negative prognostic factor was not established in recipients of alloHSCT.

A number of endothelial damage was studied in alloHSCT patients. The principal groups are adhesion molecules (ICAM, VCAM etc.), VEGF, CEC, von Willebrand factor, thrombomodulin and anti-coagulants, which are rapidly depleted in cases of extensive endothelial injury (protein C, antithrombin III etc) [8]. Among all these markers for the present study we selected VEGF A and CECs, because they are increased both in situation of endothelial injury and tumor-associated neovasculogenesis, and thus, may have a prognostic significance for both early complications after alloHSCT and relapse of the underlying hematologic malignancy.

Previously, we have reported a predictive value of VEGF A for early non-relapse mortality and relapses after alloHSCT [20] and a diagnostic significance of CEC level for VOD [19].

In the present study we evaluated predictive significance of VEGF and CECs for short- and long-term outcomes of alloHSCT and association between these two endothelial damage markers.

Patients and methods

Patients

The study was based on the blood samples and hospital records of 91 consecutive adult patients with hematologic malignancies undergoing HSCT in R.M. Gorbacheva Memorial Institute of Children Hematology and Transplantation. Samples for the study were collected prospectively between 2010 and 2012. The study was approved by the Ethical Committee of I.P. Pavlov State Medical University and informed consent was received from all patients for blood collection.

73% of patients had acute leukemia, 10% chronic myeloid leukemia, 8% myelodysplastic syndrome and 9% other hematologic malignancies. Median age was 38 years (range 18-60), median performance score and modified EBMT risk score [12, 29] ² and 8 mg/kg busulfan or 140 mg/m² melphalan in case of previous busulfan-based conditioning or anamnesis of neurological disorders. Acute GVHD prophylaxis consisted of calcineurin inhibitor (tacrolimus in 81% of patients) and short-course methotrexate. Antilymphocyte globulin (Atgam, Pfizer, NY, USA) 60 mg/kg was used for unrelated grafts. All but two patients received single allogeneic graft. Ten patients had previous autologous transplantation. Detailed patient characteristics are given in table 1. VOD prophylaxis with fixed-dose heparin was performed in all patients.

The staging and grading of acute GVHD were performed using the modified Glucksberg consensus criteria [24] and occurred at the time of initiation of treatment. VOD was diagnosed clinically according to the modified Seattle criteria extended until day +30 after HSCT, which required the presence of at least two of the following three clinical findings: jaundice with bilirubin>34 µmol/l, painful hepatomegaly and fluid retention >5% of the body weight. VOD was classified as severe in presence of multi-organ failure.

Laboratory methods

Venous blood was collected using EDTA anticoagulant from the central venous catheter before the start of conditioning, on the day of SCT (day 0) before graft transfusion, on the day of engraftment and additionally on the day of VOD diagnosis.

For VEGF A analysis, the blood samples were centrifuged for 15 minutes at 1000 g and the plasma aliquots were stored in polypropylene tubes at -80ºC until the day of the assay. Measurement of VEGF A concentrations in plasma samples was performed by enzyme-linked immunosorbent assays (ELISA) using commercially available kits (eBioscience, CA, USA) according to the instructions of the manufacturer. The detection limit was 7.9 to 1000 pg/ml. Concentrations were determined without knowledge of clinical data.

Measurement of CEC was performed within 2 hours from the blood collection. Peripheral blood samples were processed by lysing buffer (BD Pharm Lyse, BD Biosciences). Cell-surface triple staining was performed with fluorochrome-labeled monoclonal anti-human mouse antibodies incubated for 20 minutes at room temperature. The following antibody combination was used: CD31-FITC, CD146-PE, and CD45-PerCP (Becton Dickinson, San Jose, CA,USA). Data acquisition and analysis were performed by using BD FACSAria II flow cytometer and BD FACSDiva software (Becton Dickinson). For CECs measurement at least 1 million events was acquired. To exclude platelets, dead cells, and microparticles, the FSC/SSC plot was used. CECs were identified as CD45-negative CD31-bright positive CD146-bright positive (CD45-/CD31bright/ CD146bright) [16].

Statistical analysis

Experimental and clinical data were analyzed using SPSS Version 17.0. Chi-square and Wilcoxon criteria were used for univariate non-parametric analysis. Kruskal-Wallis test was used to determine the effect of pre-transplant therapy on the level of endothelial damage markers before conditioning. Kaplan–Meier survival analysis and Log Rank test were used for univariate survival, transplant-related mortality and cumulative incidence of relapse comparisons. Multivariate analysis was performed using Cox regression. Multivariate models were built with the use of stepwise forward selection, using a p-value ≤0.01 to include variables in the model. Proportional-hazards assumption was tested for each variable individually, all variables met this assumption. Separate models were created for assessment of CEC predictive value, since they were measured only in 55 consecutive patients. Cut-off levels of VEGF for survival analysis were determined based on ROC curves. Results of VEGF measurement at different time points were selected for Kaplan–Meier analysis and Cox regression if ROC area under the curve (AUC) for this time point was ≥0.5, and the time point with the highest value was selected.

Laboratory samples were collected within 30 days after transplantation and then patients were followed-up for survival and relapse. Median follow-up was 895 days (range 135-1364). NRM was defined as the cumulative incidence of death from the date of transplant not related to the relapse and its subsequent treatment. Even-free survival (EFS) was defined as the time from the date of transplantation to the documented event (relapse or death).

Results

Clinical outcomes

Engraftment was achieved in 90% of patients, 10% had either primary graft failure and/or progressive disease. Three-year overall survival (OS), EFS and NRM in the whole group were 44%, 35% and 34% respectively. Three -year cumulative incidence of relapse was 31%. VOD was diagnosed in 14% (n=13) of patients, severe VOD- in 10%. Median day of VOD diagnosis was 13 (range 6-21). Acute GVHD grade 1-4 was diagnosed in 54.4% of patients, grade 3-4 GVHD in 20.9%.

Selection of the optimal time points and cut-offs

The ROC curve analysis was performed to determine the time points of alloHSCT with highest predictive value for NRM and RR. The analysis separated early events (within 1 year after alloHSCT) and late events (after 1 year). The analysis for late relapses was not performed since there was only single such event in the study group. The results for VEGF A and CEC are presented in table 1.

Time point	Before conditioning	Day 0	Upon engraftment
VEGF A
1-year relapse incidence	0.62	0.53	0.50
1-year non-relapse mortality	0.46	0.67	0.57
Relapse incidence after one year	n.a	n.a	n.a
Non-relapse mortality after one year	0.40	0.36	0.46
Circulating endothelial cells
1-year relapse incidence	0.55	0.62	0.62
1-year non-relapse mortality	0.66	0.50	0.54
Relapse incidence after one year	n.a	n.a	n.a
Non-relapse mortality after one year	0.54	0.35	0.00

n.a.= not applicable

Table 1. ROC areas under the curves for predictive value of VEGF A and CECs

VEGF A before conditioning was found to have the highest predictive value for 1-year relapse (AUC=0.62). The ROC determined cut-off for relapse was 37 pg/ml. An additional analysis was performed to exclude the effect of pre-transplant chemotherapy on the level of VEGF A before conditioning. Neither time from diagnosis to HSCT (p=0.83), number of previous chemotherapy courses (p=0.12), number of high-dose chemotherapy courses (p=0.82), previous HSCT (p=0.11) or time from the last chemotherapy course (p=0.28) significantly effected the level of VEGF A.

Early NRM was best predicted by VEGF A level after conditioning (AUC=0.67). The determined cut-off value was the limit of quantification (<7.8 pg/ml). On the contrary, late NRM was not predicted by VEGF A concentrations with AUC<0.5 at all time points.

For CECs, early relapse was best predicted by level after conditioning ( AUC=0.62) with a cut-off 87 cells/ml. Level of CECs before conditioning was both predictive for 1-year (AUC=0.66) and late NRM (AUC=0.54) with a cut-off value of 38 cells/ml. As with VEGF time from diagnosis to HSCT (p=0.34), number of previous chemotherapy courses (p=0.40), number of high-dose chemotherapy courses (p=0.58) or time from the last chemotherapy course (p=0.25) were not significantly effecting the pre-transplant level of CECs.

As based on these results, we selected pre-transplant VEGF A level and day 0 CEC level to be tested in Kaplan–Meier survival analysis of relapse incidence, and day 0 VEGF along with pre-transplant CEC levels for NRM analysis.

Predictive value of VEGF for
relapse and non-relapse mortality

Patients with pre-conditioning level of VEGF A >37 pg/ml had significantly higher 1-year relapse incidence (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40, figure 1). Also patients VEGF A after conditioning <7.8 pg/ml demonstrated a trend to lower non-relapse mortality (17% vs 35%, p=0.10, Fig. 1). In a multivariate analysis VEGF A >37 pg/ml was a significant factor associated with relapse (HR 3.15, 95%CI 1.34-7.40, p=0.009, table 2). Moreover, when corrected for confounding factors in multivariate regression VEGF A after conditioning <7.8 pg/ml was a significant predictor of NRM (HR 0.15, 95%CI 0.03-0.69, p=0.015, table 2). Surprisingly, 3-year overall survival (OS) was not different in patients with high and low VEGF concentrations (50% vs 42% respectively, p=0.60), as majority of patients in high VEGF group responded to salvage therapy after relapse.

Figure 1. 1-year relapse incidence and non-relapse mortality according to VEGF level

Factor	Multivariate, p-value	HR	HR 95% CI
1-year cumulative relapse rate
Unrelated vs related donor	0.232
Active disease at the time of HSCT	0.002	4.05	1.68-9.79
MAC vs RIC conditioning	0.461
Acute GVHD, grade 1-4	0.002	0.26	0.11-0.61
Chronic GVHD	0.003	0.19	0.06-0.55
VEGF A before conditioning > 37 pg/ml	0.009	3.15	1.34-7.40
1-year non-relapse mortality
Active disease at the time of HSCT	0.027	4.67	1.19-18.30
Age	0.70
Unrelated vs related donor	0.022	6.64	1.32-33.40
MAC vs RIC conditioning	0.32
Acute GVHD, grade 3-4	0.024	4.87	1.24-19.14
VEGF A on day 0 < 7.8 pg/ml	0.015	0.15	0.03-0.69

Table 2. Multivariate analysis of relapse incidence and non-relapse mortality (whole group)

Predictive value of CECs for
relapse and non-relapse mortality

Univariate analysis with previously determined cut-off value showed patients with CEC level after conditioning >87 cells/ml had higher relapse incidence (60% vs 21%, p<0.001), but in multivariate analysis it was not a significant factor (p=0.09, table 3). So CECs was not an independent predictive marker of relapse, but rather demonstration the increased endothelial damage in patients with high-risk disease. This was confirmed by the fact that level >87 cells/ml was significantly more often observed in patients with active disease at the time of the alloHSCT (80% vs 20%, p=0.032).

Univariate analysis of NRM confirmed that patients with pre-conditioning level of CECs >71 had increased risk of transplant-related death during the first year (69% vs 20%, p=0.001), while the incidence of late NRM was not significantly different (0% vs 5%, p=0.70). Nevertheless, in multivariate analysis the differences in 1-year NRM were also not significant (95%CI 0.84-5.76, p=0.102, table 3). Regarding results of multivariate analysis of CEC as the predictive marker, the statistical power of the models was relatively low due to small number of patients with CEC measured, so with a larger group of patients, the CECs as the covariate might reach the significant level.

Factor	Multivariate, p-value	HR	HR 95% CI
1-year cumulative relapse rate
Active disease at the time of HSCT	0.82
MAC vs RIC conditioning	0.148
Acute GVHD, grade 1-4	0.035	0.24	0.07-0.91
Chronic GVHD	0.019	0.08	0.01-0.66
CEC after conditioning>87 cells/ml	0.086
1-year non-relapse mortality
Active disease at the time of HSCT	0.050	3.05	1.00-9.31
Acute GVHD, grade 3-4	0.040	2.98	1.05-8.45
CEC before conditioning>71 cells/ml	0.102

Table 3. Multivariate analysis of relapse incidence and non-relapse mortality (only patients with measured level of CECs)

Association between level
of VEGF A and CECs

The interesting result of the analysis was that there was no correlation between pre-transplant level of CECs and VEGF (p=0.81), as well as for after conditioning (p=0.74) and engraftment levels (p=0.59). But when the cut-off levels of CEC (>71 cells/ml) and VEGF (<7.8 pg/ml) that predicted NRM were tested, in patients with high CEC level pre-conditioning VEGF was significantly more frequently elevated on day 0 (83% vs 51%, p=0.036).

Discussion

In this study we confirmed the prognostic significance of endothelial damage markers for non-relapse mortality. As expected, these markers allow to predict only early, but not late mortality. This is due to the fact that late NRM is mostly associated with chronic GVHD or infections related to impaired immune system [26]. The factors that influence development of chronic GVHD and immune reconstitution are mostly immunologic and are associated with patient-donor major or minor HLA-antigen disparity and trigger these events in the late post-transplant period [3, 24]. On the contrary, in an early post-transplant period endothelial dysfunction plays a role in a number of acute complications. In our study due to small number of patients it was impossible to establish relationship between endothelial damage and all of the complications, but as we previously reported elevation of VEGF and CEC levels was closely related to development of VOD [19, 20]. Likewise, a number of studies demonstrated association between endothelial damage and acute GVHD [14, 15, 18],

In this study we found out that VEGF is predictive for NRM after conditioning, while CEC – when measured before conditioning. So different endothelial damage markers may represent different aspects of endothelial damage and are elevated variable time after a damage occurs. This was confirmed in our study by absence of correlation between VEGF and CEC, and only more sophisticated methods revealed association between these two biomarkers. So VEGF A is secreted a large variety of cells, including endothelial and blood mononuclears. It is eliminated via cleavage with serum proteases and binding to either soluble or cellular VEGF receptors. But also a large proportion of VEGF is bound to extracellular matrix (ECM) heparin sulfate proteoglycans. In response to endothelial and tissue damage ECM-bound VEGF is cleaved from proteoglycan complex and released into circulation to facilitate reparation. What is important is that activity of serum proteases in terms of VEGF elimination is insufficient to decrease its level in situations of its extensive release from ECM. But its levels in plasma return to normal values very rapidly, within hours, if there are no continuous stimuli [9, 28, 32]. Hence, VEGF A level in plasma represent the acute phase of endothelial damage, that is why the time-point post-conditioning is of highest predictive value. CEC levels, on the other hand, represent chronic endothelial damage and are present in circulation for a longer period of time than VEGF. That is why it is a valuable tool to predict complications in diabetes and cardiovascular disorders [3, 7]. Marginally significant predictive value of CEC in multivariate analysis may not indicate that this is less valuable prognostic marker, but may be a result of a smaller number of patients in whom it as measured. In summary, different endothelial damage markers complement each other and in further clinical research should be used in combination.

Another aspect of our study was a dual role of VEGF. Besides its role as endothelial damage biomarker, it is also a disease risk factor in hematologic malignancies [1, 5, 6, 11, 33, 34]. We have demonstrated that it is also a factor of adverse disease prognosis in HSCT, but it is important that there were no differences in OS respective to pre-transplant VEGF level. Successful salvage post-transplant chemotherapy and donor lymphocyte infusions, at least in some patients from the high-VEGF A group, demonstrates a potential utility of graft-versus-leukemia effect to overcome this factor of resistance. Allogeneic HSCT is considered a treatment of choice for high-risk disease in patients with acute leukemias, myelodysplastic syndrome, chronic myeloid leukemia and lymphomas [23, 36]. As standard therapy outcome for these malignancies was reported to be negatively influenced by VEGF A overexpression, further studies are required to determine whether patients with high level of this factor should be candidates for HSCT. Due to very low incidence of late relapses in the study group we failed to demonstrate if there was any influence of VEGF expression on late disease recurrence, so larger studies are required to test this, but given very high incidence of early relapses in our study in the high VEGF group, early post-transplant therapy should be considered for these patients.

Recently, a number of clinical scoring systems were validated to predict risk of alloHSCT, like EBMT risk score [12, 29] or Seattle PAM score [27]. The results of this study show that the endothelial damage markers are of distinct predictive value, irrelevant of clinical parameters. Therefore, further studies are required to evaluate if they could be incorporated into the risk assessment models. In conclusion, peripheral CECs and plasma VEGF levels represent a useful prognostic tool to predict the risk of alloHSCT and disease relapse.

Conflict of interests

No conflict interest is reported.

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При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (<span lang="en-US">VEGF</span>) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии <span lang="en-US">VEGF</span> при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями <span lang="en-US">VEGF</span> и частотой рецидивов после алло-ТГСК. Уровни <span lang="en-US">VEGF</span> анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни <span lang="en-US">VEGF</span>, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни <span lang="en-US">VEGF</span> в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; <span lang="en-US">HR</span> 3,15, 95%; <span lang="en-US">CI</span> 1,34-7,40, <span lang="en-US">p</span>=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, <span lang="en-US">p</span>=0,001), но не многофакторном анализе (95%<span lang="en-US">CI</span> 0.84-5.76, <span lang="en-US">p</span>=0,102). Высокие уровни <span lang="en-US">VEGF</span> <span lang="en-US">A</span> перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, <span lang="en-US">p</span>=0,001, <span lang="en-US">HR</span> 3,15, 95%<span lang="en-US">CI</span> 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, <span lang="en-US">p</span>=0.60), поскольку многие пациенты были успешно пролечены после рецидива. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(328) "Прогностическая значимость ростового фактора VEGF и циркулирующих эндотелиальных клеток для ранних и поздних исходов аллогенной трансплантации гемопоэтических стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(328) "Прогностическая значимость ростового фактора VEGF и циркулирующих эндотелиальных клеток для ранних и поздних исходов аллогенной трансплантации гемопоэтических стволовых клеток" 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Моисеев, Сергей В. Лапин, Елена А. Суркова, Маргарита Ю. Лернер, Елена В. Бабенко, Александра А. Сипол,<br>Владимир Н. Вавилов, Борис В. Афанасьев</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(305) "

Иван С. Моисеев, Сергей В. Лапин, Елена А. Суркова, Маргарита Ю. Лернер, Елена В. Бабенко, Александра А. Сипол,
Владимир Н. Вавилов, Борис В. Афанасьев

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "387" ["VALUE"]=> array(2) { ["TEXT"]=> string(393) "<p class="Autor_place_work">НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(371) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "388" ["VALUE"]=> array(2) { ["TEXT"]=> string(4349) "<p class="Summery_Rus" lang="ru-RU">В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (<span lang="en-US">VEGF</span>) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии <span lang="en-US">VEGF</span> при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями <span lang="en-US">VEGF</span> и частотой рецидивов после алло-ТГСК. Уровни <span lang="en-US">VEGF</span> анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни <span lang="en-US">VEGF</span>, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни <span lang="en-US">VEGF</span> в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; <span lang="en-US">HR</span> 3,15, 95%; <span lang="en-US">CI</span> 1,34-7,40, <span lang="en-US">p</span>=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, <span lang="en-US">p</span>=0,001), но не многофакторном анализе (95%<span lang="en-US">CI</span> 0.84-5.76, <span lang="en-US">p</span>=0,102). Высокие уровни <span lang="en-US">VEGF</span> <span lang="en-US">A</span> перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, <span lang="en-US">p</span>=0,001, <span lang="en-US">HR</span> 3,15, 95%<span lang="en-US">CI</span> 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, <span lang="en-US">p</span>=0.60), поскольку многие пациенты были успешно пролечены после рецидива. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3921) "

В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (VEGF) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии VEGF при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями VEGF и частотой рецидивов после алло-ТГСК. Уровни VEGF анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни VEGF, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни VEGF в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; HR 3,15, 95%; CI 1,34-7,40, p=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, p=0,001), но не многофакторном анализе (95%CI 0.84-5.76, p=0,102). Высокие уровни VEGF A перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, p=0,001, HR 3,15, 95%CI 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, p=0.60), поскольку многие пациенты были успешно пролечены после рецидива.

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Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol,
Vladimir N. Vavilov, Boris V. Afanasyev

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Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St.Petersburg State I. Pavlov Medical University

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Summery

A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p>0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.

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Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol, <br>Vladimir N. Vavilov, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(190) "

Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol,
Vladimir N. Vavilov, Boris V. Afanasyev

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Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol,
Vladimir N. Vavilov, Boris V. Afanasyev

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Summery

A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p>0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.

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Summery

A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p>0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.

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Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St.Petersburg State I. Pavlov Medical University

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Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St.Petersburg State I. Pavlov Medical University

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Иван С. Моисеев, Сергей В. Лапин, Елена А. Суркова, Маргарита Ю. Лернер, Елена В. Бабенко, Александра А. Сипол,
Владимир Н. Вавилов, Борис В. Афанасьев

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Иван С. Моисеев, Сергей В. Лапин, Елена А. Суркова, Маргарита Ю. Лернер, Елена В. Бабенко, Александра А. Сипол,
Владимир Н. Вавилов, Борис В. Афанасьев

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["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "377" ["VALUE"]=> string(2) "60" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(2) "60" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(57) "Ivan S. Moiseev" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "388" ["VALUE"]=> array(2) { ["TEXT"]=> string(4349) "<p class="Summery_Rus" lang="ru-RU">В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (<span lang="en-US">VEGF</span>) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии <span lang="en-US">VEGF</span> при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями <span lang="en-US">VEGF</span> и частотой рецидивов после алло-ТГСК. Уровни <span lang="en-US">VEGF</span> анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни <span lang="en-US">VEGF</span>, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни <span lang="en-US">VEGF</span> в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; <span lang="en-US">HR</span> 3,15, 95%; <span lang="en-US">CI</span> 1,34-7,40, <span lang="en-US">p</span>=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, <span lang="en-US">p</span>=0,001), но не многофакторном анализе (95%<span lang="en-US">CI</span> 0.84-5.76, <span lang="en-US">p</span>=0,102). Высокие уровни <span lang="en-US">VEGF</span> <span lang="en-US">A</span> перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, <span lang="en-US">p</span>=0,001, <span lang="en-US">HR</span> 3,15, 95%<span lang="en-US">CI</span> 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, <span lang="en-US">p</span>=0.60), поскольку многие пациенты были успешно пролечены после рецидива. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3921) "

В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (VEGF) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии VEGF при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями VEGF и частотой рецидивов после алло-ТГСК. Уровни VEGF анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни VEGF, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни VEGF в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; HR 3,15, 95%; CI 1,34-7,40, p=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, p=0,001), но не многофакторном анализе (95%CI 0.84-5.76, p=0,102). Высокие уровни VEGF A перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, p=0,001, HR 3,15, 95%CI 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, p=0.60), поскольку многие пациенты были успешно пролечены после рецидива.

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В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (VEGF) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии VEGF при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями VEGF и частотой рецидивов после алло-ТГСК. Уровни VEGF анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни VEGF, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни VEGF в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; HR 3,15, 95%; CI 1,34-7,40, p=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, p=0,001), но не многофакторном анализе (95%CI 0.84-5.76, p=0,102). Высокие уровни VEGF A перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, p=0,001, HR 3,15, 95%CI 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, p=0.60), поскольку многие пациенты были успешно пролечены после рецидива.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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Introduction 

Myocardial infarction (MI) is a common reason of death and disability worldwide. Over the last decade, different cell therapy options have been tested to improve efficiency of MI treatment, including the s.c. cardiomyoplastics. Various cells are proposed to be used for this purpose. Autologous bone marrow is a widely used source of therapeutic cell preparations, thus providing freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchimal stromal cells (MMSC). Meanwhile, existing works concerning clinical effects of MF and MMSC transplantation in acute MI yield controversial results [6, 11, 16, 24, 26, 29, 31], thus necessitating further studies and getting experience in this area.

The aim of the study

The aim of our experimental study was to compare the effects of intramyocardial MF and MMSC transplantation upon clinical course and outcome of MI, using a rabbit model during prolonged observation terms by using complex of modern functional and morphological study.

Materials and methods

The experiments were performed with male Chinchilla rabbits of 2.8+ 0.2 kg weight, aged 3 - 4 months. All experimental procedures have been carried out in accordance with guidelines of local Ethical Committee at the First St.Petersburg I.Pavlov State Medical University.

Isolation, characterization, and morphological description of bone marrow cells

Bone marrow aspirate (10+ 1mL) was obtained from a rabbit by iliac puncture, following premedication with Droperidol (0.5 mg/kg, Xylasine, 14 mg/kg body mass), and local anesthesia with 0.5 per cent Novocaine, and placed into a tube containing CPDS (citrate phosphate dextrose solution, Terumo, Japan). Mononuclear cell fraction was obtained by means of centrifugation (1600 g, 20 min) Percoll density gradient (63%). Interphase cell fraction containing nucleated cells was washed in Са²⁺ and Mg²⁺-free Hanks’ solution (Gibco, USA), and span down by centrifuging. MMSC cell culture was obtained by MF cell passaging in а-МЕМ medium (ICN, USA) with 10 per cent fetal calf serum (Hyclone, New Zealand) supplied with gentamycin sulfate (50 mcg/mL; Invitrogen, Great Britain) in a СО2 incubator, at 5 per cent CO2 and 100% humidity for three weeks. The medium was changed twice a week. Ascorbic acid (ICN, USA) was added at a final concentration of 50 mcg/mL after first medium change. After reaching a semi-confluent state, the cells were reinoculated by means of 0.25% trypsin solution (Gibco, USA), and EDTA (0.02%, Gibco, USA). Before being transplanted, the cultured cells did not display any signs of spontaneous osteogenic differentiation, as evidenced by negative staining for alkaline phosphatase with a standard BCIP-NBT reagent (5-bromine-4-chloride-3-indolyl phosphate/ nitroblue tetrazolium, Sigma, USA), or any features of adipocytic transformation detectable with Sudan III/IV mixture (BDH Chemicals Ltd, Great Britain). Meanwhile, special studies with specific induction of differentiation to osteogenic and adipocytic lineage have shown their multipotency, i.e., the cultivated cells had typical MMSC characteristics.

In some animals, MNC or MMSC were stained prior to transplant with Hoechst nuclear fluorescent dye (Sigma, USA, final concentration of 1 mcg/mL), by shaking for 60 min in a СО2 incubator.

Nucleated marrow cells were counted in Buerker chamber, and their viability was assessed with Trypan Blue solution (Labtech, Russia). The cells labelled with Hoechst dye were detected by their blue nuclear fluorescence upon microscopy, using an «Axioscope» (Zeiss, Germany).

Experimental modelling and treatment of myocardial infarction

The rabbits were subjected to a left-sided thoracotomy under mechanical ventilation of lungs, followed by ligation of anterior descendent left coronary artery at a distance of 1 cm from the heart apex (Fig. 1, A, B). Ten minutes after the coronary occlusion, intramyocardial injections of ME or MMSC suspensions were performed into 6 points of the presumed infarction area, using insulin syringes, at a mean cell number of 2±0.2 x10⁶ in 0.4 mL of а-МЕМ growth medium (modified Eagle medium), or with equivalent volumes of culture medium (placebo treatment), as shown in Fig. 1 C, D. Control animals were not subjected to myocardial injections. Surgical wounds were closed in layers, pneumothorax being eliminated by means of active air aspiration from the pleural cavity. The surviving animals were classified in four groups, each consisting of 13 animals, i.e., Group 1, (controls), Group 2 (placebo-treated), Group 3 (MMSC injections), and Group 4 (MF injections). Subgroups of ten animals were observed for 1 year after the surgery.

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Introduction 

Myocardial infarction (MI) is a common reason of death and disability worldwide. Over the last decade, different cell therapy options have been tested to improve efficiency of MI treatment, including the s.c. cardiomyoplastics. Various cells are proposed to be used for this purpose. Autologous bone marrow is a widely used source of therapeutic cell preparations, thus providing freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchimal stromal cells (MMSC). Meanwhile, existing works concerning clinical effects of MF and MMSC transplantation in acute MI yield controversial results [6, 11, 16, 24, 26, 29, 31], thus necessitating further studies and getting experience in this area.

The aim of the study

The aim of our experimental study was to compare the effects of intramyocardial MF and MMSC transplantation upon clinical course and outcome of MI, using a rabbit model during prolonged observation terms by using complex of modern functional and morphological study.

Materials and methods

The experiments were performed with male Chinchilla rabbits of 2.8+ 0.2 kg weight, aged 3 - 4 months. All experimental procedures have been carried out in accordance with guidelines of local Ethical Committee at the First St.Petersburg I.Pavlov State Medical University.

Isolation, characterization, and morphological description of bone marrow cells

Bone marrow aspirate (10+ 1mL) was obtained from a rabbit by iliac puncture, following premedication with Droperidol (0.5 mg/kg, Xylasine, 14 mg/kg body mass), and local anesthesia with 0.5 per cent Novocaine, and placed into a tube containing CPDS (citrate phosphate dextrose solution, Terumo, Japan). Mononuclear cell fraction was obtained by means of centrifugation (1600 g, 20 min) Percoll density gradient (63%). Interphase cell fraction containing nucleated cells was washed in Са²⁺ and Mg²⁺-free Hanks’ solution (Gibco, USA), and span down by centrifuging. MMSC cell culture was obtained by MF cell passaging in а-МЕМ medium (ICN, USA) with 10 per cent fetal calf serum (Hyclone, New Zealand) supplied with gentamycin sulfate (50 mcg/mL; Invitrogen, Great Britain) in a СО2 incubator, at 5 per cent CO2 and 100% humidity for three weeks. The medium was changed twice a week. Ascorbic acid (ICN, USA) was added at a final concentration of 50 mcg/mL after first medium change. After reaching a semi-confluent state, the cells were reinoculated by means of 0.25% trypsin solution (Gibco, USA), and EDTA (0.02%, Gibco, USA). Before being transplanted, the cultured cells did not display any signs of spontaneous osteogenic differentiation, as evidenced by negative staining for alkaline phosphatase with a standard BCIP-NBT reagent (5-bromine-4-chloride-3-indolyl phosphate/ nitroblue tetrazolium, Sigma, USA), or any features of adipocytic transformation detectable with Sudan III/IV mixture (BDH Chemicals Ltd, Great Britain). Meanwhile, special studies with specific induction of differentiation to osteogenic and adipocytic lineage have shown their multipotency, i.e., the cultivated cells had typical MMSC characteristics.

In some animals, MNC or MMSC were stained prior to transplant with Hoechst nuclear fluorescent dye (Sigma, USA, final concentration of 1 mcg/mL), by shaking for 60 min in a СО2 incubator.

Nucleated marrow cells were counted in Buerker chamber, and their viability was assessed with Trypan Blue solution (Labtech, Russia). The cells labelled with Hoechst dye were detected by their blue nuclear fluorescence upon microscopy, using an «Axioscope» (Zeiss, Germany).

Experimental modelling and treatment of myocardial infarction

The rabbits were subjected to a left-sided thoracotomy under mechanical ventilation of lungs, followed by ligation of anterior descendent left coronary artery at a distance of 1 cm from the heart apex (Fig. 1, A, B). Ten minutes after the coronary occlusion, intramyocardial injections of ME or MMSC suspensions were performed into 6 points of the presumed infarction area, using insulin syringes, at a mean cell number of 2±0.2 x10⁶ in 0.4 mL of а-МЕМ growth medium (modified Eagle medium), or with equivalent volumes of culture medium (placebo treatment), as shown in Fig. 1 C, D. Control animals were not subjected to myocardial injections. Surgical wounds were closed in layers, pneumothorax being eliminated by means of active air aspiration from the pleural cavity. The surviving animals were classified in four groups, each consisting of 13 animals, i.e., Group 1, (controls), Group 2 (placebo-treated), Group 3 (MMSC injections), and Group 4 (MF injections). Subgroups of ten animals were observed for 1 year after the surgery.

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На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8<span class="CharOverride-12">+</span>0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами. </p> <p class="Summery_H">Результаты</p> <p class="Summery_Rus" lang="ru-RU">Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p&lt;0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p&lt;0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p&lt;0.05), а также отсутствие акинетических участков. </p> <p class="Summery_H">Заключение</p> <p class="Summery_Rus" lang="ru-RU">Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. 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"2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "476" ["VALUE"]=> array(2) { ["TEXT"]=> string(452) "<p class="Autor">Владимир В. Давыденко¹, Андрей А. Матюков¹, Тимур Д. Власов¹, Наталия В. Цупкина², Анатолий Н. Ялфимов³, Георгий П. Пинаев², Халида К. Аминева¹</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(346) "

Владимир В. Давыденко¹, Андрей А. Матюков¹, Тимур Д. Власов¹, Наталия В. Цупкина², Анатолий Н. Ялфимов³, Георгий П. Пинаев², Халида К. Аминева¹

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "477" ["VALUE"]=> array(2) { ["TEXT"]=> string(651) "<p class="Autor_place_work-Rus">¹Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова</p> <p class="Autor_place_work-Rus">²Институт цитологии Российской Академии наук, Санкт-Петербург</p> <p class="Autor_place_work-Rus">³Российский центр радиологии и хирургических технологий, Санкт-Петербург</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(549) "

¹Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова

²Институт цитологии Российской Академии наук, Санкт-Петербург

³Российский центр радиологии и хирургических технологий, Санкт-Петербург

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На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8<span class="CharOverride-12">+</span>0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами. </p> <p class="Summery_H">Результаты</p> <p class="Summery_Rus" lang="ru-RU">Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p&lt;0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p&lt;0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p&lt;0.05), а также отсутствие акинетических участков. </p> <p class="Summery_H">Заключение</p> <p class="Summery_Rus" lang="ru-RU">Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6602) "

Резюме

Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8+0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами.

Результаты

Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p<0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p<0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p<0.05), а также отсутствие акинетических участков.

Заключение

Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов.

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Vladimir V. Davydenko¹, Andrey A. Matyukov¹, Timur D. Vlasov¹, Natalya V. Tsupkina², Anatoly N. Yalfimov³,
Georgy P. Pinaev², Khalida K. Amineva¹

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1FirstSt.Petersburg State I.Pavlov Medical University

2Institute of Cytology, Russian Academy of Sciences, St.Petersburg

3Russian Center of Radiology and Surgical Technologies, St.Petersburg

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "482" ["VALUE"]=> array(2) { ["TEXT"]=> string(3700) "<h2>Summary</h2><p class="Summery">Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8<span class="CharOverride-12">+</span>0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way. </p> <p class="Summery_H">Results</p> <p class="Summery">Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p&lt;0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p&lt;0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p&lt;0.05), and absence of akinetic areas. </p> <p class="Summery_H">Conclusions </p> <p class="Summery">MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area. </p> " ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3544) "

Summary

Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8+0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way.

Results

Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p<0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p<0.05), and absence of akinetic areas.

Conclusions

MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area.

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"37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "480" ["VALUE"]=> array(2) { ["TEXT"]=> string(360) "<p class="Autor">Vladimir V. Davydenko¹, Andrey A. Matyukov¹, Timur D. Vlasov¹, Natalya V. Tsupkina², Anatoly N. Yalfimov³, <br>Georgy P. Pinaev², Khalida K. Amineva¹</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(248) "

Vladimir V. Davydenko¹, Andrey A. Matyukov¹, Timur D. Vlasov¹, Natalya V. Tsupkina², Anatoly N. Yalfimov³,
Georgy P. Pinaev², Khalida K. Amineva¹

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Vladimir V. Davydenko¹, Andrey A. Matyukov¹, Timur D. Vlasov¹, Natalya V. Tsupkina², Anatoly N. Yalfimov³,
Georgy P. Pinaev², Khalida K. Amineva¹

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Summary

Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8+0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way.

Results

Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p<0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p<0.05), and absence of akinetic areas.

Conclusions

MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area.

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Summary

Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8+0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way.

Results

Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p<0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p<0.05), and absence of akinetic areas.

Conclusions

MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area.

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1FirstSt.Petersburg State I.Pavlov Medical University

2Institute of Cytology, Russian Academy of Sciences, St.Petersburg

3Russian Center of Radiology and Surgical Technologies, St.Petersburg

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1FirstSt.Petersburg State I.Pavlov Medical University

2Institute of Cytology, Russian Academy of Sciences, St.Petersburg

3Russian Center of Radiology and Surgical Technologies, St.Petersburg

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Davydenko" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "478" ["VALUE"]=> array(2) { ["TEXT"]=> string(6788) "<h2>Резюме</h2><p class="Summery_Rus" lang="ru-RU">Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8<span class="CharOverride-12">+</span>0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами. </p> <p class="Summery_H">Результаты</p> <p class="Summery_Rus" lang="ru-RU">Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p&lt;0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p&lt;0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p&lt;0.05), а также отсутствие акинетических участков. </p> <p class="Summery_H">Заключение</p> <p class="Summery_Rus" lang="ru-RU">Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6602) "

Резюме

Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8+0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами.

Результаты

Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p<0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p<0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p<0.05), а также отсутствие акинетических участков.

Заключение

Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов.

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Резюме

Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8+0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами.

Результаты

Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p<0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p<0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p<0.05), а также отсутствие акинетических участков.

Заключение

Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов.

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¹Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова

²Институт цитологии Российской Академии наук, Санкт-Петербург

³Российский центр радиологии и хирургических технологий, Санкт-Петербург

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¹Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова

²Институт цитологии Российской Академии наук, Санкт-Петербург

³Российский центр радиологии и хирургических технологий, Санкт-Петербург

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Опыт Беларуси" ["ELEMENT_META_KEYWORDS"]=> string(134) "Синдром Ниймеген иммунодефицит лимфома трансплантация стволовых клеток" ["ELEMENT_META_DESCRIPTION"]=> string(371) "Роль аллогенной трансплантации гемопоэтических стволовых клеток в лечении пациентов с синдромом Ниймеген. Опыт БеларусиShould Allogeneic Hematopoietic Stem Cell Transplantation be a Treatment Option for Patients with Nijmegen Breakage Syndrome? Belarusian Experience" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4903) "<p class="Summery">Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.</p> <p class="Summery">Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии. </p> <p class="Summery">Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена <span lang="en-US">NBN</span>. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.</p> <p class="Summery">Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661<span lang="en-US">delACAAA</span> в гене <span lang="en-US">NBN</span> и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (<span lang="en-US">III</span> стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.</p> <p class="Summery">Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(224) "Роль аллогенной трансплантации гемопоэтических стволовых клеток в лечении пациентов с синдромом Ниймеген. Опыт Беларуси" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(224) "Роль аллогенной трансплантации гемопоэтических стволовых клеток в лечении пациентов с синдромом Ниймеген. 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Ольга В. Алейникова, Алина С. Фёдорова, Светлана О. Шарапова

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "297" ["VALUE"]=> array(2) { ["TEXT"]=> string(262) "<p class="Autor_place_work">Республиканский научно-практический центр детской онкологии, гематологии и иммунологии, Минский район, Беларусь</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(240) "

Республиканский научно-практический центр детской онкологии, гематологии и иммунологии, Минский район, Беларусь

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "298" ["VALUE"]=> array(2) { ["TEXT"]=> string(4903) "<p class="Summery">Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.</p> <p class="Summery">Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии. </p> <p class="Summery">Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена <span lang="en-US">NBN</span>. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.</p> <p class="Summery">Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661<span lang="en-US">delACAAA</span> в гене <span lang="en-US">NBN</span> и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (<span lang="en-US">III</span> стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.</p> <p class="Summery">Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4705) "

Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.

Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии.

Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена NBN. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.

Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661delACAAA в гене NBN и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (III стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.

Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "299" ["VALUE"]=> string(35) "10.18620/1866-8836-2015-4-1-2-31-37" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(35) "10.18620/1866-8836-2015-4-1-2-31-37" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "300" ["VALUE"]=> array(2) { ["TEXT"]=> string(103) "<p class="Autor">Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(81) "

Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova

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Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "302" ["VALUE"]=> array(2) { ["TEXT"]=> string(2827) "<h2>Summery </h2> <p class="Summery"> Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma. </p> <p class="Summery"> Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment. </p> <p class="Summery"> Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually. </p> <p class="Summery"> Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated. </p> <p class="Summery"> Conclusions:<span class="CharOverride-10"> </span>NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1^st complete remission. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2671) "

Summery

Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.

Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.

Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.

Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.

Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1^st complete remission.

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string(103) "<p class="Autor">Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(81) "

Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova

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Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova

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Summery

Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.

Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.

Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.

Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.

Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1^st complete remission.

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2671) "

Summery

Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.

Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.

Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.

Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.

Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1^st complete remission.

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Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus

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Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus

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Ольга В. Алейникова, Алина С. Фёдорова, Светлана О. Шарапова

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Aleinikova" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "298" ["VALUE"]=> array(2) { ["TEXT"]=> string(4903) "<p class="Summery">Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.</p> <p class="Summery">Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии. </p> <p class="Summery">Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена <span lang="en-US">NBN</span>. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.</p> <p class="Summery">Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661<span lang="en-US">delACAAA</span> в гене <span lang="en-US">NBN</span> и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (<span lang="en-US">III</span> стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.</p> <p class="Summery">Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4705) "

Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.

Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии.

Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена NBN. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.

Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661delACAAA в гене NBN и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (III стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.

Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.

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Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.

Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии.

Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона гена NBN. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.

Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1). Наличие мутации 657-661delACAAA в гене NBN и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (III стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.

Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.

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HIV and cancer risk

Human immunodeficiency virus (HIV) infection represents a growing socio-economic and healthcare problem. Global situation and trends based on World Health Organization data (WHO): since the beginning of the epidemic 35.0 million (33.1–37.2 million) people around the world were living with HIV at the end of 2013 [46]. Patients living with HIV are at high risk of cancer. The introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HAART is affecting the incidence of several hematological malignancies: the incidence of primary central nervous system lymphoma (PCNSL) has dropped since the introduction of HAART in 1996 and non-Hodgkin lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than PCNLS. Between 1990-1995 and 1996-2002, risk declined for non-Hodgkin lymphoma [(NHL) n = 3412; SIR, 53.2 and 22.6, respectively; p < 0.0001]. In contrast, the risk of Hodgkin lymphoma increased substantially over the 1990-2002 period (n = 149; SIR, 8.1 and 13.6, respectively; p = 0.003) [10, 26].

Acute leukemias (AL) are not HIV-indicating diseases. The epidemiology and clinical outcome of acute leukemias in HIV-infected individuals is poorly documented. Rare cases of acute myeloid leukaemia (AML) have been reported during HIV infection and no clear relationship with the characteristic immune deficiency has been established [2, 11, 22, 24, 38, 41]. Like with many other malignancies, the incidence of AML appears to be increased in HIV-infected patients. The estimated risk of AML in 1990 to 1996 among HIV-infected adults was twice that of the general population (standardized incidence ratio 2.05; 95% confidence interval, 1.17±3.34) [41]. Acute lymphoblastic leukemia (ALL) is most common in childhood with a peak incidence at 2–5 years of age and rare in adults. An association with HIV infection is not typical and limited to case reports [12, 14, 33, 43]. About 55 cases of AL in HIV-infected patients have been published. Their outcome is very poor, with the median survival of 7 weeks to 7 months [1, 12].

Despite introduction of HAART, the HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy [31, 32]. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection [9, 25]. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown, due to limited number of case reports and small clinical series. In most of these patients, hematological malignancies are potentially curable by allo-HSCT [13, 19, 20]. Wide application of this method is limited by the high risk of fatal infectious complications. Over recent years, some improvements in supportive care, HAART and transplantation technology, allowed to use this therapeutic approach for highly immunocompromised patients.

Donor CCR5
mutation and potential HIV cure

Interest in finding a potential ‘cure’ for HIV in anticancer therapy has actually started since the report of an individual who underwent allo-HSCT from a donor with homozygote gene CCR5 delta 32 mutation for acute myeloid leukemia treatment. A potential role of cancer chemotherapy and HSCT treatment is discussed in the context of their role in potential HIV elimination from infected host [20, 29]. Allo-HSCT from a donor with homozygotic CCR5 del 32 mutation may cure from the both diseases: HIV and cancer. This opportunity that has been shown in case of the ‘Berlin patient’ [3, 17, 20, 47]. Most experts ascribe the successful allo-HSCT in ‘Berlin patient’ to a genetic mutation in donor’s hematopoietic cells (HSC). The unrelated donor had a del32 mutation of the CCR5 co-receptor, thus causing inability of HIV-1 to infect immune cells [20]. A homozygous state for this mutation, which was found in the population at a frequency of <1:1000, dramatically reduces the risk of HIV-1 entry inside the human lymphocytes. However, prevalence of this mutation is low, and this approach seems unacceptable for the most HIV-positive patients with high-risk hematologic malignancies [18, 34].

Allo-HSCT from donors with a wild-type CCR5, along with ongoing HAART, has looked more promising, but it has failed in clinical cases reported as ‘Boston patients’ [16, 15]. But other aspects, including HSC source, donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and novel anti-HIV and anti-cancer agents still maintain interest for allo-HSCT, as a potential cure procedure.

Choice of cord blood (CB) as a source of HSCs can increase the chances of finding an HLA-matched homozygous CCR5 del32 mutation donor for allo-HSCT, and co-transplantation with haplo-HSCs may overcome problems associated with CB HSCT, because the CB transplantation does not require as stringent HLA match between donor and recipient, as bone marrow or peripheral blood HCTs [34]. There is still unclear, which factor in ‘Berlin patient’ played a crucial role in HIV clearance (donor homozygosity for CCR5 mutation, cytotoxic chemotherapy, graft-associated immunoadoptive effect, or a combined action). There are still no reports on allo-HSCT outcome with donors heterozygous for CCR5 del32 mutation.

Several cytotoxic agents which are routinely used in pre-transplant conditioning regimen, including alkylating agents, such as cyclophosphamide, busulfan, and antimetabolites, have been shown to be effective in depleting HIV-infected cells in vivo or in vitro, and in murine models [6, 27, 29, 40]. Introduction of reduced-intensity conditioning regimens (RIC) allows to continue HAART through the transplant procedure. ‘Boston patients’ demonstrated that allo-HSCT from donor without CCR5 del 32 mutation with ongoing HAART is not sufficient for HIV clearance [15]. But some novel antiretroviral medications could have an additional curative effect post-HSCT. E.g., Maraviroc is a new antiretroviral agent of entry inhibitor class. Therefore, application of Maraviroc after allo-HSCT could functionally mimic the CCR5 del32 mutation of the HIV target cells. Moreover, it can be used not only for HIV control, but also as a component of GvHD prophylaxis [7, 30, 36].

Immune therapy

It has been shown that chemotherapy alone cannot eradicate the body reservoirs of HIV. In addition to the cytostatic impact, there is an immunoadoptive effect which can devoid the organism of HIV following allo-HSCT procedure. Moreover, some other anti-cancer post-transplant strategies can be useful in HIV cure. Reduced-intensity conditioning regimens before allo-HSCT represent a promising platform for cancer immunotherapy. This post-transplant strategy includes immunoadoptive therapy with donor lymphocyte infusions (DLI), and new anti-cancer agents that are able for selective killing of tumor cells, as based on their surface expression of tumor-associated antigens targeted by the therapeutic antibodies per se, or linked to cytotoxic compounds (Gentuzimab Ozogamicin, a humanized anti-CD33 monoclonal antibody, Brentuximab Vedotin, a doxorubicin-conjugated anti-envelope antibody). These therapeutic strategies suggest a curative potential for the both diseases, i.e., leukemia and HIV infection [5, 21, 40].

Latently HIV-infected cells comprise the major problem because they are “invisible” to the targeted killing agents. This issue can be resolved by means of activating the infected cells by anti-cancer agents applicable in post-transplant period for targeted chemotherapy, like as GvHD prophylaxis and treatment. E.g., epigenetic manipulation of malignant or virally infected cells with appropriate drugs, such as histone deacetylase inhibitors and proteasome inhibitors, yields results in new cancer therapies (vorinostat for lymphoma, romidepsin for peripheral T-cell lymphoma, and bortezomib for multiple myeloma and mantle cell lymphoma). They could be used to another aim, as HIV-activating drugs in latently infected cells, thus making them more susceptible to apoptosis, or more amenable to direct cytotoxic targeting by other agents [4, 29, 35, 37]. Moreover, bortezomib may also have additional anti-HIV effects [28, 29].

Allo-HSCT in patients with hematological malignances and HIV may present a model for the investigations in the field of adoptive therapy with engineered T cells, or stem cell-based treatment against both diseases, i.e., cancer and HIV. Recent progress in stem cell manipulation and in gene engineering of autologous HSCs with vectors carrying the CCR5 mutation has allowed rapid developments in gene therapy for HIV treatment. A number of relevant in vitro and in vivo studies have been published, but the results still are far from definite success [8, 23, 39, 42, 44, 45, 48,]. This strategy looks very promising in the near future.

Clinical cases

This report includes three cases of the allo-HSCT in patients with an HIV that were performed in Saint-Petersburg, Russia. Baseline values of the patients and transplant characteristics are shown in Table 1.

Patient 1, female, 50 years old was diagnosed with an acute myeloid leukemia in September 2008. First complete remission (CR) was achieved after the fist course of chemotherapy (CT). HIV was diagnosed in March 2009. HIV was transmitted through blood products transfusion (platelets). HAART was not initiated at that time. First early relapse of AML was confirmed in November 2009. No CR after FLAG was registered. Patient had a matched related donor. On March 26th 2010 the allogeneic stem cell transplantation with reduced intensity conditioning regimen (RIC) and standard GVHD prophylaxis (Cyclosporine A + Methotrexate) was performed. Donor: MRD, female (sister), ABO compatibility, CCR5 unknown. Peripheral blood stem cells were used for transplantation (CD34+ cells, 5.8 x 10⁶). No early complications were observed after allo-HSCT. Engraftment was registered on Day +18. On Day +30 no CR: 80% donor chimerism and no cytogenetic remission 46,XX,der(8)t(8;?)(q10;?)[4]/46,XX[16]. Cyclosporine A was discontinued. DLI with 1x10⁵ CD3+/kg was performed on Day +46. On Day +70 full donor chimerism and complete remission AML 46,XX were registered. Immunoadoptive therapy was continued: DLI was performed 7 times. HAART was started at the time of immunoadoptive therapy. No GVHD was registered. Viral loads and CD4+ counts for the patient 1 upon treatment are presented in Figure 1.

Figure 1. Patient 1: Dynamics of HIV amounts (PCR) and CD4+ counts

At 57 months after allo-HSCT, the patient is in good health and has active lifestyle, in CR AML (full chimerism, 46,XX). There are no signs of HIV-reactivation (PCR <50 copies, CD4+ 295 cells; deep virology status performed in Hamburg: Plasma VL RNA copies/ml: 1107, DNA/1 Mio. PBMC: 2265, Integrated HIV DNA/PCR: 17.670, HIVAb/p24Ag 4th generation: pos./neg.). She is still on HAART: Prezista 800 + Ritonavir 100 + Lamivudine 300.

Patient 2, female, 29 years old was diagnosed with an acute lymphoblastic leukemia in 1993 (at the age of 10). First CR was achieved after the first course of chemotherapy. A HIV/hepatitis C co-infection was diagnosed in 2005. HIV was transmitted from the patient’s husband. HAART was started in 2009. First late relapse of ALL was confirmed in October 2011. Second CR MRD (+) was achieved after second course Hyper-CVAD / MxA treatment in December 2011. Full chemotherapy program (8 cycles) of Hyper-CVAD / MxA was completed in May 2012. Patient had no related matched donors. A search for the unrelated donor was initiated in February 2012. By the time of HSCT, the patient has achieved a second remission of ALL, MRD (+), HIV status was satisfactory: PCR <50 copies, CD4+ 108 cells on HAART. On 19 July 2012, an allogeneic stem cell transplantation was performed, with reduced intensity conditioning (RIC) regimen and standard GVHD prophylaxis, including ATG + tacrolimus and MMF. Donor: MUD, female, ABO-compatible, CCR5, wt/wt. Source of HSC: PBSC (CD34+ 9.1 x 10⁶). No severe infectious complications were registered in pre-engraftment phase. Due to severe tacrolimus toxicity, the GVHD prophylaxis was modified, by switching from tacrolimus to corticosteroids. Engraftment was registered on Day +12. On Day +23, CMV reactivation with severe CMV disease of gut was diagnosed, as shown by biopsy. The patient died on Day +41 from generalized gancyclovir-resistant CMV disease affecting gut, liver, and kidneys.

Patient 3, female, 26 years old was diagnosed with HIV, and HAART was immediately administered in April 2012. HIV was transmitted from the patient’s husband. Acute leukemia of mixed phenotype was diagnosed in May 2012. First CR with MRD (+) was achieved only after at the 3^rd course of chemotherapy. The patient had no matched related donors. A search for unrelated donor was initiated in December 2012. At the moment of HSCT, the ALL disease was in its first remission, MRD (+); HIV status was satisfactory: PCR <50 copies, CD4+ 117 cells on HAART. On the April 1, 2013, allogeneic stem cell transplantation with a RIC regimen and standard GVHD prophylaxis (ATG+cyclosporine A+MMF), including Maraviroc, was performed.

Maraviroc is an antiretroviral agent belonging to the CCR5 receptor antagonists, as well as entry inhibitors, it is used for treatment of HIV infection. It also appears to reduce graft-versus-host disease in patients treated with allogeneic bone marrow transplantation for leukemia, in a phase 1/2 study [36].

We have tested the recipient and donor for a CCR5 gene mutation. The recipient (patient 3) had no CCR5 delta32 mutation (wild type/wild type). The donor harbored a single CCR5 delta32 allele (a heterozygotic state). A male, HLA-matched, ABO-incompatible, unrelated donor was used for HST. Peripheral blood stem cells were used as a source of HSCs (CD34+ cells, 6,5 x 10⁶). No relevant complications in pre-engraftment phase were registered. Engraftment and acute GVHD of the skin grade 2-3 were registered since Day +12. GVHD was treated by a high dose of CsA (control serum level) + prolonged MMF and Maraviroc + topic steroids. On the Day +60, no signs of GVHD were reported. Immunosupressive therapy was discontinued on the Day +100 due to the MRD positivity registered by flow cytometry. Local light skin chronic GVHD was observed for two months, and CR with MRD (-) was achieved. Viral loads and CD4+ counts in the patient 3 during treatment are presented in Fig. 2.

Figure 2. Patient 3: Dynamics of HIV amounts (PCR) and CD4+ counts

Currently, at 22 months after allo-HSCT, the patient is in a good health and has an active lifestyle, CR of acute leukemia (full chimerism, MRD(-)), with no signs of HIV-reactivation (PCR <50 copies, CD4+ 828 cells; deep virology status in Hamburg: Plasma VL RNA copies/ml: 43, DNA/1 Mio. PBMC: 71, Integrated HIV DNA/PCR: 517, HIVAb/p24Ag 4th generation: pos./neg.). She is still on HAART: Abacavir 600 + Lamivudine 300 + Raltegravir 800. An important fact is that the patient’s sample contained the CCR5-wildtype-allele and the CCR5 del 32 mutation = donor’s heterozygote type and was converted to heterozygote CCR5 del 32 mutation.

In conclusion, allo-HSCT with RIC is an effective and feasible therapeutic modality for high-grade hematological malignancies in patients with HIV. There were no severe toxicity and drug-drug interactions between HAART, conditioning regimen, and immunosuppressive drugs. HAART and immunosuppressive agents can be safely administered after allo-HSCT. Engraftment and full donor chimaerism were achieved at term as in the general population allo-HSCT recipients. Relapse of acute leukemia could be successful and safety treated with immunoadoptive therapy (DLI) after allo-HSCT. There were no specific infections or other particular complication in HIV positive pts after allo-HSCT. We suggest that patient 3 may be “near to functional cure”. Allo-HSCT ongoing with HAART is the same effective and safety strategy for the treatment high-risk hematologic malignancies in HIV population.

Acknowledgements

Staff of CIC 725, Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of Saint-Petersburg, Russia and International Registry Stefan Morsch Stiftung, Birkenfeld, Germany.

No conflict of interest is reported.

Characteristics	Case 1	Case 2	Case3
Demographic Age	50	29	26
Diagnosis	AML	ALL	AL, mixed phenotype
Status	CR2	CR2	CR1
HIV status at Tx CD4+	500 cells/ml	380 cells/ml	114 cells/ml
HIV-VL	700 copies/ml	<50 copies/ml	<50 copies/ml
cART	No	Yes	Yes
Transplant Donor type CCR5 del32	Sibling matched NA	MUD (12/12) wt/wt	MUD (12/12) del 32/wt; heterozygote
Conditioning	RIC (Flu150+Bu8)	RIC (Flu150+Mel140)	RIC (Flu150+Bu8)
GvHD proph	CsA	ATG, MMF, steroids	ATG, CsA, MMF, maraviroc
Engraftment Neutrophil	+ 18 d	+ 12 d	+ 18 d
Platelet	+ 19 d	+ 14 d	+ 18 d
Full donor chimaerism	+ 25 d	+ 20 d	+ 20 d
GvHD Acute, grade	No	No	II
Chronic	No	No	No
LFU	57 months	41 days	22 months
Status at LFU	Alive	Dead	Alive
HIV status at LFU CD4+	800 cells/ml	NA	480 cells/ml
HIV-VL	<50 copies/ml	NA	<50 copies/ml
cART	Continues	NA	Continues

Table 1. Baseline patients and transplants characteristics

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23. Kiem HP, Jerome KR, Deeks SG et al. Hematopoietic-stem-cell-based gene therapy for HIV disease. Stem Cell 2012; 10: 137-47.
24. King JAC, Nye DM, O’Connor MB et al. Acute myelogenous leukemia (FAB AMLM1) in the setting of HIV infection and G-CSF therapy: a case report and review of the literature. Ann Hematol 1998; 77: 69-73.
25. Krishnan A, Palmer JM, Zaia JA et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant 2010; 16(9): 1302-8.
26. Launay O, Guillevin L. Epidemiology of HIV-associated malignancies. Bull Cancer 2003; 90(5); 387-92.
27. Little RF, Pittaluga S, Grant N et al. Highly effective treatment of AIDS-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003; 101: 4653-9.
28. Liu B, Yu X, Luo K et al. Influence of primate lentiviral Vif and proteasome inhibitors on human immunodeficiency virus type 1 virion packaging of APOBEC3G. J Virol 2004; 78: 2072-81.
29. Mitsuyasu R. Curing HIV: lessons from cancer therapy. Curr Opin HIV AIDS 2013; 8(3): 224-9.
30. Nakamura R, Forman SJ. Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: considerations for evidence-based GVHD prophylaxis
    Expert Rev Hematol 2014; 7(3), :407-21.
31. Passweg J, Baldomero H, Bader P et al. Hematopoietic SCT in Europe: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplantation 2015; Suppl 50: 476-82.
32. Passweg J, Baldomero H, Peters C et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplantation 2014 ; Suppl 49: 744-50.
33. Pees HW, Radtke H, Schwamborn J et al. The BFM-protocol for HIV-negative Burkitt’ s lymphomas and L3 ALL in adult patients: a high chance for a cure. Ann Hematol 1992; 65(5): 201-5.
34. Petz L. Cord Blood Transplantation for Cure of HIV Infections. Stem Cells Transl Med 2013; 2: 635-7.
35. Piekarz RL, Frye R, Prince HM et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011; 117: 5827-34.
36. Reshef R, Luger SM, Hexner EO et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med 2012; 367(2): 135-45.
37. Reuse S, Calao M, Kabeya K et al. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One 2009;4:e6903.
38. Rivers JK, Laubenstein LJ, Postel AH. Acute monocytic leukaemia in an HIV-seropositive man. Clin Exp Dermatol 1992; 17: 203-5.
39. Shimizu S, Ringpis GE, Marsden MD et al. RNAi-mediated CCR5 knockdown provides HIV-1 resistance to memory T cells in humanized BLT mice. Mol Ther Nucl Acids 2015 Feb; 4(2): e227.
40. Simard C, Jolicoueur P. The effect of antineoplastic drugs on murine acquired immunodeficiency syndrome. Science 1991; 252:305-8.
41. Sutton L, GueAnel P, Tanguy ML et al. Acute myeloid leukaemia in human immunodeficiency virus infected adults: epidemiology, treatment feasibility and outcome. Brit J Haematol 2001; 112: 900-8.
42. Tebas P, Stein D, Tang WW et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014; 370: 901-10.
43. Turner ML, Watson HG, Russell L et al. An HIV positive haemophiliac with acute lymphoblastic leukaemia successfully treated with intensive chemotherapy and syngeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9(5): 387-9.
44. van Lunzen J, Fehse B, Hauber J. Gene Therapy Strategies: Can We Eradicate HIV? Curr HIV/AIDS 2011; Rep 8: 78-84.
45. van Lunzen J, Glaunsinger T, Stahmer I et al. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus Mol Ther 2007; 15: 1024-33.
46. World Health Organization http://www.who.int/hiv/data
47. Yukl SA, Boritz E, Busch M et al. Challenges in detecting HIV persistence during potentially curative interventions: A study of the Berlin patient. PLOS Pathogens 2013; 9 (5): e1003347. doi:10.1371/journal.ppat.1003347.
48. Zhen A, Kitchen S. Stem-cell-based gene therapy for HIV infection. Viruses 2014; 6: 1-12; doi:10.3390/v6010001.

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HIV and cancer risk

Human immunodeficiency virus (HIV) infection represents a growing socio-economic and healthcare problem. Global situation and trends based on World Health Organization data (WHO): since the beginning of the epidemic 35.0 million (33.1–37.2 million) people around the world were living with HIV at the end of 2013 [46]. Patients living with HIV are at high risk of cancer. The introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HAART is affecting the incidence of several hematological malignancies: the incidence of primary central nervous system lymphoma (PCNSL) has dropped since the introduction of HAART in 1996 and non-Hodgkin lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than PCNLS. Between 1990-1995 and 1996-2002, risk declined for non-Hodgkin lymphoma [(NHL) n = 3412; SIR, 53.2 and 22.6, respectively; p < 0.0001]. In contrast, the risk of Hodgkin lymphoma increased substantially over the 1990-2002 period (n = 149; SIR, 8.1 and 13.6, respectively; p = 0.003) [10, 26].

Acute leukemias (AL) are not HIV-indicating diseases. The epidemiology and clinical outcome of acute leukemias in HIV-infected individuals is poorly documented. Rare cases of acute myeloid leukaemia (AML) have been reported during HIV infection and no clear relationship with the characteristic immune deficiency has been established [2, 11, 22, 24, 38, 41]. Like with many other malignancies, the incidence of AML appears to be increased in HIV-infected patients. The estimated risk of AML in 1990 to 1996 among HIV-infected adults was twice that of the general population (standardized incidence ratio 2.05; 95% confidence interval, 1.17±3.34) [41]. Acute lymphoblastic leukemia (ALL) is most common in childhood with a peak incidence at 2–5 years of age and rare in adults. An association with HIV infection is not typical and limited to case reports [12, 14, 33, 43]. About 55 cases of AL in HIV-infected patients have been published. Their outcome is very poor, with the median survival of 7 weeks to 7 months [1, 12].

Despite introduction of HAART, the HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy [31, 32]. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection [9, 25]. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown, due to limited number of case reports and small clinical series. In most of these patients, hematological malignancies are potentially curable by allo-HSCT [13, 19, 20]. Wide application of this method is limited by the high risk of fatal infectious complications. Over recent years, some improvements in supportive care, HAART and transplantation technology, allowed to use this therapeutic approach for highly immunocompromised patients.

Donor CCR5
mutation and potential HIV cure

Interest in finding a potential ‘cure’ for HIV in anticancer therapy has actually started since the report of an individual who underwent allo-HSCT from a donor with homozygote gene CCR5 delta 32 mutation for acute myeloid leukemia treatment. A potential role of cancer chemotherapy and HSCT treatment is discussed in the context of their role in potential HIV elimination from infected host [20, 29]. Allo-HSCT from a donor with homozygotic CCR5 del 32 mutation may cure from the both diseases: HIV and cancer. This opportunity that has been shown in case of the ‘Berlin patient’ [3, 17, 20, 47]. Most experts ascribe the successful allo-HSCT in ‘Berlin patient’ to a genetic mutation in donor’s hematopoietic cells (HSC). The unrelated donor had a del32 mutation of the CCR5 co-receptor, thus causing inability of HIV-1 to infect immune cells [20]. A homozygous state for this mutation, which was found in the population at a frequency of <1:1000, dramatically reduces the risk of HIV-1 entry inside the human lymphocytes. However, prevalence of this mutation is low, and this approach seems unacceptable for the most HIV-positive patients with high-risk hematologic malignancies [18, 34].

Allo-HSCT from donors with a wild-type CCR5, along with ongoing HAART, has looked more promising, but it has failed in clinical cases reported as ‘Boston patients’ [16, 15]. But other aspects, including HSC source, donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and novel anti-HIV and anti-cancer agents still maintain interest for allo-HSCT, as a potential cure procedure.

Choice of cord blood (CB) as a source of HSCs can increase the chances of finding an HLA-matched homozygous CCR5 del32 mutation donor for allo-HSCT, and co-transplantation with haplo-HSCs may overcome problems associated with CB HSCT, because the CB transplantation does not require as stringent HLA match between donor and recipient, as bone marrow or peripheral blood HCTs [34]. There is still unclear, which factor in ‘Berlin patient’ played a crucial role in HIV clearance (donor homozygosity for CCR5 mutation, cytotoxic chemotherapy, graft-associated immunoadoptive effect, or a combined action). There are still no reports on allo-HSCT outcome with donors heterozygous for CCR5 del32 mutation.

Several cytotoxic agents which are routinely used in pre-transplant conditioning regimen, including alkylating agents, such as cyclophosphamide, busulfan, and antimetabolites, have been shown to be effective in depleting HIV-infected cells in vivo or in vitro, and in murine models [6, 27, 29, 40]. Introduction of reduced-intensity conditioning regimens (RIC) allows to continue HAART through the transplant procedure. ‘Boston patients’ demonstrated that allo-HSCT from donor without CCR5 del 32 mutation with ongoing HAART is not sufficient for HIV clearance [15]. But some novel antiretroviral medications could have an additional curative effect post-HSCT. E.g., Maraviroc is a new antiretroviral agent of entry inhibitor class. Therefore, application of Maraviroc after allo-HSCT could functionally mimic the CCR5 del32 mutation of the HIV target cells. Moreover, it can be used not only for HIV control, but also as a component of GvHD prophylaxis [7, 30, 36].

Immune therapy

It has been shown that chemotherapy alone cannot eradicate the body reservoirs of HIV. In addition to the cytostatic impact, there is an immunoadoptive effect which can devoid the organism of HIV following allo-HSCT procedure. Moreover, some other anti-cancer post-transplant strategies can be useful in HIV cure. Reduced-intensity conditioning regimens before allo-HSCT represent a promising platform for cancer immunotherapy. This post-transplant strategy includes immunoadoptive therapy with donor lymphocyte infusions (DLI), and new anti-cancer agents that are able for selective killing of tumor cells, as based on their surface expression of tumor-associated antigens targeted by the therapeutic antibodies per se, or linked to cytotoxic compounds (Gentuzimab Ozogamicin, a humanized anti-CD33 monoclonal antibody, Brentuximab Vedotin, a doxorubicin-conjugated anti-envelope antibody). These therapeutic strategies suggest a curative potential for the both diseases, i.e., leukemia and HIV infection [5, 21, 40].

Latently HIV-infected cells comprise the major problem because they are “invisible” to the targeted killing agents. This issue can be resolved by means of activating the infected cells by anti-cancer agents applicable in post-transplant period for targeted chemotherapy, like as GvHD prophylaxis and treatment. E.g., epigenetic manipulation of malignant or virally infected cells with appropriate drugs, such as histone deacetylase inhibitors and proteasome inhibitors, yields results in new cancer therapies (vorinostat for lymphoma, romidepsin for peripheral T-cell lymphoma, and bortezomib for multiple myeloma and mantle cell lymphoma). They could be used to another aim, as HIV-activating drugs in latently infected cells, thus making them more susceptible to apoptosis, or more amenable to direct cytotoxic targeting by other agents [4, 29, 35, 37]. Moreover, bortezomib may also have additional anti-HIV effects [28, 29].

Allo-HSCT in patients with hematological malignances and HIV may present a model for the investigations in the field of adoptive therapy with engineered T cells, or stem cell-based treatment against both diseases, i.e., cancer and HIV. Recent progress in stem cell manipulation and in gene engineering of autologous HSCs with vectors carrying the CCR5 mutation has allowed rapid developments in gene therapy for HIV treatment. A number of relevant in vitro and in vivo studies have been published, but the results still are far from definite success [8, 23, 39, 42, 44, 45, 48,]. This strategy looks very promising in the near future.

Clinical cases

This report includes three cases of the allo-HSCT in patients with an HIV that were performed in Saint-Petersburg, Russia. Baseline values of the patients and transplant characteristics are shown in Table 1.

Patient 1, female, 50 years old was diagnosed with an acute myeloid leukemia in September 2008. First complete remission (CR) was achieved after the fist course of chemotherapy (CT). HIV was diagnosed in March 2009. HIV was transmitted through blood products transfusion (platelets). HAART was not initiated at that time. First early relapse of AML was confirmed in November 2009. No CR after FLAG was registered. Patient had a matched related donor. On March 26th 2010 the allogeneic stem cell transplantation with reduced intensity conditioning regimen (RIC) and standard GVHD prophylaxis (Cyclosporine A + Methotrexate) was performed. Donor: MRD, female (sister), ABO compatibility, CCR5 unknown. Peripheral blood stem cells were used for transplantation (CD34+ cells, 5.8 x 10⁶). No early complications were observed after allo-HSCT. Engraftment was registered on Day +18. On Day +30 no CR: 80% donor chimerism and no cytogenetic remission 46,XX,der(8)t(8;?)(q10;?)[4]/46,XX[16]. Cyclosporine A was discontinued. DLI with 1x10⁵ CD3+/kg was performed on Day +46. On Day +70 full donor chimerism and complete remission AML 46,XX were registered. Immunoadoptive therapy was continued: DLI was performed 7 times. HAART was started at the time of immunoadoptive therapy. No GVHD was registered. Viral loads and CD4+ counts for the patient 1 upon treatment are presented in Figure 1.

Figure 1. Patient 1: Dynamics of HIV amounts (PCR) and CD4+ counts

At 57 months after allo-HSCT, the patient is in good health and has active lifestyle, in CR AML (full chimerism, 46,XX). There are no signs of HIV-reactivation (PCR <50 copies, CD4+ 295 cells; deep virology status performed in Hamburg: Plasma VL RNA copies/ml: 1107, DNA/1 Mio. PBMC: 2265, Integrated HIV DNA/PCR: 17.670, HIVAb/p24Ag 4th generation: pos./neg.). She is still on HAART: Prezista 800 + Ritonavir 100 + Lamivudine 300.

Patient 2, female, 29 years old was diagnosed with an acute lymphoblastic leukemia in 1993 (at the age of 10). First CR was achieved after the first course of chemotherapy. A HIV/hepatitis C co-infection was diagnosed in 2005. HIV was transmitted from the patient’s husband. HAART was started in 2009. First late relapse of ALL was confirmed in October 2011. Second CR MRD (+) was achieved after second course Hyper-CVAD / MxA treatment in December 2011. Full chemotherapy program (8 cycles) of Hyper-CVAD / MxA was completed in May 2012. Patient had no related matched donors. A search for the unrelated donor was initiated in February 2012. By the time of HSCT, the patient has achieved a second remission of ALL, MRD (+), HIV status was satisfactory: PCR <50 copies, CD4+ 108 cells on HAART. On 19 July 2012, an allogeneic stem cell transplantation was performed, with reduced intensity conditioning (RIC) regimen and standard GVHD prophylaxis, including ATG + tacrolimus and MMF. Donor: MUD, female, ABO-compatible, CCR5, wt/wt. Source of HSC: PBSC (CD34+ 9.1 x 10⁶). No severe infectious complications were registered in pre-engraftment phase. Due to severe tacrolimus toxicity, the GVHD prophylaxis was modified, by switching from tacrolimus to corticosteroids. Engraftment was registered on Day +12. On Day +23, CMV reactivation with severe CMV disease of gut was diagnosed, as shown by biopsy. The patient died on Day +41 from generalized gancyclovir-resistant CMV disease affecting gut, liver, and kidneys.

Patient 3, female, 26 years old was diagnosed with HIV, and HAART was immediately administered in April 2012. HIV was transmitted from the patient’s husband. Acute leukemia of mixed phenotype was diagnosed in May 2012. First CR with MRD (+) was achieved only after at the 3^rd course of chemotherapy. The patient had no matched related donors. A search for unrelated donor was initiated in December 2012. At the moment of HSCT, the ALL disease was in its first remission, MRD (+); HIV status was satisfactory: PCR <50 copies, CD4+ 117 cells on HAART. On the April 1, 2013, allogeneic stem cell transplantation with a RIC regimen and standard GVHD prophylaxis (ATG+cyclosporine A+MMF), including Maraviroc, was performed.

Maraviroc is an antiretroviral agent belonging to the CCR5 receptor antagonists, as well as entry inhibitors, it is used for treatment of HIV infection. It also appears to reduce graft-versus-host disease in patients treated with allogeneic bone marrow transplantation for leukemia, in a phase 1/2 study [36].

We have tested the recipient and donor for a CCR5 gene mutation. The recipient (patient 3) had no CCR5 delta32 mutation (wild type/wild type). The donor harbored a single CCR5 delta32 allele (a heterozygotic state). A male, HLA-matched, ABO-incompatible, unrelated donor was used for HST. Peripheral blood stem cells were used as a source of HSCs (CD34+ cells, 6,5 x 10⁶). No relevant complications in pre-engraftment phase were registered. Engraftment and acute GVHD of the skin grade 2-3 were registered since Day +12. GVHD was treated by a high dose of CsA (control serum level) + prolonged MMF and Maraviroc + topic steroids. On the Day +60, no signs of GVHD were reported. Immunosupressive therapy was discontinued on the Day +100 due to the MRD positivity registered by flow cytometry. Local light skin chronic GVHD was observed for two months, and CR with MRD (-) was achieved. Viral loads and CD4+ counts in the patient 3 during treatment are presented in Fig. 2.

Figure 2. Patient 3: Dynamics of HIV amounts (PCR) and CD4+ counts

Currently, at 22 months after allo-HSCT, the patient is in a good health and has an active lifestyle, CR of acute leukemia (full chimerism, MRD(-)), with no signs of HIV-reactivation (PCR <50 copies, CD4+ 828 cells; deep virology status in Hamburg: Plasma VL RNA copies/ml: 43, DNA/1 Mio. PBMC: 71, Integrated HIV DNA/PCR: 517, HIVAb/p24Ag 4th generation: pos./neg.). She is still on HAART: Abacavir 600 + Lamivudine 300 + Raltegravir 800. An important fact is that the patient’s sample contained the CCR5-wildtype-allele and the CCR5 del 32 mutation = donor’s heterozygote type and was converted to heterozygote CCR5 del 32 mutation.

In conclusion, allo-HSCT with RIC is an effective and feasible therapeutic modality for high-grade hematological malignancies in patients with HIV. There were no severe toxicity and drug-drug interactions between HAART, conditioning regimen, and immunosuppressive drugs. HAART and immunosuppressive agents can be safely administered after allo-HSCT. Engraftment and full donor chimaerism were achieved at term as in the general population allo-HSCT recipients. Relapse of acute leukemia could be successful and safety treated with immunoadoptive therapy (DLI) after allo-HSCT. There were no specific infections or other particular complication in HIV positive pts after allo-HSCT. We suggest that patient 3 may be “near to functional cure”. Allo-HSCT ongoing with HAART is the same effective and safety strategy for the treatment high-risk hematologic malignancies in HIV population.

Acknowledgements

Staff of CIC 725, Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of Saint-Petersburg, Russia and International Registry Stefan Morsch Stiftung, Birkenfeld, Germany.

No conflict of interest is reported.

Characteristics	Case 1	Case 2	Case3
Demographic Age	50	29	26
Diagnosis	AML	ALL	AL, mixed phenotype
Status	CR2	CR2	CR1
HIV status at Tx CD4+	500 cells/ml	380 cells/ml	114 cells/ml
HIV-VL	700 copies/ml	<50 copies/ml	<50 copies/ml
cART	No	Yes	Yes
Transplant Donor type CCR5 del32	Sibling matched NA	MUD (12/12) wt/wt	MUD (12/12) del 32/wt; heterozygote
Conditioning	RIC (Flu150+Bu8)	RIC (Flu150+Mel140)	RIC (Flu150+Bu8)
GvHD proph	CsA	ATG, MMF, steroids	ATG, CsA, MMF, maraviroc
Engraftment Neutrophil	+ 18 d	+ 12 d	+ 18 d
Platelet	+ 19 d	+ 14 d	+ 18 d
Full donor chimaerism	+ 25 d	+ 20 d	+ 20 d
GvHD Acute, grade	No	No	II
Chronic	No	No	No
LFU	57 months	41 days	22 months
Status at LFU	Alive	Dead	Alive
HIV status at LFU CD4+	800 cells/ml	NA	480 cells/ml
HIV-VL	<50 copies/ml	NA	<50 copies/ml
cART	Continues	NA	Continues

Table 1. Baseline patients and transplants characteristics

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20. Hütter G, Nowak D, Mossner M et al. Long-term control of HIV by CCR5 delta32/ delta32 stem-cell transplantation. N Engl J Med 2009; 360: 692-8.
21. Johansson S, Goldenberg DM, Griffiths GL et al. Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated antienvelope antibody. AIDS 2006; 20: 1911-5.
22. Kane D, Keating S, McCann S, Mulcahy F. The management of acute myeloid leukaemia (AML) in human immunodeficiency virus (HIV) infection: a case report and review. Int J STD and AIDS, 1997; 8: 272-4.
23. Kiem HP, Jerome KR, Deeks SG et al. Hematopoietic-stem-cell-based gene therapy for HIV disease. Stem Cell 2012; 10: 137-47.
24. King JAC, Nye DM, O’Connor MB et al. Acute myelogenous leukemia (FAB AMLM1) in the setting of HIV infection and G-CSF therapy: a case report and review of the literature. Ann Hematol 1998; 77: 69-73.
25. Krishnan A, Palmer JM, Zaia JA et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant 2010; 16(9): 1302-8.
26. Launay O, Guillevin L. Epidemiology of HIV-associated malignancies. Bull Cancer 2003; 90(5); 387-92.
27. Little RF, Pittaluga S, Grant N et al. Highly effective treatment of AIDS-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003; 101: 4653-9.
28. Liu B, Yu X, Luo K et al. Influence of primate lentiviral Vif and proteasome inhibitors on human immunodeficiency virus type 1 virion packaging of APOBEC3G. J Virol 2004; 78: 2072-81.
29. Mitsuyasu R. Curing HIV: lessons from cancer therapy. Curr Opin HIV AIDS 2013; 8(3): 224-9.
30. Nakamura R, Forman SJ. Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: considerations for evidence-based GVHD prophylaxis
    Expert Rev Hematol 2014; 7(3), :407-21.
31. Passweg J, Baldomero H, Bader P et al. Hematopoietic SCT in Europe: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplantation 2015; Suppl 50: 476-82.
32. Passweg J, Baldomero H, Peters C et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplantation 2014 ; Suppl 49: 744-50.
33. Pees HW, Radtke H, Schwamborn J et al. The BFM-protocol for HIV-negative Burkitt’ s lymphomas and L3 ALL in adult patients: a high chance for a cure. Ann Hematol 1992; 65(5): 201-5.
34. Petz L. Cord Blood Transplantation for Cure of HIV Infections. Stem Cells Transl Med 2013; 2: 635-7.
35. Piekarz RL, Frye R, Prince HM et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011; 117: 5827-34.
36. Reshef R, Luger SM, Hexner EO et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med 2012; 367(2): 135-45.
37. Reuse S, Calao M, Kabeya K et al. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One 2009;4:e6903.
38. Rivers JK, Laubenstein LJ, Postel AH. Acute monocytic leukaemia in an HIV-seropositive man. Clin Exp Dermatol 1992; 17: 203-5.
39. Shimizu S, Ringpis GE, Marsden MD et al. RNAi-mediated CCR5 knockdown provides HIV-1 resistance to memory T cells in humanized BLT mice. Mol Ther Nucl Acids 2015 Feb; 4(2): e227.
40. Simard C, Jolicoueur P. The effect of antineoplastic drugs on murine acquired immunodeficiency syndrome. Science 1991; 252:305-8.
41. Sutton L, GueAnel P, Tanguy ML et al. Acute myeloid leukaemia in human immunodeficiency virus infected adults: epidemiology, treatment feasibility and outcome. Brit J Haematol 2001; 112: 900-8.
42. Tebas P, Stein D, Tang WW et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014; 370: 901-10.
43. Turner ML, Watson HG, Russell L et al. An HIV positive haemophiliac with acute lymphoblastic leukaemia successfully treated with intensive chemotherapy and syngeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9(5): 387-9.
44. van Lunzen J, Fehse B, Hauber J. Gene Therapy Strategies: Can We Eradicate HIV? Curr HIV/AIDS 2011; Rep 8: 78-84.
45. van Lunzen J, Glaunsinger T, Stahmer I et al. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus Mol Ther 2007; 15: 1024-33.
46. World Health Organization http://www.who.int/hiv/data
47. Yukl SA, Boritz E, Busch M et al. Challenges in detecting HIV persistence during potentially curative interventions: A study of the Berlin patient. PLOS Pathogens 2013; 9 (5): e1003347. doi:10.1371/journal.ppat.1003347.
48. Zhen A, Kitchen S. Stem-cell-based gene therapy for HIV infection. Viruses 2014; 6: 1-12; doi:10.3390/v6010001.

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Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти <span lang="en-US">HLA</span>-совместимого донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32. Алло-ТГСК от донора без мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. 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Афанасьев, Марина Попова, Сергей Бондаренко, Илья Зюзгин, Елена Бабенко, Александр Алянский, Сюзанна Морш, Ян ван Лунзен, Борис Фезе, Аксель Цандер, Людмила С. Зубаровская</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(361) "

Борис В. Афанасьев, Марина Попова, Сергей Бондаренко, Илья Зюзгин, Елена Бабенко, Александр Алянский, Сюзанна Морш, Ян ван Лунзен, Борис Фезе, Аксель Цандер, Людмила С. Зубаровская

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "239" ["VALUE"]=> array(2) { ["TEXT"]=> string(4127) "<p class="Summery_Rus" lang="ru-RU">Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти <span lang="en-US">HLA</span>-совместимого донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32. Алло-ТГСК от донора без мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3853) "

Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена CCR5 del 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена CCR5 del 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти HLA-совместимого донора с гомозиготной мутацией гена CCR5 del 32. Алло-ТГСК от донора без мутации гена CCR5 del 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена CCR5 del 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.

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Boris V. Afanasyev¹, Marina Popova¹, Sergey Bondarenko¹, Ilya Zyuzgin², Elena Babenko¹, Aleksander Alyanskiy¹, Susanne Morsch³, Jan van Lunzen⁴, Boris Fehse⁵, Axel R. Zander ⁵, Ludmila S. Zubarovskaya¹

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¹Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,

First Pavlov State Medical University of Saint-Petersburg, Russia

²Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia

³Stefan Morsch Stiftung, Birkenfeld, Germany

⁴Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

⁵Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation

First Pavlov State Medical University of Saint-Petersburg, Russia

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Summery

Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.

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Afanasyev¹, Marina Popova¹, Sergey Bondarenko¹, Ilya Zyuzgin², Elena Babenko¹, Aleksander Alyanskiy¹, Susanne Morsch³, Jan van Lunzen⁴, Boris Fehse⁵, Axel R. Zander ⁵, Ludmila S. Zubarovskaya¹</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(343) "

Boris V. Afanasyev¹, Marina Popova¹, Sergey Bondarenko¹, Ilya Zyuzgin², Elena Babenko¹, Aleksander Alyanskiy¹, Susanne Morsch³, Jan van Lunzen⁴, Boris Fehse⁵, Axel R. Zander ⁵, Ludmila S. Zubarovskaya¹

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Boris V. Afanasyev¹, Marina Popova¹, Sergey Bondarenko¹, Ilya Zyuzgin², Elena Babenko¹, Aleksander Alyanskiy¹, Susanne Morsch³, Jan van Lunzen⁴, Boris Fehse⁵, Axel R. Zander ⁵, Ludmila S. Zubarovskaya¹

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Summery

Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.

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Summery

Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.

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¹Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,

First Pavlov State Medical University of Saint-Petersburg, Russia

²Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia

³Stefan Morsch Stiftung, Birkenfeld, Germany

⁴Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

⁵Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation

First Pavlov State Medical University of Saint-Petersburg, Russia

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¹Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,

First Pavlov State Medical University of Saint-Petersburg, Russia

²Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia

³Stefan Morsch Stiftung, Birkenfeld, Germany

⁴Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

⁵Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation

First Pavlov State Medical University of Saint-Petersburg, Russia

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Борис В. Афанасьев, Марина Попова, Сергей Бондаренко, Илья Зюзгин, Елена Бабенко, Александр Алянский, Сюзанна Морш, Ян ван Лунзен, Борис Фезе, Аксель Цандер, Людмила С. Зубаровская

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Борис В. Афанасьев, Марина Попова, Сергей Бондаренко, Илья Зюзгин, Елена Бабенко, Александр Алянский, Сюзанна Морш, Ян ван Лунзен, Борис Фезе, Аксель Цандер, Людмила С. Зубаровская

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string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "239" ["VALUE"]=> array(2) { ["TEXT"]=> string(4127) "<p class="Summery_Rus" lang="ru-RU">Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти <span lang="en-US">HLA</span>-совместимого донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32. Алло-ТГСК от донора без мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3853) "

Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена CCR5 del 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена CCR5 del 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти HLA-совместимого донора с гомозиготной мутацией гена CCR5 del 32. Алло-ТГСК от донора без мутации гена CCR5 del 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена CCR5 del 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.

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Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена CCR5 del 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена CCR5 del 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти HLA-совместимого донора с гомозиготной мутацией гена CCR5 del 32. Алло-ТГСК от донора без мутации гена CCR5 del 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена CCR5 del 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.

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Introduction

Solid organ transplantation (SOT) is widely used for the treatment of end-stage organ insufficiency. About 30000 SOTs were performed in the European Union in 2011, comprising approximately 19000 kidney, 7000 liver and 2000 heart and other (including combined) transplants [3]. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure or the most effective treatment for a large number of malignant and non-malignant diseases of the lympho-hematopoietic system with an otherwise poor prognosis. At present, the number of allogeneic HSCTs in Europe is approximately 15000 per year [8]. With these large numbers of patients, the likelihood of coincidental occurrence of disorders potentially indicating SOT and HSCT in the same patient is increasing. Such transplantation combinations can be problematic for many reasons.

Allogeneic HSCT is an intensive treatment which causes frequently organ injury and failure, resulting in a potential indication for a SOT. The mechanisms of organ injury include cytotoxic drugs and radiotherapy in the pretransplant conditioning, organ-toxic agents in supportive care, and immunological mechanisms. The organs most often affected are kidney, liver, lung and heart. Factors that may complicate a SOT in this setting are the fragility of the patient as a consequence of the toxicity of HSCT, immunosuppressive treatment for the HSCT which may not be optimal for the SOT, potential immunological problems caused by tissue type differences between the recipient, the hematopoietic graft and the solid organ graft, and infections. In SOT recipients, the long-lasting immunosuppressive medication may affect the function of organs, and increase the risk of infections. SOT can be associated with development of hematological disorders comprising aplastic anemia, post-transplant lymphoproliferative disease, acute myeloid leukemia and myelodysplastic syndromes [1] which may be a potential indication for allogeneic HSCT.

As the clinical situation is often found to be complicated and the risk of treatment failure regarded as high, the numbers of SOTs to HSCT recipients and those of HSCTs to SOT recipients have been low as compared to the number of patients who would have a potential indication for such treatment. Until recent years the literature of such transplantations consisted mainly of case reports as reviewed by Basak et al. [1], Chiang and Lazarus [2], Koenecke et al. [7], with obvious risk of publication bias. As the results of such combined transplantations were not well known, the European Society for Blood and Marrow Transplantation (EBMT) carried out two surveys to collect the experience in Europe and to analyze the outcome. One survey evaluated the experience with SOT in HSCT recipients, the other HSCTs carried out in SOT recipients.

EBMT surveys

In the EBMT survey of SOTs carried out in HSCT recipients by Koenecke et al [7], 107 centers with the total of 67000 allogeneic HSCTs carried out between 1984 and 2007 participated. Among them, 28 centers reported having carried out a total of 45 SOTs in 40 patients for organ failure after HSCT. The transplantations comprised 15 renal, 15 liver, 13 lung grafts, 1 heart, and 1 skin transplantation. In approximately 2/3 of the HSCTs, they were performed for malignant hematological disease (n=28), the other patients had aplastic anemia, or an inherited disorder (n=6 for both). In most cases, the donor had been a sibling, and bone marrow has been transplanted. Almost all patients had received a standard full-intensity conditioning. Twenty-two patients had developed grade II or higher acute GVHD and 23 patients, extensive chronic GVHD before the SOT. This was the cause for SOT in six patients receiving liver transplants, and in 13 patients undergoing lung transplantation. In all other patients, clinically significant GVHD resolved before the SOT. Median age at the time of the renal transplantation was 35 (range 8-64) years, for liver transplantation, 20 (1-56) years, and for lung transplantation, 32 (11-55) years. The median time between HSCT and renal transplantation was 84 (range 8-188) months, that in liver transplantations 34 (range 1-137) months, and in lung transplantations, 69 (range 7-196) months. In renal transplantations following HSCT, the most common cause was drug- or radiation-induced kidney failure. Patients receiving liver transplantation could be divided in two groups, early and late transplantation after HSCT. Early liver transplantation (up to six months post-HSCT) was performed due to acute liver failure caused by veno-occlusive disease (VOD) or acute GVHD, late transplantation (usually, 2-5 years after HSCT) was mostly carried out because of chronic liver-GVHD or cirrhosis. The indication for lung transplantation was bronchiolitis obliterans (BOS)/ chronic GVHD in all these patients. The overall 5-year survival after SOT was 78%, in renal transplantations, 100%, in liver transplantations, 71% and in lung transplantations, 63%. None of the renal transplantation patients was on dialysis at the end of the follow-up. The overall 2-year incidence of SOT failure was 16% (20% in patients with GVHD preceding SOT versus 7% in GVHD-free cases). Graft rejection occurred in approximately 30% of the patients with each type of transplantation, but it could be usually treated. Two patients with renal transplantation, 2 with liver transplantation and 4 with lung transplantation experienced graft failure. The relapse incidence of the underlying malignant disease was 4% at 5 years after the SOT. Six patients received the SOT from the original HSCT donors (4 kidneys, 1 liver, 1 lung transplantation). All of them, except of the lung transplantation patient, were alive at the time of the analysis.

In the course of EBMT survey by Basak et al [1], with 101 centers participating, 18 centers reported a total of 31 HSCTs in 28 SOT recipients. Thirteen of the patients have received a liver transplantation, 12 patients received renal grafts, and three underwent heart transplantation. Malignant hematological disease was the reason for HSCT in 22 of the 28 patients, the most common indications being acute myeloblastic leukemia (AML) in 8 cases, acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in 4 cases each. The diagnosis leading to HSCT was known before the SOT in 8/28 patients (AML, ALL, CML, chronic granulomatous disease, primary immunodeficiency, severe aplastic anemia). The patients were young, with median age at the HSCT of 25 (1-62) years. The median time from SOT to HSCT was 37 (1-315) months. The sources of hematopoietic graft were as follows: peripheral blood stem cells in 21, bone marrow in 9, and the both in one patient. The donor was a HLA-identical sibling in 12, a matched unrelated donor in 14, and haploidentical, in 4 cases. Seventeen patients received myeloablative conditioning. In the rest of this group, intensity of the conditioning was reduced. Ex vivo T-cell depletion was carried out in five cases. Successful engraftment was registered in 25/26 evaluable patients. Eight patients developed grade II-IV acute GVHD. Chronic GVHD occurred in seven patients. Despite commonly advanced stage of the underlying disease at the time of HSCT, the relapse rate was low (22%). With a 5-year follow-up, solid organ graft failure occurred in 9 of 31 patients, i.e., in 5/13 (38%) of the renal transplantations, 3/15 (20%) of the liver transplantations, and in one of the three heart transplantations. Five of the nine failures were defined as graft rejection. The median time to graft failure was 1.8 months, with a range of 0 to 131 months. Transplant-related mortality at three months was 25%. Infection was the most common cause of death. The overall survival at five years after allogeneic HSCT was 40% for the entire group, 51% for liver transplant recipients and 42% for renal transplant recipients. There were no significant differences in the outcomes between different types of HSCT donors or grafts, or the conditioning intensity.

Other clinical experience

Numerous case reports have described successful liver, lung, kidney and heart transplantation after HSCT. Similarly, several case reports over the last 20 years have detailed encouraging results of allogeneic HSCT in solid organ transplant recipients. These experiences have been summarized by Chiang and Lazarus [2], Koenecke et al [7], and Basak et al [1].

Holm and coworkers [5, 6] presented a survey from the Nordic countries about lung transplantations carried out for BOS after allogeneic HSCT. Thirteen patients were reported. The indication for the HSCT had been a malignant hematological disease in all but two patients. All had clinical chronic GVHD. The median time from the HSCT to the lung transplantation was 8.2 (range 0.7-16) years. The median age at the lung transplantation was 34 (16-55) years. With a median follow-up time from the lung transplantation of 4.2 years, the survival of the patients was 90% at one year, and 75% at 5 years. Of the two deceased patients, one died with a relapse of underlying disease, and one of infection. These results were compared to the data obtained from the Scandiatransplant registry and did not differ from the general cohort of lung transplant patients. Four patients developed BOS in the transplanted lung; in one case a retransplantation was carried out.

Vogl et al. [9] reported a cohort of seven patients who received lung transplantation for BOS after allogeneic HSCT. In this cohort there was a case fatality rate of 57%, and median survival was 24 months after the lung transplantation. In this cohort the interval between HSCT and lung transplantation was much shorter than in the study of Holm et al. [5], with a median of 18 (6-120) months.

Discussion

Although a considerable number of reports describing SOT following HSCT have been published [2, 7], the number of such transplantations has been small in relation to the frequent problems of organ injury and failure seen in clinical practice. There are apparently many reasons to this, including the often complicated clinical situation, poor general condition of the patient, and possibly a certain resistance of clinicians to consider such treatment approach, but also insufficient information of such transplantations results. The described recent publications show that the outcomes can be quite good. In a survey by Koenecke et al. [7], the 5-year survival of patients receiving a renal transplantation was 100%, with no patient being on dialysis. The 5-year survival for liver transplantation was 71% and that for lung transplantation 63%. These figures are nor markedly different from the outcomes in general SOT populations. It is clear that the patient populations in dual transplantations have been selected, with young patient age, benign diseases somewhat overrepresented, and underlying malignant disease under good control, but the results show that SOT carried out for organ failure after HSCT is a feasible treatment option in carefully selected patients. There is no indication that prolonged immunosuppressive treatment due to the SOT would significantly increase the risk of disease relapse. However, it was noted by Koenecke et al. [7], that in a large proportion of the patients with SOTs following HSCT, they were carried out late, when the risk of relapse is already relatively low.

BOS is a serious and problematic complication of allogeneic HSCT, for which there is no effective treatment. Therefore, good results of lung transplantations for this disorder are encouraging. According to a report by Holm et al. [5], the 5-year OS was 75%, as compared with 63% in the study by Koenecke [7]. In contrast, the results presented by Vogl et al. [9] are showing that the median survival in a group of seven patients was only 24 months, and the case-fatality rate was 57%. As discussed by Holm et al. [6], the timing of lung transplantation comprised the major difference between clinical data in their study and those by Vogl et al., i.e., the median time from HSCT having been 8.2 years in the Holm study versus 18 months in the Vogl study. This difference may reflect, at least in part, the general importance of patient selection: the patients undergoing SOT early after HSCT being more likely to be at a higher risk of failure because of rapidly progressing complications and a poorer general condition due to the recently performed HSCT.

The number of dual transplantations including cardiac transplantation published is small. Chiang and Lazarus [2] have identified only one patient presented. In the survey [7], one such patient was identified from EBMT centers, and three, in the survey by Basak [1]. Therefore, no general conclusions can be drawn on heart transplantations combined with HSCT.

In a HSCT recipient treated with SOT, the immunological conditions may be complicated. The immunosuppressive strategy applied in the two types of transplantations is somewhat different. These factors might affect the risk of solid organ graft rejection. In the survey of Koenecke et al [7], graft rejection was seen in 4/13 cases of renal transplantationsn, leading to kidney failure in two patients. These were treated with a second renal transplantation. In 2/14 liver transplantations, the rejection led to graft failure. In 2/10 lung transplantations rejection resulted in respiratory failure; in one case this was treated with repeated transplantation. Among the patients treated with lung transplantation in the study of Holm et al [6], no rejection causing organ failure took place. Therefore, also given the small numbers of patients, the incidences of graft rejection were not markedly different from those that can be seen in non-HSCT SOT patients. The occurrence or absence of GVHD did not significantly affect the outcome.

The number of reports of HSCT in SOT recipients in the literature is quite limited (1,2). In such HSCTs the function and fate of the solid organ graft would be a concern. As shown in the survey by Basak et al [1], graft failure presents a distinct risk, as it was seen in 9/31 patients. There was a renal graft failure in 38%, liver graft failure in 20% and heart graft failure in 1/3 of the patients. In approximately half of the cases, this was considered a result of rejection. There were no major problems with hematopoietic engraftment: with one exception, engraftment took place in all evaluable patients.

There are many possible mechanisms of graft rejection in this transplant setting. An immune response can be directed against mismatched HLA molecules, because the hematopoietic graft is HLA-matched with the recipient rather than the solid organ. However, recent studies [4] have suggested that allogeneic HSCT can have a tolerogenic effect, allowing maintenance of a solid organ graft without immune suppression. Conditioning prior to allogeneic HSCT and infection may increase the immunogenicity of the organ graft by enhancing antigen presentation, increasing costimulatory signals, changing the properties of the vascular endothelium, and suppressing regulatory T-cell function. Whereas the majority of solid organ grafts are matched with the recipient based on their blood group, this is no require for HSCT donors. Thus, the majority of hematopoietic transplants are probably not matched with the solid organ graft, and this could affect the survival of the organ graft. Moreover, in most patients, the immunosuppressive regimen is changed after allogeneic HSCT from a regimen typical for SOT to an HSCT-specific regimen, which could be suboptimal in this situation.

In summary, SOT can represent a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic HSCT and experience long-term survival without loss of organ function.

Acknowledgements

The authors declare no conflicts of interest.

References

1. Basak GW, Wiktor-Jedrzejczak W, Labopin M, Schoemans H, Ljungman P, Kobbe G, Beguin Y, Lang P, Koenecke C, Sykora KW, te Boome L, van Biezen A, van der Werf S, Mohty M, de Witte T, Marsh J, Dreger P, Kröger N, Duarte R, Ruutu T. Allogeneic hematopoietic stem cell transplantation in solid organ transplant recipients: a retrospective, multicenter study of the EBMT. Am J Transplant 2015; 15: 705-14.
2. Chiang KY, Lazarus HM. Should we be performing more combined hematopoietic stem cell plus solid organ transplants? Bone Marrow Transplant 2003; 31: 633-42.
3. European Transplant Coordinators Organization. International donation and transplantation activity 2012. Available from: http://www.europeantransplantcoordinators.org.
4. Fandrich F. Cell therapy approaches aiming at minimization immunosuppression in solid organ transplantation. Curr Opin Organ Transplant 2010; 15: 703-8.
5. Holm AM, Riise GC, Hansson L, Brinch L, Bjortuft O, Iversen M, Simonsen S, Floisand Y. Lung transplantation for bronchiolitis obliterans syndrome after allo-SCT. Bone Marrow Transplantation 2013a; 48: 703-7.
6. Holm AM, Riise GC, Brinch L, Bjortuft O, Iversen M, Simonsen S, Floisand Y. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: unsolved questions. Transplantation 2013b; 96: e21-e22.
7. Koenecke C, Hertenstein B, Schetelig J, van Biezen A, Dammann E, Gratwohl A, Ganser A, Schleuning M, Bornhäuser M, Jacobsen N., Kröger N, Niederwieser D, de Witte T, Ruutu T. Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT. Am J Transplant 2010; 10: 1897-906.
8. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, Duarte RF, Dufour C, Falkenburg JHF, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Nagler A, Sureda A, Mohty M for the European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant advance online publication, February 2, 2015; doi:10.1038/bmt.2014.312
9. Vogl UM, Nagayama K, Bojic M, Hoda MAR, Klepetko W, Jaksch P, Dekan S, Siersch V, Mitterbauer M, Schellongowski P, Greinix HT, Petkov V, Schulenburg A, Kalhs P, Rabitsch W. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience. Transplantation 2013; 95: 623-28.

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Introduction

Solid organ transplantation (SOT) is widely used for the treatment of end-stage organ insufficiency. About 30000 SOTs were performed in the European Union in 2011, comprising approximately 19000 kidney, 7000 liver and 2000 heart and other (including combined) transplants [3]. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure or the most effective treatment for a large number of malignant and non-malignant diseases of the lympho-hematopoietic system with an otherwise poor prognosis. At present, the number of allogeneic HSCTs in Europe is approximately 15000 per year [8]. With these large numbers of patients, the likelihood of coincidental occurrence of disorders potentially indicating SOT and HSCT in the same patient is increasing. Such transplantation combinations can be problematic for many reasons.

Allogeneic HSCT is an intensive treatment which causes frequently organ injury and failure, resulting in a potential indication for a SOT. The mechanisms of organ injury include cytotoxic drugs and radiotherapy in the pretransplant conditioning, organ-toxic agents in supportive care, and immunological mechanisms. The organs most often affected are kidney, liver, lung and heart. Factors that may complicate a SOT in this setting are the fragility of the patient as a consequence of the toxicity of HSCT, immunosuppressive treatment for the HSCT which may not be optimal for the SOT, potential immunological problems caused by tissue type differences between the recipient, the hematopoietic graft and the solid organ graft, and infections. In SOT recipients, the long-lasting immunosuppressive medication may affect the function of organs, and increase the risk of infections. SOT can be associated with development of hematological disorders comprising aplastic anemia, post-transplant lymphoproliferative disease, acute myeloid leukemia and myelodysplastic syndromes [1] which may be a potential indication for allogeneic HSCT.

As the clinical situation is often found to be complicated and the risk of treatment failure regarded as high, the numbers of SOTs to HSCT recipients and those of HSCTs to SOT recipients have been low as compared to the number of patients who would have a potential indication for such treatment. Until recent years the literature of such transplantations consisted mainly of case reports as reviewed by Basak et al. [1], Chiang and Lazarus [2], Koenecke et al. [7], with obvious risk of publication bias. As the results of such combined transplantations were not well known, the European Society for Blood and Marrow Transplantation (EBMT) carried out two surveys to collect the experience in Europe and to analyze the outcome. One survey evaluated the experience with SOT in HSCT recipients, the other HSCTs carried out in SOT recipients.

EBMT surveys

In the EBMT survey of SOTs carried out in HSCT recipients by Koenecke et al [7], 107 centers with the total of 67000 allogeneic HSCTs carried out between 1984 and 2007 participated. Among them, 28 centers reported having carried out a total of 45 SOTs in 40 patients for organ failure after HSCT. The transplantations comprised 15 renal, 15 liver, 13 lung grafts, 1 heart, and 1 skin transplantation. In approximately 2/3 of the HSCTs, they were performed for malignant hematological disease (n=28), the other patients had aplastic anemia, or an inherited disorder (n=6 for both). In most cases, the donor had been a sibling, and bone marrow has been transplanted. Almost all patients had received a standard full-intensity conditioning. Twenty-two patients had developed grade II or higher acute GVHD and 23 patients, extensive chronic GVHD before the SOT. This was the cause for SOT in six patients receiving liver transplants, and in 13 patients undergoing lung transplantation. In all other patients, clinically significant GVHD resolved before the SOT. Median age at the time of the renal transplantation was 35 (range 8-64) years, for liver transplantation, 20 (1-56) years, and for lung transplantation, 32 (11-55) years. The median time between HSCT and renal transplantation was 84 (range 8-188) months, that in liver transplantations 34 (range 1-137) months, and in lung transplantations, 69 (range 7-196) months. In renal transplantations following HSCT, the most common cause was drug- or radiation-induced kidney failure. Patients receiving liver transplantation could be divided in two groups, early and late transplantation after HSCT. Early liver transplantation (up to six months post-HSCT) was performed due to acute liver failure caused by veno-occlusive disease (VOD) or acute GVHD, late transplantation (usually, 2-5 years after HSCT) was mostly carried out because of chronic liver-GVHD or cirrhosis. The indication for lung transplantation was bronchiolitis obliterans (BOS)/ chronic GVHD in all these patients. The overall 5-year survival after SOT was 78%, in renal transplantations, 100%, in liver transplantations, 71% and in lung transplantations, 63%. None of the renal transplantation patients was on dialysis at the end of the follow-up. The overall 2-year incidence of SOT failure was 16% (20% in patients with GVHD preceding SOT versus 7% in GVHD-free cases). Graft rejection occurred in approximately 30% of the patients with each type of transplantation, but it could be usually treated. Two patients with renal transplantation, 2 with liver transplantation and 4 with lung transplantation experienced graft failure. The relapse incidence of the underlying malignant disease was 4% at 5 years after the SOT. Six patients received the SOT from the original HSCT donors (4 kidneys, 1 liver, 1 lung transplantation). All of them, except of the lung transplantation patient, were alive at the time of the analysis.

In the course of EBMT survey by Basak et al [1], with 101 centers participating, 18 centers reported a total of 31 HSCTs in 28 SOT recipients. Thirteen of the patients have received a liver transplantation, 12 patients received renal grafts, and three underwent heart transplantation. Malignant hematological disease was the reason for HSCT in 22 of the 28 patients, the most common indications being acute myeloblastic leukemia (AML) in 8 cases, acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in 4 cases each. The diagnosis leading to HSCT was known before the SOT in 8/28 patients (AML, ALL, CML, chronic granulomatous disease, primary immunodeficiency, severe aplastic anemia). The patients were young, with median age at the HSCT of 25 (1-62) years. The median time from SOT to HSCT was 37 (1-315) months. The sources of hematopoietic graft were as follows: peripheral blood stem cells in 21, bone marrow in 9, and the both in one patient. The donor was a HLA-identical sibling in 12, a matched unrelated donor in 14, and haploidentical, in 4 cases. Seventeen patients received myeloablative conditioning. In the rest of this group, intensity of the conditioning was reduced. Ex vivo T-cell depletion was carried out in five cases. Successful engraftment was registered in 25/26 evaluable patients. Eight patients developed grade II-IV acute GVHD. Chronic GVHD occurred in seven patients. Despite commonly advanced stage of the underlying disease at the time of HSCT, the relapse rate was low (22%). With a 5-year follow-up, solid organ graft failure occurred in 9 of 31 patients, i.e., in 5/13 (38%) of the renal transplantations, 3/15 (20%) of the liver transplantations, and in one of the three heart transplantations. Five of the nine failures were defined as graft rejection. The median time to graft failure was 1.8 months, with a range of 0 to 131 months. Transplant-related mortality at three months was 25%. Infection was the most common cause of death. The overall survival at five years after allogeneic HSCT was 40% for the entire group, 51% for liver transplant recipients and 42% for renal transplant recipients. There were no significant differences in the outcomes between different types of HSCT donors or grafts, or the conditioning intensity.

Other clinical experience

Numerous case reports have described successful liver, lung, kidney and heart transplantation after HSCT. Similarly, several case reports over the last 20 years have detailed encouraging results of allogeneic HSCT in solid organ transplant recipients. These experiences have been summarized by Chiang and Lazarus [2], Koenecke et al [7], and Basak et al [1].

Holm and coworkers [5, 6] presented a survey from the Nordic countries about lung transplantations carried out for BOS after allogeneic HSCT. Thirteen patients were reported. The indication for the HSCT had been a malignant hematological disease in all but two patients. All had clinical chronic GVHD. The median time from the HSCT to the lung transplantation was 8.2 (range 0.7-16) years. The median age at the lung transplantation was 34 (16-55) years. With a median follow-up time from the lung transplantation of 4.2 years, the survival of the patients was 90% at one year, and 75% at 5 years. Of the two deceased patients, one died with a relapse of underlying disease, and one of infection. These results were compared to the data obtained from the Scandiatransplant registry and did not differ from the general cohort of lung transplant patients. Four patients developed BOS in the transplanted lung; in one case a retransplantation was carried out.

Vogl et al. [9] reported a cohort of seven patients who received lung transplantation for BOS after allogeneic HSCT. In this cohort there was a case fatality rate of 57%, and median survival was 24 months after the lung transplantation. In this cohort the interval between HSCT and lung transplantation was much shorter than in the study of Holm et al. [5], with a median of 18 (6-120) months.

Discussion

Although a considerable number of reports describing SOT following HSCT have been published [2, 7], the number of such transplantations has been small in relation to the frequent problems of organ injury and failure seen in clinical practice. There are apparently many reasons to this, including the often complicated clinical situation, poor general condition of the patient, and possibly a certain resistance of clinicians to consider such treatment approach, but also insufficient information of such transplantations results. The described recent publications show that the outcomes can be quite good. In a survey by Koenecke et al. [7], the 5-year survival of patients receiving a renal transplantation was 100%, with no patient being on dialysis. The 5-year survival for liver transplantation was 71% and that for lung transplantation 63%. These figures are nor markedly different from the outcomes in general SOT populations. It is clear that the patient populations in dual transplantations have been selected, with young patient age, benign diseases somewhat overrepresented, and underlying malignant disease under good control, but the results show that SOT carried out for organ failure after HSCT is a feasible treatment option in carefully selected patients. There is no indication that prolonged immunosuppressive treatment due to the SOT would significantly increase the risk of disease relapse. However, it was noted by Koenecke et al. [7], that in a large proportion of the patients with SOTs following HSCT, they were carried out late, when the risk of relapse is already relatively low.

BOS is a serious and problematic complication of allogeneic HSCT, for which there is no effective treatment. Therefore, good results of lung transplantations for this disorder are encouraging. According to a report by Holm et al. [5], the 5-year OS was 75%, as compared with 63% in the study by Koenecke [7]. In contrast, the results presented by Vogl et al. [9] are showing that the median survival in a group of seven patients was only 24 months, and the case-fatality rate was 57%. As discussed by Holm et al. [6], the timing of lung transplantation comprised the major difference between clinical data in their study and those by Vogl et al., i.e., the median time from HSCT having been 8.2 years in the Holm study versus 18 months in the Vogl study. This difference may reflect, at least in part, the general importance of patient selection: the patients undergoing SOT early after HSCT being more likely to be at a higher risk of failure because of rapidly progressing complications and a poorer general condition due to the recently performed HSCT.

The number of dual transplantations including cardiac transplantation published is small. Chiang and Lazarus [2] have identified only one patient presented. In the survey [7], one such patient was identified from EBMT centers, and three, in the survey by Basak [1]. Therefore, no general conclusions can be drawn on heart transplantations combined with HSCT.

In a HSCT recipient treated with SOT, the immunological conditions may be complicated. The immunosuppressive strategy applied in the two types of transplantations is somewhat different. These factors might affect the risk of solid organ graft rejection. In the survey of Koenecke et al [7], graft rejection was seen in 4/13 cases of renal transplantationsn, leading to kidney failure in two patients. These were treated with a second renal transplantation. In 2/14 liver transplantations, the rejection led to graft failure. In 2/10 lung transplantations rejection resulted in respiratory failure; in one case this was treated with repeated transplantation. Among the patients treated with lung transplantation in the study of Holm et al [6], no rejection causing organ failure took place. Therefore, also given the small numbers of patients, the incidences of graft rejection were not markedly different from those that can be seen in non-HSCT SOT patients. The occurrence or absence of GVHD did not significantly affect the outcome.

The number of reports of HSCT in SOT recipients in the literature is quite limited (1,2). In such HSCTs the function and fate of the solid organ graft would be a concern. As shown in the survey by Basak et al [1], graft failure presents a distinct risk, as it was seen in 9/31 patients. There was a renal graft failure in 38%, liver graft failure in 20% and heart graft failure in 1/3 of the patients. In approximately half of the cases, this was considered a result of rejection. There were no major problems with hematopoietic engraftment: with one exception, engraftment took place in all evaluable patients.

There are many possible mechanisms of graft rejection in this transplant setting. An immune response can be directed against mismatched HLA molecules, because the hematopoietic graft is HLA-matched with the recipient rather than the solid organ. However, recent studies [4] have suggested that allogeneic HSCT can have a tolerogenic effect, allowing maintenance of a solid organ graft without immune suppression. Conditioning prior to allogeneic HSCT and infection may increase the immunogenicity of the organ graft by enhancing antigen presentation, increasing costimulatory signals, changing the properties of the vascular endothelium, and suppressing regulatory T-cell function. Whereas the majority of solid organ grafts are matched with the recipient based on their blood group, this is no require for HSCT donors. Thus, the majority of hematopoietic transplants are probably not matched with the solid organ graft, and this could affect the survival of the organ graft. Moreover, in most patients, the immunosuppressive regimen is changed after allogeneic HSCT from a regimen typical for SOT to an HSCT-specific regimen, which could be suboptimal in this situation.

In summary, SOT can represent a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic HSCT and experience long-term survival without loss of organ function.

Acknowledgements

The authors declare no conflicts of interest.

References

1. Basak GW, Wiktor-Jedrzejczak W, Labopin M, Schoemans H, Ljungman P, Kobbe G, Beguin Y, Lang P, Koenecke C, Sykora KW, te Boome L, van Biezen A, van der Werf S, Mohty M, de Witte T, Marsh J, Dreger P, Kröger N, Duarte R, Ruutu T. Allogeneic hematopoietic stem cell transplantation in solid organ transplant recipients: a retrospective, multicenter study of the EBMT. Am J Transplant 2015; 15: 705-14.
2. Chiang KY, Lazarus HM. Should we be performing more combined hematopoietic stem cell plus solid organ transplants? Bone Marrow Transplant 2003; 31: 633-42.
3. European Transplant Coordinators Organization. International donation and transplantation activity 2012. Available from: http://www.europeantransplantcoordinators.org.
4. Fandrich F. Cell therapy approaches aiming at minimization immunosuppression in solid organ transplantation. Curr Opin Organ Transplant 2010; 15: 703-8.
5. Holm AM, Riise GC, Hansson L, Brinch L, Bjortuft O, Iversen M, Simonsen S, Floisand Y. Lung transplantation for bronchiolitis obliterans syndrome after allo-SCT. Bone Marrow Transplantation 2013a; 48: 703-7.
6. Holm AM, Riise GC, Brinch L, Bjortuft O, Iversen M, Simonsen S, Floisand Y. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: unsolved questions. Transplantation 2013b; 96: e21-e22.
7. Koenecke C, Hertenstein B, Schetelig J, van Biezen A, Dammann E, Gratwohl A, Ganser A, Schleuning M, Bornhäuser M, Jacobsen N., Kröger N, Niederwieser D, de Witte T, Ruutu T. Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT. Am J Transplant 2010; 10: 1897-906.
8. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, Duarte RF, Dufour C, Falkenburg JHF, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Nagler A, Sureda A, Mohty M for the European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant advance online publication, February 2, 2015; doi:10.1038/bmt.2014.312
9. Vogl UM, Nagayama K, Bojic M, Hoda MAR, Klepetko W, Jaksch P, Dekan S, Siersch V, Mitterbauer M, Schellongowski P, Greinix HT, Petkov V, Schulenburg A, Kalhs P, Rabitsch W. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience. Transplantation 2013; 95: 623-28.

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Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. 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["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(4) "1188" [1]=> string(4) "1189" [2]=> string(4) "1190" [3]=> string(4) "1191" [4]=> string(4) "1192" } ["VALUE"]=> array(5) { [0]=> string(2) "21" [1]=> string(2) "22" [2]=> string(2) "23" [3]=> string(2) "24" [4]=> string(2) "25" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(2) "21" [1]=> string(2) "22" [2]=> string(2) "23" [3]=> string(2) "24" [4]=> string(2) "25" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "43" ["VALUE"]=> string(19) "08.03.2015 10:43:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "08.03.2015 10:43:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "44" ["VALUE"]=> string(19) "23.06.2015 10:43:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "23.06.2015 10:43:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "867" ["VALUE"]=> string(19) "08.09.2015 17:36:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "08.09.2015 17:36:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" 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["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(1) "7" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(3) { [0]=> string(2) "39" [1]=> string(2) "40" [2]=> string(2) "41" } ["VALUE"]=> array(3) { [0]=> string(1) "8" [1]=> string(2) "10" [2]=> string(1) "7" } ["DESCRIPTION"]=> array(3) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(3) { [0]=> string(1) "8" [1]=> string(2) "10" [2]=> string(1) "7" } ["~DESCRIPTION"]=> array(3) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "14" ["VALUE"]=> array(2) { ["TEXT"]=> string(225) "<p class="Autor_Rus" lang="ru-RU">Тапани Рууту¹, Христиан Кенеке², Гжегож В. Басак³</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(157) "

Тапани Рууту¹, Христиан Кенеке², Гжегож В. Басак³

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "118" ["VALUE"]=> array(2) { ["TEXT"]=> string(860) "<p class="Autor_place_work-Rus">¹Центральный госпиталь Университета Хельсинки, Центр исследований рака, Отделение трансплантации стволовых клеток, Хельсинки, Финляндия;</p> <p class="Autor_place_work-Rus">²Высшая медицинская Школа Ганновера, Отдел Гематологии и гемостаза, Ганновер, Германия;</p> <p class="Autor_place_work-Rus">³Варшавский медицинский университет, Отдел гематологии, онкологии и внутренних болезней, Варшава, Польша</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(758) "

¹Центральный госпиталь Университета Хельсинки, Центр исследований рака, Отделение трансплантации стволовых клеток, Хельсинки, Финляндия;

²Высшая медицинская Школа Ганновера, Отдел Гематологии и гемостаза, Ганновер, Германия;

³Варшавский медицинский университет, Отдел гематологии, онкологии и внутренних болезней, Варшава, Польша

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "119" ["VALUE"]=> array(2) { ["TEXT"]=> string(7408) "<h2>Резюме</h2> <p class="Summery_Rus ParaOverride-6" lang="ru-RU">Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО. </p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7236) "

Резюме

Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО.

Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.

У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.

Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.

Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа.

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Tapani Ruutu¹, Christian Koenecke² and Grzegorz W. Basak³

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²Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover, Germany;
³The Medical University of Warsaw, Department of Hematology, Oncology and Internal Diseases, Poland" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "42" ["VALUE"]=> array(2) { ["TEXT"]=> string(1032) "<h2>Summary</h2> <p> The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1008) "

Summary

The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.

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Summary

The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.

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Summary

The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.

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Тапани Рууту¹, Христиан Кенеке², Гжегож В. Басак³

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["PROPERTY_VALUE_ID"]=> string(2) "13" ["VALUE"]=> string(1) "7" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(1) "7" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(53) "Tapani Ruutu" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "119" ["VALUE"]=> array(2) { ["TEXT"]=> string(7408) "<h2>Резюме</h2> <p class="Summery_Rus ParaOverride-6" lang="ru-RU">Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО. </p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7236) "

Резюме

Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО.

Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.

У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.

Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.

Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа.

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Резюме

Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО.

Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.

У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.

Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.

Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа.

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Introduction

Progress in adult acute lymphoblastic leukemia (ALL) in recent years is based on new diagnostic procedures, particularly the evaluation of Minimal Residual Disease (MRD), and detection of novel genetic aberrations.

At the therapeutic site the instrumentarium has been extended with targeted therapy; either with tyrosine kinase inhibitors (TKI) in Ph/bcr-abl+ ALL or, more recently, with immunotherapeutic approaches [7].

Minimal Residual Disease

There exist standard methods and definitions of MRD in ALL, in order to detect leukemic blast cells (LBC) not assessable by microscopic examination of bone marrow. Therefore, molecular complete remission (MolCR) is defined as ≤ 0,01% = ≤1 LBC in 10.000 normal cells. The molecular methods include flow cytometry (FC), or molecular biology (nucleic acid-based) approaches. Appropriate sensitivity thresholds are: 10-3-10-4 for FC, and 10-5, for RT PCR (e.g., bcr/abl detection) [4]. Clonal gene rearrangements of immunoglobulin heavy chain (IgH) or T-cell receptor (TCR-β, δ, γ) are as sensitive as 10-4. In sum, the quantitative MDR biomarkers are applicable in >90% of ALL cases.

The best time point for MRD evaluation and MRD-based treatment stratification is shown to be ca. 14-16 weeks after induction/consolidation treatment, according to the most studies. A molecular response by the week 16 after Consolidation I is most informative, with highest molecular CR rates, in order to predict outcomes of CR in standard-risk (Ph-negative) ALL, according to the GMALL Studies (06/99-07/03).

Failure of treatment by molecular criteria identifies now the worst ALL subgroup. In cases of MRD-positivity after induction/consolidation, stem cell transplantation (SCT) is considered as an option which provides sufficient increase in disease-free survival in adult ALL (standard and high risk groups) [1]. Preparation for SCT requires fast donor search, reserving place for potential haplo-, or cord blood SCT. Reduction of MRD load before SCT is quite desirable.

Pre-SCT tumor load reduction:
window studies

Reduction of MRD load before SCT is quite desirable. What approaches should be considered when treating patients positive for MRD before SCT? The so-called window studies with new cytostatic drugs (TKIs or MoABs) are aimed to reduce the tumor load before SCT. These studies allow to explore clinical effects of new drugs, measured quantitatively by MRD levels. One of those window studies was done with Nelarabine (Atriance/ Arranon), a T cell-specific drug, in relapsed/refractory T-ALL/T-LBL [5]. In this study, the CR rate was >40%, but the rate of MRD-negativity was even higher, thus allowing more MRD-negative patients to receive a transplant. Also, TKI as well as immunotherapeutic approaches have been explored in this situation.

Overall, window studies in ALL seem to be the best place for exploring new drugs. According to regulations from authorities, the novel drugs are initially explored in refractory/relapsing ALL, but it seems that some of the new drugs should be preferentially tested in the MRD-positive situation, since they might be more active if a patient has only a smaller tumor load.

The question whether it is useful to reduce the tumor load before SCT arises particularly in Ph+ ALL. It could be demonstrated in several studies that the TKI treatment during induction and consolidation increases the molecular CR rate measured by the quantitative RT-PCR bcr-abl assay to 50-70%, as compared to only 5% with chemotherapy [2]. However, it is not quite clear in Ph/bcr-abl+ ALL whether TKI post-treatment can compensate for MRD positivity before SCT. Nevertheless, in one randomized and several confirmatory studies, it has been convincingly demonstrated that a TKI treatment post-SCT is of benefit, even in patients who are MRD-negative after SCT. The TKI treatment, mostly with Imatinib, but also other TKIs, improved the outcome. Another question concerns duration of the TKI treatment. Different options are suggested for the following therapeutic regimens: (1) until bcr-abl-negativity for 2-3 time points; (2) for 2.5 years as maintenance therapy in B-lineage ALL, or forever (a discussed item).

Ph+ ALL in the era of TKI

Ph+ ALL adult studies have demonstrated a substantial advantage for SCT in CR1 with an overall survival of 60-70%. In one childhood study, intensive chemotherapy + TKI was sufficient to achieve a similar cure rate compared to a cohort with sibling- or unrelated donor transplant [11]. However, it has to be considered that Ph+ ALL in childhood is slightly different from adults, since many more additional cytogenetic aberrations are present in adult Ph+ALL. Some studies in adults, particularly with Dasatinib, currently explore whether a reasonable cure rate can be achieved without SCT. It seems, however, that the fraction of adult Ph+ ALL patients without a SCT is ~30-40%, all the other patients in these studies were later transplanted in cases of becoming bcr-abl-positive, or relapse, or in second CR. Thus, a randomized study is required in adult ALL in order to learn whether SCT is still needed in bcr/abl-negative patients in CR1.

Moreover, there is a newly discovered subtype, BCR-ABL-like ALL. For these cases, either a TKI, or a JAK2 inhibitor is indicated, depending on genetic aberrations [10].

For the newly discovered early T cell precursor (ETP) ALL, there are no new drugs proposed, except of Nelarabine evaluation, and those patients are candidates for allo-SCT in CR1, since they have a poor prognosis.

Immunotherapeutic approaches
in ALL

Several surface antigens, representing the differentiation steps in B-lineage ALL, express antigens which could be targeted by antibodies. The available drugs include monoclonal anti-CD20 antibody (Rituximab), anti-CD22 (Inotuzumab Ozogamicin, IO), the bispecific CD3/CD19-directed antibody (Blinatumomab), or Chimeric Antigen Receptor modified T (CART) cells, directed against CD19 (Table 2).

The results with Rituximab are most convincing in adult Burkitt leukemia/lymphoma, where CD20-expression is >90%. Addition of Rituximab to intensive chemotherapy has resulted in a survival rate of >80% [8]. CD20 is also positive in ~40% of cells in сommon/pre-B ALL . When referring to GMALL study 07/2003, the Rituximab addition (day -1, 375mg/m2 for eight administrations) has further improved the outcomes of standard-risk patients, by about 15%, to ~70%. The reason is a faster and higher MRD-negativity which is translated to increased disease-free survival. The question remains open, if Rituximab addition is also of benefit in high-risk patients, being candidates for a SCT in CR1.

Anti-CD22 antibody has been studied in relapsed/refractory ALL with a good CR rate, whereby a high percentage of those patients achieved a molecular remission [9]. Interestingly, this medication has been also piloted in a small study with elderly patients where the antibody was added to a reduced chemotherapy (Mini-HyperCVAD), yielding promising results. However, the follow-up in this trial was extremely short.

Blinatumomab is a novel bispecific construct that reacts simultaneously with normal CD3 T cells and CD19 ALL cells, creating a tight intercellular connection followed by T cell–mediated cytotoxicity directed against CD19 blast cells (BiTE mechanism). An appropriate Phase 2 study was carried out in pre-B ALL patients being in hematological CR, but with molecular failure or molecular relapse after ≥ 3 cycles of chemotherapy (n=21). The endpoints included a complete molecular response (CMR), time to hematologic relapse, as well as incidence and severity of adverse events [12]. As a result, long-term remissions were achieved in some patients without SCT or any other treatment [13]. Very promising studies were performed with Blinatunomab in refractory/relapsed, or MRD-positive ALL patients. In heavily pre-treated cases, MRD was again chosen as primary endpoint, i.e., conversion from MRD positivity to MRD negativity ≤10-4 is clearly defined and measurable within weeks to months [6].

A novel option represents chimeric antigen receptor-modified T cells (CART), autologous T cells expressing a CD19-specific CD28/CD3ζ, dual-signaling, second-generation chimeric antigen receptor (CAR) termed as 19-28z. The CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory ALL [3].

Conclusions

Evaluation of minimal residual disease is a new parameter for treatment stratification. The conversion of MRD-positivity to MRD-negativity is also a new endpoint for studies.

Targeted therapy with TKIs, either first-generation drug (Imatinib), or second-generation agents (Dasatinib/Nilotinib), has substantially improved the outcome for adult Ph+ ALL patients, eventually, by increased molecular remission rates and substantial improvement of survival to 60-70% after SCT.

Maintenance therapy with TKI is recommended after SCT, whereby its optimal duration is so far not known.

Nearly all Ph+/bcr-abl+ patients relapsing after chemo or SCT have specific mutations of the fusion gene, in particular, T351I. Such pharmaceutical products as the new third-generation TKI, Ponatinib, or other substances have to be explored, aiming to overcome drug resistance caused by such mutations.

Immunotherapeutic approaches offer new treatment options, required especially in adult ALL. Anti-CD20 Rituximab, as well as anti-CD22 Inotuzumab Ozogamicin, have been successfully explored in refractory/relapsed ALL, MRD-positive clinical situations, and also in cases of de novo treatment.

A new approach is to activate the patients’ own T-cells to be directed against the targeted leukemic blast cells. Blinatumomab, a bispecific antibody, has shown its efficiency in MRD-positive patients, refractory/relapsed disease, and in ongoing studies concerning de novo induction/consolidation therapy.

A novel option concerns potential treatment with Chimeric Antigen Receptor (CAR)- modified T cells, where autologous T-cells against CD19-bearing leukemic cells could be generated. The results are promising, although small groups of patients, short follow-up terms, and considerable treatment-associated toxicity still leave many questions open.

References

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13. Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 2012; 120(26): 5185-7.

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Introduction

Progress in adult acute lymphoblastic leukemia (ALL) in recent years is based on new diagnostic procedures, particularly the evaluation of Minimal Residual Disease (MRD), and detection of novel genetic aberrations.

At the therapeutic site the instrumentarium has been extended with targeted therapy; either with tyrosine kinase inhibitors (TKI) in Ph/bcr-abl+ ALL or, more recently, with immunotherapeutic approaches [7].

Minimal Residual Disease

There exist standard methods and definitions of MRD in ALL, in order to detect leukemic blast cells (LBC) not assessable by microscopic examination of bone marrow. Therefore, molecular complete remission (MolCR) is defined as ≤ 0,01% = ≤1 LBC in 10.000 normal cells. The molecular methods include flow cytometry (FC), or molecular biology (nucleic acid-based) approaches. Appropriate sensitivity thresholds are: 10-3-10-4 for FC, and 10-5, for RT PCR (e.g., bcr/abl detection) [4]. Clonal gene rearrangements of immunoglobulin heavy chain (IgH) or T-cell receptor (TCR-β, δ, γ) are as sensitive as 10-4. In sum, the quantitative MDR biomarkers are applicable in >90% of ALL cases.

The best time point for MRD evaluation and MRD-based treatment stratification is shown to be ca. 14-16 weeks after induction/consolidation treatment, according to the most studies. A molecular response by the week 16 after Consolidation I is most informative, with highest molecular CR rates, in order to predict outcomes of CR in standard-risk (Ph-negative) ALL, according to the GMALL Studies (06/99-07/03).

Failure of treatment by molecular criteria identifies now the worst ALL subgroup. In cases of MRD-positivity after induction/consolidation, stem cell transplantation (SCT) is considered as an option which provides sufficient increase in disease-free survival in adult ALL (standard and high risk groups) [1]. Preparation for SCT requires fast donor search, reserving place for potential haplo-, or cord blood SCT. Reduction of MRD load before SCT is quite desirable.

Pre-SCT tumor load reduction:
window studies

Reduction of MRD load before SCT is quite desirable. What approaches should be considered when treating patients positive for MRD before SCT? The so-called window studies with new cytostatic drugs (TKIs or MoABs) are aimed to reduce the tumor load before SCT. These studies allow to explore clinical effects of new drugs, measured quantitatively by MRD levels. One of those window studies was done with Nelarabine (Atriance/ Arranon), a T cell-specific drug, in relapsed/refractory T-ALL/T-LBL [5]. In this study, the CR rate was >40%, but the rate of MRD-negativity was even higher, thus allowing more MRD-negative patients to receive a transplant. Also, TKI as well as immunotherapeutic approaches have been explored in this situation.

Overall, window studies in ALL seem to be the best place for exploring new drugs. According to regulations from authorities, the novel drugs are initially explored in refractory/relapsing ALL, but it seems that some of the new drugs should be preferentially tested in the MRD-positive situation, since they might be more active if a patient has only a smaller tumor load.

The question whether it is useful to reduce the tumor load before SCT arises particularly in Ph+ ALL. It could be demonstrated in several studies that the TKI treatment during induction and consolidation increases the molecular CR rate measured by the quantitative RT-PCR bcr-abl assay to 50-70%, as compared to only 5% with chemotherapy [2]. However, it is not quite clear in Ph/bcr-abl+ ALL whether TKI post-treatment can compensate for MRD positivity before SCT. Nevertheless, in one randomized and several confirmatory studies, it has been convincingly demonstrated that a TKI treatment post-SCT is of benefit, even in patients who are MRD-negative after SCT. The TKI treatment, mostly with Imatinib, but also other TKIs, improved the outcome. Another question concerns duration of the TKI treatment. Different options are suggested for the following therapeutic regimens: (1) until bcr-abl-negativity for 2-3 time points; (2) for 2.5 years as maintenance therapy in B-lineage ALL, or forever (a discussed item).

Ph+ ALL in the era of TKI

Ph+ ALL adult studies have demonstrated a substantial advantage for SCT in CR1 with an overall survival of 60-70%. In one childhood study, intensive chemotherapy + TKI was sufficient to achieve a similar cure rate compared to a cohort with sibling- or unrelated donor transplant [11]. However, it has to be considered that Ph+ ALL in childhood is slightly different from adults, since many more additional cytogenetic aberrations are present in adult Ph+ALL. Some studies in adults, particularly with Dasatinib, currently explore whether a reasonable cure rate can be achieved without SCT. It seems, however, that the fraction of adult Ph+ ALL patients without a SCT is ~30-40%, all the other patients in these studies were later transplanted in cases of becoming bcr-abl-positive, or relapse, or in second CR. Thus, a randomized study is required in adult ALL in order to learn whether SCT is still needed in bcr/abl-negative patients in CR1.

Moreover, there is a newly discovered subtype, BCR-ABL-like ALL. For these cases, either a TKI, or a JAK2 inhibitor is indicated, depending on genetic aberrations [10].

For the newly discovered early T cell precursor (ETP) ALL, there are no new drugs proposed, except of Nelarabine evaluation, and those patients are candidates for allo-SCT in CR1, since they have a poor prognosis.

Immunotherapeutic approaches
in ALL

Several surface antigens, representing the differentiation steps in B-lineage ALL, express antigens which could be targeted by antibodies. The available drugs include monoclonal anti-CD20 antibody (Rituximab), anti-CD22 (Inotuzumab Ozogamicin, IO), the bispecific CD3/CD19-directed antibody (Blinatumomab), or Chimeric Antigen Receptor modified T (CART) cells, directed against CD19 (Table 2).

The results with Rituximab are most convincing in adult Burkitt leukemia/lymphoma, where CD20-expression is >90%. Addition of Rituximab to intensive chemotherapy has resulted in a survival rate of >80% [8]. CD20 is also positive in ~40% of cells in сommon/pre-B ALL . When referring to GMALL study 07/2003, the Rituximab addition (day -1, 375mg/m2 for eight administrations) has further improved the outcomes of standard-risk patients, by about 15%, to ~70%. The reason is a faster and higher MRD-negativity which is translated to increased disease-free survival. The question remains open, if Rituximab addition is also of benefit in high-risk patients, being candidates for a SCT in CR1.

Anti-CD22 antibody has been studied in relapsed/refractory ALL with a good CR rate, whereby a high percentage of those patients achieved a molecular remission [9]. Interestingly, this medication has been also piloted in a small study with elderly patients where the antibody was added to a reduced chemotherapy (Mini-HyperCVAD), yielding promising results. However, the follow-up in this trial was extremely short.

Blinatumomab is a novel bispecific construct that reacts simultaneously with normal CD3 T cells and CD19 ALL cells, creating a tight intercellular connection followed by T cell–mediated cytotoxicity directed against CD19 blast cells (BiTE mechanism). An appropriate Phase 2 study was carried out in pre-B ALL patients being in hematological CR, but with molecular failure or molecular relapse after ≥ 3 cycles of chemotherapy (n=21). The endpoints included a complete molecular response (CMR), time to hematologic relapse, as well as incidence and severity of adverse events [12]. As a result, long-term remissions were achieved in some patients without SCT or any other treatment [13]. Very promising studies were performed with Blinatunomab in refractory/relapsed, or MRD-positive ALL patients. In heavily pre-treated cases, MRD was again chosen as primary endpoint, i.e., conversion from MRD positivity to MRD negativity ≤10-4 is clearly defined and measurable within weeks to months [6].

A novel option represents chimeric antigen receptor-modified T cells (CART), autologous T cells expressing a CD19-specific CD28/CD3ζ, dual-signaling, second-generation chimeric antigen receptor (CAR) termed as 19-28z. The CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory ALL [3].

Conclusions

Evaluation of minimal residual disease is a new parameter for treatment stratification. The conversion of MRD-positivity to MRD-negativity is also a new endpoint for studies.

Targeted therapy with TKIs, either first-generation drug (Imatinib), or second-generation agents (Dasatinib/Nilotinib), has substantially improved the outcome for adult Ph+ ALL patients, eventually, by increased molecular remission rates and substantial improvement of survival to 60-70% after SCT.

Maintenance therapy with TKI is recommended after SCT, whereby its optimal duration is so far not known.

Nearly all Ph+/bcr-abl+ patients relapsing after chemo or SCT have specific mutations of the fusion gene, in particular, T351I. Such pharmaceutical products as the new third-generation TKI, Ponatinib, or other substances have to be explored, aiming to overcome drug resistance caused by such mutations.

Immunotherapeutic approaches offer new treatment options, required especially in adult ALL. Anti-CD20 Rituximab, as well as anti-CD22 Inotuzumab Ozogamicin, have been successfully explored in refractory/relapsed ALL, MRD-positive clinical situations, and also in cases of de novo treatment.

A new approach is to activate the patients’ own T-cells to be directed against the targeted leukemic blast cells. Blinatumomab, a bispecific antibody, has shown its efficiency in MRD-positive patients, refractory/relapsed disease, and in ongoing studies concerning de novo induction/consolidation therapy.

A novel option concerns potential treatment with Chimeric Antigen Receptor (CAR)- modified T cells, where autologous T-cells against CD19-bearing leukemic cells could be generated. The results are promising, although small groups of patients, short follow-up terms, and considerable treatment-associated toxicity still leave many questions open.

References

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Дитер Хельцер

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Университет Й.-В. Гете, Франкфурт-на Майне, Германия

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "147" ["VALUE"]=> array(2) { ["TEXT"]=> string(3222) "<p class="Summery_Rus" lang="ru-RU">Существуют стандартные молекулярные методы и оценки минимальной остаточной болезни (MОД) при остром лимфобластном лейкозе (ОЛЛ), чтобы выявлять лейкозные костном мозге бласты, не выявляемые с помощью микроскопии. Наилучший период для оценки МОД и основанной на ней стратификации терапии при ОЛЛ – примерно 14-16 недель после индукции/консолидации. Снижение уровня МОД весьма желательно после трансплантации гемопоэтических стволовых клеток (ТГСК) как следующего этапа лечения. Например, индукция и консолидация ремиссии ингибиторами тирозинкиназы (ИТК) повышает частоту молекулярной ремиссии, в сравнении с обычной химиотерапией, по данным количественной ПЦР онкогена bcr/abl. Неудачный исход лечения по молекулярным критериям идентифицирует подгруппу ОЛЛ с худшими исходами. Несколько «интервальных» исследований при ОЛЛ с применением новых цитостатиков (ИТК и моноклональных антител) были направлены на снижение опухолевой нагрузки перед ТГСК. Кроме того, новые иммунотерапевтические подходы включают в себя применение антител к специфическим поверхностным антигенам, характерным для определенных этапов дифференцировки В-клеточного ростка. </p> <p class="Summery_Rus" lang="ru-RU">Таким образом, оценка МОД является новым параметром для назначения схем лечения. Переход от МОД-позитивности к МОД-негативности также является отдельным критерием исхода в клинических исследованиях. Целевая терапия ИТК значительно улучшила исходы лечения взрослых пациентов с Ph+ ОЛЛ по более высоким показателям частоты молекулярной ремиссии и существенному увеличению выживаемости после ТГСК. В то же время, после ТГСК рекомендуется поддерживающая терапия ИТК причем ее оптимальная длительность до сих пор не выяснена. </p> " ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3158) "

Существуют стандартные молекулярные методы и оценки минимальной остаточной болезни (MОД) при остром лимфобластном лейкозе (ОЛЛ), чтобы выявлять лейкозные костном мозге бласты, не выявляемые с помощью микроскопии. Наилучший период для оценки МОД и основанной на ней стратификации терапии при ОЛЛ – примерно 14-16 недель после индукции/консолидации. Снижение уровня МОД весьма желательно после трансплантации гемопоэтических стволовых клеток (ТГСК) как следующего этапа лечения. Например, индукция и консолидация ремиссии ингибиторами тирозинкиназы (ИТК) повышает частоту молекулярной ремиссии, в сравнении с обычной химиотерапией, по данным количественной ПЦР онкогена bcr/abl. Неудачный исход лечения по молекулярным критериям идентифицирует подгруппу ОЛЛ с худшими исходами. Несколько «интервальных» исследований при ОЛЛ с применением новых цитостатиков (ИТК и моноклональных антител) были направлены на снижение опухолевой нагрузки перед ТГСК. Кроме того, новые иммунотерапевтические подходы включают в себя применение антител к специфическим поверхностным антигенам, характерным для определенных этапов дифференцировки В-клеточного ростка.

Таким образом, оценка МОД является новым параметром для назначения схем лечения. Переход от МОД-позитивности к МОД-негативности также является отдельным критерием исхода в клинических исследованиях. Целевая терапия ИТК значительно улучшила исходы лечения взрослых пациентов с Ph+ ОЛЛ по более высоким показателям частоты молекулярной ремиссии и существенному увеличению выживаемости после ТГСК. В то же время, после ТГСК рекомендуется поддерживающая терапия ИТК причем ее оптимальная длительность до сих пор не выяснена.

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Dieter Hoelzer

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J. W. Goethe University, Frankfurt

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Summery

There exist standard molecular methods of minimal residual disease (MRD) evaluation in acute lymphoblastic leukemia (ALL), in order to detect leukemic blast cells (LBC) not assessable by microscopy of bone marrow. The best time point for MRD evaluation and MRD-based treatment stratification in ALL is shown to be ca.14-16 weeks after induction/ consolidation treatment. Reduction of MRD load before SCT, as a next step of therapy, is quite desirable. E.g., induction and consolidation treatment with tyrosine kinase inhibitors (NKI) increase the molecular CR rate compared to conventional chemotherapy, as measured by the quantitative RT-PCR assays of bcr/abl fusion oncogene. Failure of treatment by molecular criteria identifies the worst ALL subgroup. Several window studies in ALL with new cytostatic drugs (TKIs or MoABs) were aimed to reduce the tumor load before SCT. Moreover, novel immunotherapeutic approaches include application of monoclonal antibodies against specific surface antigens typical to certain differentiation steps in B-lineage.

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Dieter Hoelzer

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Dieter Hoelzer

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Summery

There exist standard molecular methods of minimal residual disease (MRD) evaluation in acute lymphoblastic leukemia (ALL), in order to detect leukemic blast cells (LBC) not assessable by microscopy of bone marrow. The best time point for MRD evaluation and MRD-based treatment stratification in ALL is shown to be ca.14-16 weeks after induction/ consolidation treatment. Reduction of MRD load before SCT, as a next step of therapy, is quite desirable. E.g., induction and consolidation treatment with tyrosine kinase inhibitors (NKI) increase the molecular CR rate compared to conventional chemotherapy, as measured by the quantitative RT-PCR assays of bcr/abl fusion oncogene. Failure of treatment by molecular criteria identifies the worst ALL subgroup. Several window studies in ALL with new cytostatic drugs (TKIs or MoABs) were aimed to reduce the tumor load before SCT. Moreover, novel immunotherapeutic approaches include application of monoclonal antibodies against specific surface antigens typical to certain differentiation steps in B-lineage.

Hence, evaluation of minimal residual disease is a new parameter for treatment stratification. The conversion of MRD-positivity to MRD-negativity is also a new endpoint for studies. Targeted therapy with TKI has improved the outcome for adult Ph+ ALL patients substantially, evidently by an increased molecular remission rate, and a substantial improvement of survival after SCT. Meanwhile, maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known. Maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known.

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Summery

There exist standard molecular methods of minimal residual disease (MRD) evaluation in acute lymphoblastic leukemia (ALL), in order to detect leukemic blast cells (LBC) not assessable by microscopy of bone marrow. The best time point for MRD evaluation and MRD-based treatment stratification in ALL is shown to be ca.14-16 weeks after induction/ consolidation treatment. Reduction of MRD load before SCT, as a next step of therapy, is quite desirable. E.g., induction and consolidation treatment with tyrosine kinase inhibitors (NKI) increase the molecular CR rate compared to conventional chemotherapy, as measured by the quantitative RT-PCR assays of bcr/abl fusion oncogene. Failure of treatment by molecular criteria identifies the worst ALL subgroup. Several window studies in ALL with new cytostatic drugs (TKIs or MoABs) were aimed to reduce the tumor load before SCT. Moreover, novel immunotherapeutic approaches include application of monoclonal antibodies against specific surface antigens typical to certain differentiation steps in B-lineage.

Hence, evaluation of minimal residual disease is a new parameter for treatment stratification. The conversion of MRD-positivity to MRD-negativity is also a new endpoint for studies. Targeted therapy with TKI has improved the outcome for adult Ph+ ALL patients substantially, evidently by an increased molecular remission rate, and a substantial improvement of survival after SCT. Meanwhile, maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known. Maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known.

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J. W. Goethe University, Frankfurt

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J. W. Goethe University, Frankfurt

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Дитер Хельцер

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Дитер Хельцер

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Наилучший период для оценки МОД и основанной на ней стратификации терапии при ОЛЛ – примерно 14-16 недель после индукции/консолидации. Снижение уровня МОД весьма желательно после трансплантации гемопоэтических стволовых клеток (ТГСК) как следующего этапа лечения. Например, индукция и консолидация ремиссии ингибиторами тирозинкиназы (ИТК) повышает частоту молекулярной ремиссии, в сравнении с обычной химиотерапией, по данным количественной ПЦР онкогена bcr/abl. Неудачный исход лечения по молекулярным критериям идентифицирует подгруппу ОЛЛ с худшими исходами. Несколько «интервальных» исследований при ОЛЛ с применением новых цитостатиков (ИТК и моноклональных антител) были направлены на снижение опухолевой нагрузки перед ТГСК. Кроме того, новые иммунотерапевтические подходы включают в себя применение антител к специфическим поверхностным антигенам, характерным для определенных этапов дифференцировки В-клеточного ростка. </p> <p class="Summery_Rus" lang="ru-RU">Таким образом, оценка МОД является новым параметром для назначения схем лечения. Переход от МОД-позитивности к МОД-негативности также является отдельным критерием исхода в клинических исследованиях. Целевая терапия ИТК значительно улучшила исходы лечения взрослых пациентов с Ph+ ОЛЛ по более высоким показателям частоты молекулярной ремиссии и существенному увеличению выживаемости после ТГСК. В то же время, после ТГСК рекомендуется поддерживающая терапия ИТК причем ее оптимальная длительность до сих пор не выяснена. </p> " ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3158) "

Существуют стандартные молекулярные методы и оценки минимальной остаточной болезни (MОД) при остром лимфобластном лейкозе (ОЛЛ), чтобы выявлять лейкозные костном мозге бласты, не выявляемые с помощью микроскопии. Наилучший период для оценки МОД и основанной на ней стратификации терапии при ОЛЛ – примерно 14-16 недель после индукции/консолидации. Снижение уровня МОД весьма желательно после трансплантации гемопоэтических стволовых клеток (ТГСК) как следующего этапа лечения. Например, индукция и консолидация ремиссии ингибиторами тирозинкиназы (ИТК) повышает частоту молекулярной ремиссии, в сравнении с обычной химиотерапией, по данным количественной ПЦР онкогена bcr/abl. Неудачный исход лечения по молекулярным критериям идентифицирует подгруппу ОЛЛ с худшими исходами. Несколько «интервальных» исследований при ОЛЛ с применением новых цитостатиков (ИТК и моноклональных антител) были направлены на снижение опухолевой нагрузки перед ТГСК. Кроме того, новые иммунотерапевтические подходы включают в себя применение антител к специфическим поверхностным антигенам, характерным для определенных этапов дифференцировки В-клеточного ростка.

Таким образом, оценка МОД является новым параметром для назначения схем лечения. Переход от МОД-позитивности к МОД-негативности также является отдельным критерием исхода в клинических исследованиях. Целевая терапия ИТК значительно улучшила исходы лечения взрослых пациентов с Ph+ ОЛЛ по более высоким показателям частоты молекулярной ремиссии и существенному увеличению выживаемости после ТГСК. В то же время, после ТГСК рекомендуется поддерживающая терапия ИТК причем ее оптимальная длительность до сих пор не выяснена.

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Существуют стандартные молекулярные методы и оценки минимальной остаточной болезни (MОД) при остром лимфобластном лейкозе (ОЛЛ), чтобы выявлять лейкозные костном мозге бласты, не выявляемые с помощью микроскопии. Наилучший период для оценки МОД и основанной на ней стратификации терапии при ОЛЛ – примерно 14-16 недель после индукции/консолидации. Снижение уровня МОД весьма желательно после трансплантации гемопоэтических стволовых клеток (ТГСК) как следующего этапа лечения. Например, индукция и консолидация ремиссии ингибиторами тирозинкиназы (ИТК) повышает частоту молекулярной ремиссии, в сравнении с обычной химиотерапией, по данным количественной ПЦР онкогена bcr/abl. Неудачный исход лечения по молекулярным критериям идентифицирует подгруппу ОЛЛ с худшими исходами. Несколько «интервальных» исследований при ОЛЛ с применением новых цитостатиков (ИТК и моноклональных антител) были направлены на снижение опухолевой нагрузки перед ТГСК. Кроме того, новые иммунотерапевтические подходы включают в себя применение антител к специфическим поверхностным антигенам, характерным для определенных этапов дифференцировки В-клеточного ростка.

Таким образом, оценка МОД является новым параметром для назначения схем лечения. Переход от МОД-позитивности к МОД-негативности также является отдельным критерием исхода в клинических исследованиях. Целевая терапия ИТК значительно улучшила исходы лечения взрослых пациентов с Ph+ ОЛЛ по более высоким показателям частоты молекулярной ремиссии и существенному увеличению выживаемости после ТГСК. В то же время, после ТГСК рекомендуется поддерживающая терапия ИТК причем ее оптимальная длительность до сих пор не выяснена.

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Университет Й.-В. Гете, Франкфурт-на Майне, Германия

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Университет Й.-В. Гете, Франкфурт-на Майне, Германия

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Introduction

Little is known about cancer chemotherapy in the elderly. There are only a few studies which include patients with cancer who at the same time are older than seventy years of age. It is a common practice to treat elderly patients according to existing protocols for younger patients with reduced doses and off the record; the data are not collected and analyzed. Outcome of the chemotherapy in the elderly is influenced by age-related changes in body composition and normal organ function as well as age related deficiencies in cognitive processes. Reduced visual performance and reduced manual dexterity in the elderly lead frequently to dosing and compliance errors. Another complicating factor is the increasing use of complementary and alternative medicines by elderly patients. This article will review the age related changes of body function, organ toxicity after chemotherapy in the elderly and the potential impact of complementary and alternative medicines.

Defining old is a complex process. The age of 60 or 65, roughly equivalent to the age of retirement in most Western countries, is said to be the beginning of old age. The aging process is of course a biological reality with its own dynamic largely beyond individual control. In view of the increasing age of the population in industrialized countries, a differentiation by age (61-75 years: elderly persons; 76-90 years of age: old persons; above 90 years: very old persons) seems to be useful.

There are age-related changes in body composition such as increased body fat that amounts to circa 35% at age 75, reduction of total body water that amounts to about 17% at age 60, and decrease in extracellular liquid, to circa 40% at age 65. Aside from changes in body composition, there is a reduction of normal organ function every year: cardiac output, by about 1%; liver size, by 2%; liver blood flow, 1%; kidney blood flow, by 1%; tubular function, by 1%, and glomerular filtration rate (GFR), by 1ml/min/1,73m².

Changes in biological functions in old age lead to consequences for pharmacotherapy. Reduced secretion of gastric acid and gastrointestinal tract motility might lead to a reduction of bioavailability of certain drugs. Increased body fat might change the distribution volume of lipophilic drugs. Reduction of albumin concentration might lead to an increase of non-albumin bound drugs. Reduction of GFR and tubular secretional function might lead to an accumulation of renally eliminated active substances.

Other age related deficiencies might complicate effective chemotherapy in old and very old patients. Reduced mobility and increased risk of osteoporosis increase the risk and the frequency of falls. Impairment of short-term memory leads to dosing errors and compliance problems and an increased belief in “tonics”, which might lead to drug interactions. Functional deficiencies, including emotional changes reduce the ability for directed and efficient actions and might lead to lethargy and non-adherence to treatment schedules. Reduced visual performance and reduced manual dexterity might lead to orientation problems, dosage errors and manual difficulties with splitting of tablets.

Polypharmacotherapy leads to particular problems in the elderly patient population. According to one study, the PRISCUS Project, every health insured older patient is prescribed 3.6 drugs on the average. Over-the-counter (OTC) products are added to this number. 25% of the prescribed drugs are potentially inadequate medications. [1]

The problem of non-compliance is already evident in twice daily (bid) vs. once daily (qd) dosing of medications. Published data on other twice daily medications (eg. metformine, glipizide, metoprolol) show that adequate adherence (defined as greater than 80% of pills taken) may be only 52-65% [11]. A Polish study comparing beta-blockers given once daily (betaxolol) or twice daily (metoprolol) to patients with stable angina pectoris showed 58.6% vs. 42.0% for doses taken in the correct time window and 77.4% vs. 53.1% for correct interdose intervals in favor of the drug taken once daily [8].

Hamaker et al. [6] state that currently ongoing trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients, as those outcome measures, that are of primary importance to this patient population are still included in only a minority of studies. A broader database of chemotherapy data in elderly patients is needed to enable the oncologist to deliver evidence based and patient focused cancer care.

The experience with chemotherapeutic agents and their pharmacokinetics in patients with old age is limited. Hurria and Lichtman [7] analyze clinical pharmacology of cancer therapies in older patients in a mini review. In 18 studies older and younger patient groups were compared. When treated with Paclitaxel (3 studies), Docetaxel (4 studies), Oxaliplatin (1 study), Temozolomide (1 study), Vinorelbine (2 studies), 5- Fluorouracil (1 study), Capecitabine (1 study), Etoposide (3 studies), Doxorubicin (2 studies) only 5/18 studies could actually demonstrate age-related differences in clinical pharmacokinetics, but this remains controversial.

The International Society of Geriatric Oncology (SIOG) arrived at the following recommendations (Table 1) for the adjustment of dosing in elderly patients, according to the underlying renal function but also including clinical experience [10].

INN	90-60 ml/min	60-30 ml/min	30-15 ml/min
Melphalan	100-200 mg/m2	75%	50%
Oxaliplatine	85-100 mg/m2	100%	100%
Fludarabine	25 mg/m2	20 mg/m2	15 mg/m2
Capecitabine	1250 mg/m2 every 12 h	950 mg/m2 every 12 h	Contraindicated

Table 1: Dosing adjustment in elderly cancer patients. Recommendations of the International Society of Geriatric Oncology (SIOG) according to the underlying renal function [10]

Kintzel and Dorr [9] recommended dose modification for another set of antineoplastic drugs for patients with renal dysfunction (Table 2). The dose modification is clearly related to the fraction of renally excreted active or toxic moiety of the drug. Etoposide with a fraction of 32% requires nearly no reduction in patients with a creatinine clearance of 30 ml/min., whereas methotrexate with a fraction of 77% of renally excreted or toxic moiety requires a reduction of 50% in patients with INN of 45 ml/min. and should not be given to patients with lower renal functions.

INN	f	60 ml/min	45 ml/min	30 ml/min
Etoposide	32%	0.85	0.80	0.75
Hydroxyurea	36%	0.85	0.80	0.75
Dacarbazine	41%	0.80	0.75	0.70
Fludarabine	44%	0.80	0.75	0.65
Lomustine (CCNU)	50%	0.75	0.70	-
Bleomycine	62%	0.70	0.60	-
HD-AraC, MTX	77%	0.65	0.50	-

Table 2. Dose modification for antineoplastic drugs in renal dysfunction [9]

Decreased organ functions, besides renal clearance that may lead to consequences for pharmacotherapy, are heart function, with a reduction of myocytes and reduction of dromotrophy, eventually: left ventricular ejection function (LVEF) that may lead to congestive heart failure and cardiac arrhythmias. Regarding the nervous system, co-morbidities, such as Diabetes Mellitus may lead to higher risk for sensory neuropathies. Reduced vital and diffusion capacity of the lung may lead to higher risk for lung toxic side-affects. The reduction of bone marrow reserve may lead to severe cytopenias. An increase in fibrinogen concentration may lead to a higher risk for venous thromboembolism.

An older study from von Hoff et al. [12] compares cumulative doses of Doxorubicin on incidence of cardiotoxicity in patients aged 40-59 vs. in patients older than 60 years of age. There was an increase in cardiotoxicity with all dose ranges in the older patient group. This difference was seen in the groups that received Doxorubicin every seven days as well as in the group that received the drug every three weeks.

Cumulative dose (mg/m2)	q7d 40-59 y	q7d > 60 y	q3w 40-59 y	q3w > 60 y
300	0.6	0.9	2.2	3.4
400	0.7	1.2	2.3	4.6
500	1.5	2.3	5.8	8.9
600	3.9	6.1	14.9	22.4
700	8.7	13.2	30.5	43.5

Table 3: Doxorubicin-induced cardiotoxicity (%) related to cumulative dose. Modified from [12].

Newer orally available “targeted” anti-cancer agents are of special interest in the elderly patient group. E.c., target protein produced by bcr-abl fusion gene can be attacked by Imatinib (GLIVEC), Dasatinib (SPRYCEL), Nilotinib (TASIGNA), Bosutinib (BOSULIF), and Ponatinib (ICLUSIG). The epidermal growth factor receptor (EGFR) is target for several drugs like Erlotinib (TARCEVA), Imatinib (GLIVEC), Afatinib (GILOTRIF), and Lapatinib (TYVERB). Other drugs like Sorafenib (NEXAVAR) and Sunitinib (SUTENT) interfere with Vascular Endothelial Growth Factor (VEGF). Other drugs like Vemurafenib (ZELBORAF) and Dabrafenib (TAFINLAR) interfere with mutations of BRAF, the serine/threonine-protein kinase. Other targeted therapies include Crizotinib (XALKORI), Everolimus (AFINITOR), Vismodegib (ERIVEDGE), Trametinib (MEKINIST), and Ibrutinib (IMBRUVICA) as well as Thalidomide, Lenalidomide (REVLIMID), and Pomalidomide (IMNOVID) which in partly modulate the immune system.

Particular attention needs to be directed toward the toxicity of targeted anti-cancer therapy in the elderly [5]. The older human population compared to the younger population shows more toxicity in several areas. Imatinib shows more hematologic and non-hematologic toxicities in older patients. Bevacizumab shows more thromboembolism, more fatigue and more asthenia. Bortezomib shows more gastrointestinal problems, fatigue and neuropathies. Thalidomide shows more deeper vein thrombosis. Lenalidomide needed to be discontinued more frequently in the older population related to hematological and non-hematological toxicities. No age related differences in toxicity were seen in Trastuzumab.

A well-known example for influencing therapeutically needed drug levels are the Calcineurin inhibitors (CNI). Drugs which inhibit the Cytochrome P450 3A4 enzyme system that metabolizes CNIs lead to an increased risk for toxicity, drugs which induce enzymes catabolizing CNIs lead to a decreased drug concentrations and therefore an increased risk of treatment failure. Therefore, close attention needs to be given to the drug concentration, particularly if other drugs are given which induce or inhibit enzymes.

A particular problem of drug interference constitutes over-the-counter (OTC) and complementary and alternative medicine (CAM). There are many-fold explanations:

• OTCs require no prescription, “therefore they cannot be dangerous”.
• There is a need to address personal fears and worries
• Desire to do something for one’s health
• Therapy considered to be harmless (natural)
• Belief: “natural” things are good
• Can do no harm
• Strengthen the immune system
• Intriguing and useful information from friends, fellow sufferers and the Internet.

Complementary and alternative medicine are based on mysticism and magic:

Mysticism (nature is benign and curing negative damaging effects are ignored); Magic (delusions and wishful thinking attempt to influence processes outside one’s control).

There are only a few interactions between prescription drugs and CAM known and reported. One example is the interaction between Imatinib/St. John’s Wort (hypericum perforatum), a Cyp3A-inductor. Frye et al. [3] reported an increase of Imatinib-clearance by 43% through the effect of concomitantly given St. John’s Wort.

Another publication points to probable interaction of etoposide with Echinacea [2]. In this case, it was likely that Echinacea contributed to a patient’s profound life-threatening thrombocytopenia and therefore should be avoided in patients receiving etoposide and possible other chemotherapeutic drugs that are CYP 3A4 substrates.

Green Tea is widely used as a CAM. It has been reported in the treatment of patients with asymptomatic CLL, has been reported to induce cell death in AML, has been reported to prevent prostate cancer and pre-menopausal breast cancer. On the other hand, one of the active agents of green tea, the Epigallocatechin gallate (EGCG) decreases the bio-availability of Bortezomid, one of the most active agents in the treatment of multiple myeloma [4].

Phytopharmaca	Active substance	Possible pharmacokintetic interaction
Cranberry fruit (Vaccinium macrocarpon)	Anthocyane, Flavonoide	Cyp (1A2, 2C9, 3A4)- and PgP-inhibition
Garlic (Allium sativum)	Allicin,	Cyp3A- and PgP-induktion, Cyp2C9, 2C19, 2E1-inhibition
Ginkgo (Ginkgo biloba)	Ginkgolide, Flavonoide	Cyp3A- induction, free radical scavenger properties; PD: TAH
Ginseng (Panax ginseng)	Ginsenoside	Cyp3A-induction (& inhibition)
Green tea (Camellia sinensis)	Catechine (ECG, EGCG)	Cyp3A, 2A6, 2C19, 2E1-Inhibition, increased Cyp1A2, 2B and NDAPH-Cyp450-reduktase-activity, PgP-inhibition, inhibits SULT1A1, SULT1A3 and OATP1A2, OAT1B1, OATP2B1-transport, stimulates OATP1B3-transport
St John´s wort (Hypericum perforatum)	Hyperforin, Hypericin et al.	Broad spectrum of Cyp- and PgP-induction

Table 4: Possible pharmacokinetic interaction of phytopharmaca with prescription drugs.

Conclusions

What needs to be generally considered regarding tumor therapy in older patients?

Many PK-studies in geriatric patients are contradictory, the problem being: small patient numbers, co-factors, analytical methods (standardization),

Especially, the kidney function is age-related and requires adherence to the treatment guides (e.g. SIOG),

Age-related co-morbidities and toxicity profiles of the involved active substances need to be correlated,

Polypharmacy (OTC) can create complex interactions in older patients. The medical history of an oncology patient should include his prescription drugs as well as the complimentary and alternative medicines.

More attention needs to be directed toward investigating these interactions. Education of patients, relatives and supportive staff is critical to achieve this.

There is a definite need for drug studies in elderly patients. It would be a first step if a means could be found to collect data from patients above the age cut-off of oncology studies when they are treated according to the protocol with or without “age adjustment” of drug doses. A second step may be the inclusion of elderly patients by increasing the age limit of the studies, and by designing specific chemotherapy studies for old patients in need of treatment.

Conflict of interest

All authors have no conflict of interest to declare.

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7. Hurria A, Lichtman SM. Clinical pharmacology of cancer therapies in older adults. Br J Cancer 2008; 98(3): 517-22.
8. Kardas P. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 2007; 3(2): 235-42.
9. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treatm Rev 1995; 21(1): 33-64.
10. Lichtman SM, Wildiers H, Launay-Vacher V, Steer C, Chatelut E, Aapro M. International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 2007; 43(1): 14-34.
11. Tu W, Morris AB, Li J et al. Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure. Clin Pharmacol Ther 2005; 77(3): 189-201.
12. Von Hoff DD, Layard MW, Basa P, Davis HL, Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91(5): 710-7.

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Introduction

Little is known about cancer chemotherapy in the elderly. There are only a few studies which include patients with cancer who at the same time are older than seventy years of age. It is a common practice to treat elderly patients according to existing protocols for younger patients with reduced doses and off the record; the data are not collected and analyzed. Outcome of the chemotherapy in the elderly is influenced by age-related changes in body composition and normal organ function as well as age related deficiencies in cognitive processes. Reduced visual performance and reduced manual dexterity in the elderly lead frequently to dosing and compliance errors. Another complicating factor is the increasing use of complementary and alternative medicines by elderly patients. This article will review the age related changes of body function, organ toxicity after chemotherapy in the elderly and the potential impact of complementary and alternative medicines.

Defining old is a complex process. The age of 60 or 65, roughly equivalent to the age of retirement in most Western countries, is said to be the beginning of old age. The aging process is of course a biological reality with its own dynamic largely beyond individual control. In view of the increasing age of the population in industrialized countries, a differentiation by age (61-75 years: elderly persons; 76-90 years of age: old persons; above 90 years: very old persons) seems to be useful.

There are age-related changes in body composition such as increased body fat that amounts to circa 35% at age 75, reduction of total body water that amounts to about 17% at age 60, and decrease in extracellular liquid, to circa 40% at age 65. Aside from changes in body composition, there is a reduction of normal organ function every year: cardiac output, by about 1%; liver size, by 2%; liver blood flow, 1%; kidney blood flow, by 1%; tubular function, by 1%, and glomerular filtration rate (GFR), by 1ml/min/1,73m².

Changes in biological functions in old age lead to consequences for pharmacotherapy. Reduced secretion of gastric acid and gastrointestinal tract motility might lead to a reduction of bioavailability of certain drugs. Increased body fat might change the distribution volume of lipophilic drugs. Reduction of albumin concentration might lead to an increase of non-albumin bound drugs. Reduction of GFR and tubular secretional function might lead to an accumulation of renally eliminated active substances.

Other age related deficiencies might complicate effective chemotherapy in old and very old patients. Reduced mobility and increased risk of osteoporosis increase the risk and the frequency of falls. Impairment of short-term memory leads to dosing errors and compliance problems and an increased belief in “tonics”, which might lead to drug interactions. Functional deficiencies, including emotional changes reduce the ability for directed and efficient actions and might lead to lethargy and non-adherence to treatment schedules. Reduced visual performance and reduced manual dexterity might lead to orientation problems, dosage errors and manual difficulties with splitting of tablets.

Polypharmacotherapy leads to particular problems in the elderly patient population. According to one study, the PRISCUS Project, every health insured older patient is prescribed 3.6 drugs on the average. Over-the-counter (OTC) products are added to this number. 25% of the prescribed drugs are potentially inadequate medications. [1]

The problem of non-compliance is already evident in twice daily (bid) vs. once daily (qd) dosing of medications. Published data on other twice daily medications (eg. metformine, glipizide, metoprolol) show that adequate adherence (defined as greater than 80% of pills taken) may be only 52-65% [11]. A Polish study comparing beta-blockers given once daily (betaxolol) or twice daily (metoprolol) to patients with stable angina pectoris showed 58.6% vs. 42.0% for doses taken in the correct time window and 77.4% vs. 53.1% for correct interdose intervals in favor of the drug taken once daily [8].

Hamaker et al. [6] state that currently ongoing trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients, as those outcome measures, that are of primary importance to this patient population are still included in only a minority of studies. A broader database of chemotherapy data in elderly patients is needed to enable the oncologist to deliver evidence based and patient focused cancer care.

The experience with chemotherapeutic agents and their pharmacokinetics in patients with old age is limited. Hurria and Lichtman [7] analyze clinical pharmacology of cancer therapies in older patients in a mini review. In 18 studies older and younger patient groups were compared. When treated with Paclitaxel (3 studies), Docetaxel (4 studies), Oxaliplatin (1 study), Temozolomide (1 study), Vinorelbine (2 studies), 5- Fluorouracil (1 study), Capecitabine (1 study), Etoposide (3 studies), Doxorubicin (2 studies) only 5/18 studies could actually demonstrate age-related differences in clinical pharmacokinetics, but this remains controversial.

The International Society of Geriatric Oncology (SIOG) arrived at the following recommendations (Table 1) for the adjustment of dosing in elderly patients, according to the underlying renal function but also including clinical experience [10].

INN	90-60 ml/min	60-30 ml/min	30-15 ml/min
Melphalan	100-200 mg/m2	75%	50%
Oxaliplatine	85-100 mg/m2	100%	100%
Fludarabine	25 mg/m2	20 mg/m2	15 mg/m2
Capecitabine	1250 mg/m2 every 12 h	950 mg/m2 every 12 h	Contraindicated

Table 1: Dosing adjustment in elderly cancer patients. Recommendations of the International Society of Geriatric Oncology (SIOG) according to the underlying renal function [10]

Kintzel and Dorr [9] recommended dose modification for another set of antineoplastic drugs for patients with renal dysfunction (Table 2). The dose modification is clearly related to the fraction of renally excreted active or toxic moiety of the drug. Etoposide with a fraction of 32% requires nearly no reduction in patients with a creatinine clearance of 30 ml/min., whereas methotrexate with a fraction of 77% of renally excreted or toxic moiety requires a reduction of 50% in patients with INN of 45 ml/min. and should not be given to patients with lower renal functions.

INN	f	60 ml/min	45 ml/min	30 ml/min
Etoposide	32%	0.85	0.80	0.75
Hydroxyurea	36%	0.85	0.80	0.75
Dacarbazine	41%	0.80	0.75	0.70
Fludarabine	44%	0.80	0.75	0.65
Lomustine (CCNU)	50%	0.75	0.70	-
Bleomycine	62%	0.70	0.60	-
HD-AraC, MTX	77%	0.65	0.50	-

Table 2. Dose modification for antineoplastic drugs in renal dysfunction [9]

Decreased organ functions, besides renal clearance that may lead to consequences for pharmacotherapy, are heart function, with a reduction of myocytes and reduction of dromotrophy, eventually: left ventricular ejection function (LVEF) that may lead to congestive heart failure and cardiac arrhythmias. Regarding the nervous system, co-morbidities, such as Diabetes Mellitus may lead to higher risk for sensory neuropathies. Reduced vital and diffusion capacity of the lung may lead to higher risk for lung toxic side-affects. The reduction of bone marrow reserve may lead to severe cytopenias. An increase in fibrinogen concentration may lead to a higher risk for venous thromboembolism.

An older study from von Hoff et al. [12] compares cumulative doses of Doxorubicin on incidence of cardiotoxicity in patients aged 40-59 vs. in patients older than 60 years of age. There was an increase in cardiotoxicity with all dose ranges in the older patient group. This difference was seen in the groups that received Doxorubicin every seven days as well as in the group that received the drug every three weeks.

Cumulative dose (mg/m2)	q7d 40-59 y	q7d > 60 y	q3w 40-59 y	q3w > 60 y
300	0.6	0.9	2.2	3.4
400	0.7	1.2	2.3	4.6
500	1.5	2.3	5.8	8.9
600	3.9	6.1	14.9	22.4
700	8.7	13.2	30.5	43.5

Table 3: Doxorubicin-induced cardiotoxicity (%) related to cumulative dose. Modified from [12].

Newer orally available “targeted” anti-cancer agents are of special interest in the elderly patient group. E.c., target protein produced by bcr-abl fusion gene can be attacked by Imatinib (GLIVEC), Dasatinib (SPRYCEL), Nilotinib (TASIGNA), Bosutinib (BOSULIF), and Ponatinib (ICLUSIG). The epidermal growth factor receptor (EGFR) is target for several drugs like Erlotinib (TARCEVA), Imatinib (GLIVEC), Afatinib (GILOTRIF), and Lapatinib (TYVERB). Other drugs like Sorafenib (NEXAVAR) and Sunitinib (SUTENT) interfere with Vascular Endothelial Growth Factor (VEGF). Other drugs like Vemurafenib (ZELBORAF) and Dabrafenib (TAFINLAR) interfere with mutations of BRAF, the serine/threonine-protein kinase. Other targeted therapies include Crizotinib (XALKORI), Everolimus (AFINITOR), Vismodegib (ERIVEDGE), Trametinib (MEKINIST), and Ibrutinib (IMBRUVICA) as well as Thalidomide, Lenalidomide (REVLIMID), and Pomalidomide (IMNOVID) which in partly modulate the immune system.

Particular attention needs to be directed toward the toxicity of targeted anti-cancer therapy in the elderly [5]. The older human population compared to the younger population shows more toxicity in several areas. Imatinib shows more hematologic and non-hematologic toxicities in older patients. Bevacizumab shows more thromboembolism, more fatigue and more asthenia. Bortezomib shows more gastrointestinal problems, fatigue and neuropathies. Thalidomide shows more deeper vein thrombosis. Lenalidomide needed to be discontinued more frequently in the older population related to hematological and non-hematological toxicities. No age related differences in toxicity were seen in Trastuzumab.

A well-known example for influencing therapeutically needed drug levels are the Calcineurin inhibitors (CNI). Drugs which inhibit the Cytochrome P450 3A4 enzyme system that metabolizes CNIs lead to an increased risk for toxicity, drugs which induce enzymes catabolizing CNIs lead to a decreased drug concentrations and therefore an increased risk of treatment failure. Therefore, close attention needs to be given to the drug concentration, particularly if other drugs are given which induce or inhibit enzymes.

A particular problem of drug interference constitutes over-the-counter (OTC) and complementary and alternative medicine (CAM). There are many-fold explanations:

• OTCs require no prescription, “therefore they cannot be dangerous”.
• There is a need to address personal fears and worries
• Desire to do something for one’s health
• Therapy considered to be harmless (natural)
• Belief: “natural” things are good
• Can do no harm
• Strengthen the immune system
• Intriguing and useful information from friends, fellow sufferers and the Internet.

Complementary and alternative medicine are based on mysticism and magic:

Mysticism (nature is benign and curing negative damaging effects are ignored); Magic (delusions and wishful thinking attempt to influence processes outside one’s control).

There are only a few interactions between prescription drugs and CAM known and reported. One example is the interaction between Imatinib/St. John’s Wort (hypericum perforatum), a Cyp3A-inductor. Frye et al. [3] reported an increase of Imatinib-clearance by 43% through the effect of concomitantly given St. John’s Wort.

Another publication points to probable interaction of etoposide with Echinacea [2]. In this case, it was likely that Echinacea contributed to a patient’s profound life-threatening thrombocytopenia and therefore should be avoided in patients receiving etoposide and possible other chemotherapeutic drugs that are CYP 3A4 substrates.

Green Tea is widely used as a CAM. It has been reported in the treatment of patients with asymptomatic CLL, has been reported to induce cell death in AML, has been reported to prevent prostate cancer and pre-menopausal breast cancer. On the other hand, one of the active agents of green tea, the Epigallocatechin gallate (EGCG) decreases the bio-availability of Bortezomid, one of the most active agents in the treatment of multiple myeloma [4].

Phytopharmaca	Active substance	Possible pharmacokintetic interaction
Cranberry fruit (Vaccinium macrocarpon)	Anthocyane, Flavonoide	Cyp (1A2, 2C9, 3A4)- and PgP-inhibition
Garlic (Allium sativum)	Allicin,	Cyp3A- and PgP-induktion, Cyp2C9, 2C19, 2E1-inhibition
Ginkgo (Ginkgo biloba)	Ginkgolide, Flavonoide	Cyp3A- induction, free radical scavenger properties; PD: TAH
Ginseng (Panax ginseng)	Ginsenoside	Cyp3A-induction (& inhibition)
Green tea (Camellia sinensis)	Catechine (ECG, EGCG)	Cyp3A, 2A6, 2C19, 2E1-Inhibition, increased Cyp1A2, 2B and NDAPH-Cyp450-reduktase-activity, PgP-inhibition, inhibits SULT1A1, SULT1A3 and OATP1A2, OAT1B1, OATP2B1-transport, stimulates OATP1B3-transport
St John´s wort (Hypericum perforatum)	Hyperforin, Hypericin et al.	Broad spectrum of Cyp- and PgP-induction

Table 4: Possible pharmacokinetic interaction of phytopharmaca with prescription drugs.

Conclusions

What needs to be generally considered regarding tumor therapy in older patients?

Many PK-studies in geriatric patients are contradictory, the problem being: small patient numbers, co-factors, analytical methods (standardization),

Especially, the kidney function is age-related and requires adherence to the treatment guides (e.g. SIOG),

Age-related co-morbidities and toxicity profiles of the involved active substances need to be correlated,

Polypharmacy (OTC) can create complex interactions in older patients. The medical history of an oncology patient should include his prescription drugs as well as the complimentary and alternative medicines.

More attention needs to be directed toward investigating these interactions. Education of patients, relatives and supportive staff is critical to achieve this.

There is a definite need for drug studies in elderly patients. It would be a first step if a means could be found to collect data from patients above the age cut-off of oncology studies when they are treated according to the protocol with or without “age adjustment” of drug doses. A second step may be the inclusion of elderly patients by increasing the age limit of the studies, and by designing specific chemotherapy studies for old patients in need of treatment.

Conflict of interest

All authors have no conflict of interest to declare.

References

1. Amann U, Schmidt N, Garbe E. Prescribing of potentially inappropriate medications for the elderly: an analysis based on the PRISCUS list. Dtsch Arztebl Int 2012; 109(5): 69-75.
2. Bossaer JB, Odle BL. Probable etoposide interaction with Echinacea. J Diet Suppl 2012;9(2): 90-5.
3. Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 2004; 76(4): 323-9.
4. Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schönthal AH. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 2009; 113(23): 5927-37.
5. Gonsalves W, Ganti AK. Targeted anti-cancer therapy in the elderly. Crit Rev Oncol Hematol 2011; 78(3): 227-42.
6. Hamaker ME, Stauder R, van Munster BC. Ongoing clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points? Ann Oncol 2014; 25(3): 675-81.
7. Hurria A, Lichtman SM. Clinical pharmacology of cancer therapies in older adults. Br J Cancer 2008; 98(3): 517-22.
8. Kardas P. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 2007; 3(2): 235-42.
9. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treatm Rev 1995; 21(1): 33-64.
10. Lichtman SM, Wildiers H, Launay-Vacher V, Steer C, Chatelut E, Aapro M. International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 2007; 43(1): 14-34.
11. Tu W, Morris AB, Li J et al. Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure. Clin Pharmacol Ther 2005; 77(3): 189-201.
12. Von Hoff DD, Layard MW, Basa P, Davis HL, Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91(5): 710-7.

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Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.</p> <p class="Summery_Rus" lang="ru-RU">Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (<span class="CharOverride-4">Hypericum perforatum</span>), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.</p> <p class="Summery_Rus" lang="ru-RU">Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. 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["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(6) { [0]=> string(4) "1180" [1]=> string(4) "1181" [2]=> string(4) "1182" [3]=> string(4) "1183" [4]=> string(4) "1184" [5]=> string(4) "1185" } ["VALUE"]=> array(6) { [0]=> string(2) "15" [1]=> string(2) "16" [2]=> string(2) "17" [3]=> string(2) "18" [4]=> string(2) "19" [5]=> string(2) "20" } ["DESCRIPTION"]=> array(6) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(6) { [0]=> string(2) "15" [1]=> string(2) "16" [2]=> string(2) "17" [3]=> string(2) "18" [4]=> string(2) "19" [5]=> string(2) "20" } ["~DESCRIPTION"]=> array(6) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "923" ["VALUE"]=> string(19) "25.01.2015 17:40:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "25.01.2015 17:40:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "924" ["VALUE"]=> string(19) "23.06.2015 17:40:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "23.06.2015 17:40:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "925" ["VALUE"]=> string(19) "08.09.2015 17:36:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "08.09.2015 17:36:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "21" ["VALUE"]=> string(2) "11" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(2) "11" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(3) { [0]=> string(2) "24" [1]=> string(2) "25" [2]=> string(2) "84" } ["VALUE"]=> array(3) { [0]=> string(2) "11" [1]=> string(2) "12" [2]=> string(2) "14" } ["DESCRIPTION"]=> array(3) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(3) { [0]=> string(2) "11" [1]=> string(2) "12" [2]=> string(2) "14" } ["~DESCRIPTION"]=> array(3) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "97" ["VALUE"]=> array(2) { ["TEXT"]=> string(225) "<p class="Autor_Rus" lang="ru-RU">Аксель Р. Цандер¹, Рене Дж. Хорнунг², Ханс П. Липп³</p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(157) "

Аксель Р. Цандер¹, Рене Дж. Хорнунг², Ханс П. Липп³

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "98" ["VALUE"]=> array(2) { ["TEXT"]=> string(756) "<p class="Autor_place_work-Rus">¹Отдел трансплантации стволовых клеток, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия </p> <p class="Autor_place_work-Rus">²Университетский медицинский центр Гамбург-Эппендорф, Германия</p> <p class="Autor_place_work-Rus">³<span class="affiliation">Отдел госпитальной фармации, Университет Тюбинген, Тюбинген, Германия</span></p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(632) "

¹Отдел трансплантации стволовых клеток, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия

²Университетский медицинский центр Гамбург-Эппендорф, Германия

³Отдел госпитальной фармации, Университет Тюбинген, Тюбинген, Германия

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "99" ["VALUE"]=> array(2) { ["TEXT"]=> string(5589) "<h2>Резюме</h2><p class="Summery_Rus" lang="ru-RU">Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.</p> <p class="Summery_Rus" lang="ru-RU">Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (<span class="CharOverride-4">Hypericum perforatum</span>), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.</p> <p class="Summery_Rus" lang="ru-RU">Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5459) "

Резюме

Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.

Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (Hypericum perforatum), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.

Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов.

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Axel R. Zander¹, René J. Hornung², Hans-Peter Lipp³

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Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany¹

University Medical Centre Hamburg-Eppendorf, Hamburg, Germany²

Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany³

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Summary

Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.

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Axel R. Zander¹, René J. Hornung², Hans-Peter Lipp³

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Axel R. Zander¹, René J. Hornung², Hans-Peter Lipp³

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Summary

Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.

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Summary

Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.

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Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany¹

University Medical Centre Hamburg-Eppendorf, Hamburg, Germany²

Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany³

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Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany¹

University Medical Centre Hamburg-Eppendorf, Hamburg, Germany²

Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany³

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Аксель Р. Цандер¹, Рене Дж. Хорнунг², Ханс П. Липп³

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Аксель Р. Цандер¹, Рене Дж. Хорнунг², Ханс П. Липп³

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string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "21" ["VALUE"]=> string(2) "11" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(2) "11" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(56) "Axel R. Zander" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(2) "99" ["VALUE"]=> array(2) { ["TEXT"]=> string(5589) "<h2>Резюме</h2><p class="Summery_Rus" lang="ru-RU">Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.</p> <p class="Summery_Rus" lang="ru-RU">Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (<span class="CharOverride-4">Hypericum perforatum</span>), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.</p> <p class="Summery_Rus" lang="ru-RU">Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов. </p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5459) "

Резюме

Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.

Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (Hypericum perforatum), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.

Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов.

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Резюме

Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.

Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (Hypericum perforatum), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.

Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов.

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²Университетский медицинский центр Гамбург-Эппендорф, Германия

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²Университетский медицинский центр Гамбург-Эппендорф, Германия

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                    [TEXT] => <p class="Summery_Rus" lang="ru-RU">В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (<span lang="en-US">VEGF</span>) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии <span lang="en-US">VEGF</span> при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями <span lang="en-US">VEGF</span> и частотой рецидивов после алло-ТГСК. Уровни <span lang="en-US">VEGF</span> анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни <span lang="en-US">VEGF</span>, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни <span lang="en-US">VEGF</span> в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; <span lang="en-US">HR</span> 3,15, 95%; <span lang="en-US">CI</span> 1,34-7,40, <span lang="en-US">p</span>=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, <span lang="en-US">p</span>=0,001), но не многофакторном анализе (95%<span lang="en-US">CI</span> 0.84-5.76, <span lang="en-US">p</span>=0,102). Высокие уровни <span lang="en-US">VEGF</span> <span lang="en-US">A</span> перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, <span lang="en-US">p</span>=0,001, <span lang="en-US">HR</span> 3,15, 95%<span lang="en-US">CI</span> 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, <span lang="en-US">p</span>=0.60), поскольку многие пациенты были успешно пролечены после рецидива. </p>
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В ряде исследований проводилось изучение прогностического значения маркеров повреждения эндотелия для анализа риска различных исходов аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). При этом, однако, редко сравнивали информативность различных лабораторных маркеров при длительных сроках наблюдения. В настоящей работе мы оценивали прогностическую значимость фактора роста сосудистого эндотелия (VEGF) в плазме крови и содержания циркулирующих эндотелиальных клеток (ЦЭК) как возможных факторов, ассоциированных с ранней и поздней смертностью, не связанной с рецидивами. Учитывая известный негативный прогностический эффект экспрессии VEGF при онкогематологических заболеваниях, леченных цитостатической терапией, другой целью работы была оценка ассоциаций между уровнями VEGF и частотой рецидивов после алло-ТГСК. Уровни VEGF анализировали у 91 пациента перед началом кондиционирующей терапии, в день трансплантации и в день приживления трансплантата. Содержание ЦЭК в крови определяли у 55 больных из той же группы и в те же сроки. Как уровни VEGF, так и содержание ЦЭК коррелировали с ранней, но не более поздней нерецидивной смертностью. Высокие уровни VEGF в день 0 при использовании мультивариантного анализа были ассоциированы с более высокой однолетней безрецидивной выживаемостью (55% против 22%; HR 3,15, 95%; CI 1,34-7,40, p=0,009), тогда как высокое содержание ЦЭК до кондиционирования было ассоциировано с повышенной безрецидивной выживаемостью при унивариантном (69% против 20%, p=0,001), но не многофакторном анализе (95%CI 0.84-5.76, p=0,102). Высокие уровни VEGF A перед кондиционированием были ассоциированы с повышенной частотой рецидивов в течение 1 года (55% против 22%, p=0,001, HR 3,15, 95%CI 1,34-7,40), но не были связаны с поздними рецидивами и общей 3-летней выживаемостью (50% против 42%, соответственно, p=0.60), поскольку многие пациенты были успешно пролечены после рецидива. 
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Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol, 
Vladimir N. Vavilov, Boris V. Afanasyev
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	 A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p&gt;0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.
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	 A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p>0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.

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                    [TEXT] => <p class="Autor_place_work-Rus"><sup>1</sup>Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова</p>
<p class="Autor_place_work-Rus"><sup>2</sup>Институт цитологии Российской Академии наук, Санкт-Петербург</p>
<p class="Autor_place_work-Rus"><sup>3</sup>Российский центр радиологии и хирургических технологий, Санкт-Петербург</p>
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1Первый Санкт-Петербургский государственный медицинский Университет им. И.П.Павлова
2Институт цитологии Российской Академии наук, Санкт-Петербург
3Российский центр радиологии и хирургических технологий, Санкт-Петербург
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                    [TEXT] => <h2>Резюме</h2><p class="Summery_Rus" lang="ru-RU">Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8<span class="CharOverride-12">+</span>0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами. </p>
<p class="Summery_H">Результаты</p>
<p class="Summery_Rus" lang="ru-RU">Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p&lt;0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p&lt;0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p&lt;0.05), а также отсутствие акинетических участков. </p>
<p class="Summery_H">Заключение</p>
<p class="Summery_Rus" lang="ru-RU">Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов. </p>
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Резюме
Введение. На протяжении последних 10 лет изучались различные варианты клеточной терапии, направленной на улучшение результатов лечения инфаркта миокарда (ИМ), включая кардиомиопластику. Аутологичный костный мозг широко применяется в качестве источника изолированных препаратов клеток, в т.ч. свежеполученные мононуклеарные клетки (МНК) и культивированные мультипотентные мезенхимные стволовые клетки (ММСК). Целью нашего пилотного исследования было сравнение кратко- и долгосрочных эффектов интрамиокардиального введения МНК и ММСК на клиническое течение и исходы экспериментального ИМ. Материалы и методы. Эксперименты проводили на кроликах Шиншилла весом 2.8+0.2 кг. ИМ моделировали путем лигирования передней нисходящей левой коронарной артерии. Фракцию МНК получали из аспирата костного мозга. Культуру ММСК выращивали путем пассажей МНК в среде Игла с 10% фетальной телячьей сыворотки. Инъекции суспензий МНК и ММСК осуществляли в 6 точек области инфаркта. Выжившие животные были разделены на 4 группы (по 13 в каждой): группа 1 (контроль); группа 2 (плацебо); группа 3 (введение ММСК), и группа 4 (введение МНК). ЭКГ и эхо-КГ проводились всем животным од хирургического вмешательства, а также через 1 мес. и 1 год после него. Показатели перфузии миокарда оценивали с помощью технологии SPECT. Размеры зоны ИМ (зоны перфузии) определяли посредством окрашивания срезов сердечной ткани с помощью 2,3,5-ТТС. Также проводили рутинные гистологические исследования срезов миокарда. Степень васкуляризации различных областей миокарда оценивали морфологическими методами. 
Результаты
Внутрисердечная пересадка аутологичных клеток костного мозга (МНК и ММСК) в области экспериментального ИМ у кроликов в его острой фазе приводила к модификации его естественного развития и вызывала принципиально различные морфофункциональные исходы. Через 10 дней после коронарной окклюзии у всех животных отмечалось резкое снижение перфузии передней стенки левого желудочка мио­карда. (p<0,05). В то же время у животных, леченых ММСК или МНК, уровни перфузии были снижены в меньшей мере, нежели в контроле и группе плацебо (p<0.05). Спустя 1,5 мес. после лечения наблюдалось постепенное восстановление средних уровней перфузии поврежденного миокарда в группах, леченных ММСК и МНК. Эти изменения подтверждены перфузионной томосцинтиграфией миокарда через 1,5 и 12 месяцев после ИМ. Гистологические исследования показали, что после трансплантации ММСК отмечалась картина микроочагового кардиосклероза, а впоследствии – восстановлении структуры миокарда, тогда как после инъекций МНК наблюдалось развитие фибротической аневризмы, поражающей как левый, так и правый желудочек. Через год после хирургического вмешательства отмечен более выраженный положительный эффект трансплантации при введении ММСК, т.е. почти полное восстановление по всем функциональным параметрам (фракция выброса левого желудочка, показатель EDSLV, конечный диастолический размер левого желудочка, скорость кровотока в восходящей аорте) через 12 мес. после операции (p<0.05), а также отсутствие акинетических участков. 
Заключение
Инъекции ММСК были ассоциированы с выраженным терапевтическим эффектом, а именно – снижением области повреждения миокарда. Напротив, трансплантация МНК сопровождалась негативным эффектом, с расширением области поражения миокарда и нарушением систолических функций. Трансплантация ММНК, и МНК приводят к стимуляции неоангиогенеза и улучшению перфузии в области экспериментального ИМ у кроликов. 
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                    [TEXT] => <p class="Autor">Vladimir V. Davydenko<sup>1</sup>, Andrey A. Matyukov<sup>1</sup>, Timur D. Vlasov<sup>1</sup>, Natalya V. Tsupkina<sup>2</sup>, Anatoly N. Yalfimov<sup>3</sup>, <br>Georgy P. Pinaev<sup>2</sup>,  Khalida K. Amineva<sup>1</sup></p>
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Vladimir V. Davydenko1, Andrey A. Matyukov1, Timur D. Vlasov1, Natalya V. Tsupkina2, Anatoly N. Yalfimov3, 
Georgy P. Pinaev2,  Khalida K. Amineva1
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			<p class="Autor_place_work"><span class="CharOverride-2" lang="en-US">2</span><span lang="en-US">Institute of Cytology, Russian Academy of Sciences, St.Petersburg</span></p>
			<p class="Autor_place_work"><span class="CharOverride-2" lang="en-US">3</span><span lang="en-US">Russian Center of Radiology and Surgical Technologies, St.Petersburg</span></p>
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1FirstSt.Petersburg State I.Pavlov Medical University 
			
2Institute of Cytology, Russian Academy of Sciences, St.Petersburg
			
3Russian Center of Radiology and Surgical Technologies, St.Petersburg
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                    [TEXT] => <h2>Summary</h2><p class="Summery">Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8<span class="CharOverride-12">+</span>0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way. </p>
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Summary
Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8+0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way. 
Results
Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p<0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p<0.05), and absence of akinetic areas. 
Conclusions 
MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area. 

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                    [TEXT] => <p class="Summery">Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.</p>
<p class="Summery">Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии. </p>
<p class="Summery">Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона  гена <span lang="en-US">NBN</span>. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.</p>
<p class="Summery">Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1).  Наличие мутации 657-661<span lang="en-US">delACAAA</span> в гене <span lang="en-US">NBN</span> и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (<span lang="en-US">III</span> стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после  трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.</p>
<p class="Summery">Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.</p>
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Актуальность: Синдром Ниймеген (СН) характеризуется хромосомной нестабильностью, комбинированным иммунодефицитом, повышенной чувствительностью к радиоактивному излучению и предрасположенностью к развитию лимфоидных неоплазий. Специфических методов лечения СН нет, но считается оправданным проведение трансплантации гемопоэтических стволовых клеток (ТГСК) пациентам с рецидивами или с рефрактерными формами лимфомы/лейкоза.
Цель: анализ данных по диагностике и лечению белорусских пациентов с СН и обсуждение показаний к проведению аллогенной трансплантации при этой патологии. 
Пациенты и методы: Диагноз первичного иммунодефициты (ПИД) установлен у 238 пациентов, включая 19 случаев СН. Анализ ДНК проводился методом прямого секвенирования 6 экзона  гена NBN. Гистологическая верификация лимфоидных неоплазий проводилась в соответствии с классификацией ВОЗ 2008 года. Пациенты получали протокольную или индивидуальную химиотерапию.
Результаты: СН составил 8.0% от всех случаев ПИД и был диагностирован в возрасте от 0.3 до 21.6 лет (медиана – 7.1).  Наличие мутации 657-661delACAAA в гене NBN и комбинированного иммунодефицита было подтверждено у всех пациентов. Злокачественные лимфопролиферативные заболевания развились у 9 (47.4%) пациентов с СН в возрасте от 4.3 до 21.6 лет (медиана – 10.7), Т-клеточные в большинстве (77.8%) случаев, острый лейкоз – у 4, неходжкинская лимфома (III стадия) – у 5. Полная ремиссия (ПР) была достигнута у 66.7% пациентов. События на лечении: смерть от инфекций на этапе индукции или в ПР – 3, прогрессирование/рецидив – 3, вторая лимфома – 1. Всего умерли 7 пациентов с СН, все после развития гемобластоза. Двоим пациентам с Т-зрелой лимфомой/лейкозом, не ответившим на индукционную химиотерапию, была проведена неродственная ТГСК в 1ПР. Эти пациенты живы, без признаков рецидива 6 и 13 месяцев после  трансплантации. Также ТГСК от совместимого родственного донора была проведена 9.8 лет назад мальчику без опухоли, но с инфекционными и аутоиммунными осложнениями. Всем троим пациентам было проведено немиелоаблативное кондиционирование, без тяжёлых осложнений.
Заключение: СН должен диагностироваться рано. Учитывая прогрессирующую иммунологическую недостаточность и высокий риск развития лимфоидных неоплазий с неопределённым потенциалом излечения, мы считаем оправданным проведение аллогенной ТГСК с немиелоаблативным режимом кондиционирования пациентам с СН с тяжелой иммунологической недостаточностью или с лимфомой/лейкозом в 1ПР.
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Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus
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                    [TEXT] => <h2>Summery </h2>
<p class="Summery">
	 Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.
</p>
<p class="Summery">
	 Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.
</p>
<p class="Summery">
	 Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.
</p>
<p class="Summery">
	 Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.
</p>
<p class="Summery">
	 Conclusions:<span class="CharOverride-10"> </span>NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1<sup>st</sup> complete remission.
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Summery 

	 Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.


	 Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.


	 Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.


	 Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.


	 Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1st complete remission.

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Борис В. Афанасьев, Марина Попова, Сергей Бондаренко, Илья Зюзгин, Елена Бабенко, Александр Алянский, Сюзанна Морш, Ян ван Лунзен, Борис Фезе, Аксель Цандер, Людмила С. Зубаровская 
		
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                    [TEXT] => <p class="Summery_Rus" lang="ru-RU">Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти <span lang="en-US">HLA</span>-совместимого донора с гомозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32. Алло-ТГСК от донора без мутации гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена <span lang="en-US">CCR</span>5 <span lang="en-US">del</span> 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.</p>
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Внедрение высокоактивной антиретровирусной терапии (ВААРТ) в 1996 году изменило ситуацию с лечением ВИЧ-инфекции. Несмотря на широкое применение ВААРТ, пациенты с ВИЧ по-прежнему относятся к группе высокого риска развития злокачественных опухолей кроветворной и лимфатической ткани. Трансплантация гемопоэтических стволовых клеток (ТГСК) является стандартным лечением для большинства этих опухолей. Противоопухолевая химиотерапия (ПХТ), включая высокодозную ПХТ с аутологичной ТГСК, так же эффективна как у пациентов без ВИЧ при применении ВААРТ. В то время как результаты аллогенной ТГСК (алло-ТГСК) неизвестны, публикации ограничены отдельными случаями или небольшими группами пациентов. Часть пациентов потенциально могут быть излечены от двух заболеваний при проведении алло-ТГСК от донора с гомозиготной мутацией гена CCR5 del 32: злокачественная опухоль и ВИЧ, что было продемонстрировано у «Берлинского пациента». Встречаемость мутации гена CCR5 del 32 в популяции невысока, такой способ лечения малоперспективен для большинства пациентов с ВИЧ и онкогематологическим заболеванием из-за низкой вероятности найти HLA-совместимого донора с гомозиготной мутацией гена CCR5 del 32. Алло-ТГСК от донора без мутации гена CCR5 del 32 на фоне ВААРТ выглядело более перспективным, но опыт «Бостонских пациентов» продемонстрировал неэффективность такого подхода. При этом, другие аспекты, включающие тип донора, режим кондиционирования и профилактики РТПХ, посттрансплантационную иммуноадоптивную терапию, поддерживают интерес к алло-ТГСК у пациентов с ВИЧ, как потенциального метода излечения от двух заболеваний. Нет опубликованных данных об алло-ТГСК от донора с гетерозиготной мутацией гена CCR5 del 32, а ВААРТ в посттрансплантационном периоде может быть использована в качестве компонента профилактики РТПХ. Мы представляем собственный опыт алло-ТГСК у пациентов с острыми лейкозами и ВИЧ-инфекцией, выполненные в Санкт-Петербурге.
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                    [TEXT] => <p class="Autor">Boris V. Afanasyev<sup>1</sup>, Marina Popova<sup>1</sup>, Sergey Bondarenko<sup>1</sup>, Ilya Zyuzgin<sup>2</sup>, Elena Babenko<sup>1</sup>, Aleksander Alyanskiy<sup>1</sup>, Susanne Morsch<sup>3</sup>, Jan van Lunzen<sup>4</sup>, Boris Fehse<sup>5</sup>, Axel R. Zander <sup>5</sup>, Ludmila S. Zubarovskaya<sup>1</sup></p>
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Boris V. Afanasyev1, Marina Popova1, Sergey Bondarenko1, Ilya Zyuzgin2, Elena Babenko1, Aleksander Alyanskiy1, Susanne Morsch3, Jan van Lunzen4, Boris Fehse5, Axel R. Zander 5, Ludmila S. Zubarovskaya1
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		<sup>1</sup>Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,
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		First Pavlov State Medical University of Saint-Petersburg, Russia
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		<sup>2</sup>Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia
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		<sup>3</sup>Stefan Morsch Stiftung, Birkenfeld, Germany
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		<sup>4</sup>Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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		<sup>5</sup>Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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		Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation
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		First Pavlov State Medical University of Saint-Petersburg, Russia
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		1Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,
	
	

		First Pavlov State Medical University of Saint-Petersburg, Russia
	
	

		2Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia
	
	

		3Stefan Morsch Stiftung, Birkenfeld, Germany
	
	

		4Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
	
	

		5Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
	
	

		Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation
	
	

		First Pavlov State Medical University of Saint-Petersburg, Russia
	
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                    [TEXT] => <h2 class="Summery"> <span style="font-family: Arial, sans-serif;">Summery</span><br>
 </h2>
<p class="Summery">
	 Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.
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 Summery

 

	 Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.

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            [VERSION] => 1
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                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
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                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
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            [VALUE] => 7
            [DESCRIPTION] => 
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            [VALUE_XML_ID] => 
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            [~NAME] => Авторы
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            [LIST_TYPE] => L
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            [XML_ID] => 25
            [FILE_TYPE] => 
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            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
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                    [height] => 200
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            [HINT] => 
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            [VALUE] => Array
                (
                    [TEXT] => <p class="Autor_Rus" lang="ru-RU">Тапани Рууту<sup>1</sup>, Христиан Кенеке<sup>2</sup>, Гжегож В. Басак<sup>3</sup></p>
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            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
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Тапани Рууту1, Христиан Кенеке2, Гжегож В. Басак3
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            [~DESCRIPTION] => 
            [~NAME] => Авторы
            [~DEFAULT_VALUE] => Array
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            [VALUE] => Array
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                    [TEXT] => <p class="Autor_place_work-Rus"><sup>1</sup>Центральный госпиталь Университета Хельсинки, Центр исследований рака, Отделение трансплантации стволовых клеток, Хельсинки, Финляндия;</p>
			<p class="Autor_place_work-Rus"><sup>2</sup>Высшая медицинская Школа Ганновера, Отдел Гематологии и гемостаза, Ганновер, Германия;</p>
			<p class="Autor_place_work-Rus"><sup>3</sup>Варшавский медицинский университет, Отдел гематологии, онкологии и внутренних болезней, Варшава, Польша</p>
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                (
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2Высшая медицинская Школа Ганновера, Отдел Гематологии и гемостаза, Ганновер, Германия;
			
3Варшавский медицинский университет, Отдел гематологии, онкологии и внутренних болезней, Варшава, Польша
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            [~DESCRIPTION] => 
            [~NAME] => Организации
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            [TIMESTAMP_X] => 2015-09-02 18:01:20
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<p class="Summery_Rus ParaOverride-6" lang="ru-RU">Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО. </p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.</p><p class="Summery_Rus ParaOverride-6" lang="ru-RU">Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа. </p>
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Резюме
Трансплантация солидных органов (ТСО) широко применяется для лечения пациентов с органной недостаточностью терминальной степени. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) представляет собой метод интенсивной терапии , который сам по себе часто вызывает повреждение и недостаточность различных органов, что является потенциальным показанием к ТСО. 
Настоящий обзор основан, в основном, на нескольких небольших исследованиях больных, которым выполнялась как ТГСК, так и ТСО, проведенных под эгидой Европейского общества трансплантации костного мозга в группе. Так, Koenecke et al. опубликовали сводку по 107 трансплантационным центрам, где проведено 67000 аллогенных ТГСК с 1984 по 2007 гг. Из них, В 28 центрах были выполнены 45 ТСО в связи с органной недостаточностью после ТГСК, в том числе 15 пересадок почек, 15 – печени, 13 – легких lung, 1 – сердца. Кроме того, рассматриваются и данные о ряде других исследований, в частности анализ результатов трансплантации легких, выполненных в связи с облитерирующим альвеолитом на фоне хронической реакции «трансплантат против хозяина» после аллогенной ТГСК, проведенной для лечения онкогематологических заболеваний (Holm et al., 2013). Средний срок от ТГСКT до пересадки легких составил 8,2 года (от 0,7 до 16 лет) при возрасте пациентов от 16 до 55 лет. При средних сроках наблюдения 4,2 года, выживаемость больных составила 90% через 1 год и 75% через 5 лет после пересадки легких.
У реципиентов кроветворных клеток с применением ТСО после ТГСК, весьма вероятны иммунологические осложнения. Стратегии иммуносупрессии, принятые при этих двух типах трансплантации, существенно различаются. Однако частота отторжения трансплантата незначительно отличается от той, которая наблюдается у пациентов после пересадки солидных органов. Возникновение или отсутствие реакции «трансплантат против хозяина» несущественно влияет на конечный исход.
Существует множество вероятных механизмов отторжения трансплантата в этих ситуациях. Так, иммунный ответ может быть направлен против чужеродных молекул HLA, так как HLA-совместимость кроветворного трансплантата с тканями реципиента намного выше, чем совместимость донорского органа. Однако можно предположить, что алло-ТГСК может оказать и толерогенный эффект, позволяющий сохранить солидный орган без иммуносупрессии. Кондиционирование перед аллогенной ТГСК и инфекционные осложнения могут повысить иммуногенность пересаженного органа посредством повышения уровней презентации антигенов, повышения костимулирующих сигналов, изменений свойств сосудистого эндотелия и ингибируюших влияний Т-регуляторных клеток. В то же время большинство донорских органов подобраны к пациенту по группам крови, что не требуется для доноров гемопоэтических клеток. Таким образом, большинство кроветворных трансплантатов несовместимы с тканями солидного органа, что может повлиять на его переживание. Кроме того, у большинства больных после ТСО и ТГСК иммуносупрессивные режимы изменяются на протоколы, применяемые при алло-ТГСК, что может быть недостаточным в данной ситуации.
Исходя из вышесказанного, можно заключить, что ТСО представляет собой полезную тактику лечения у пациентов после ТГСК с осложнениями в виде органной недостаточности. При тщательном отборе молодых пациентов, общая выживаемость и переживание органа, по-видимому, сравнимы с показателями общего контингента больных после ТСО. Часты осложнения, такие, как инфекции и отторжение трансплантата, но они обычно поддаются терапии. Следовательно, ТСО является важным вариантом лечения для некоторых пациентов с органной недостаточностью после ТГСК. Кроме того, некоторые реципиенты солидных органов при развитии гематологических заболеваний могут выиграть от аллогенной ТГСК и жить в течение длительных сроков без утраты функций органа. 
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Tapani Ruutu1, Christian Koenecke2 and Grzegorz W. Basak3
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                    [TEXT] => <sup>1</sup>Helsinki University Central Hospital, Comprehensive Cancer Center, Stem Cell Transplantation Unit, Helsinki, Finland;<br>
 <sup>2</sup>Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover, Germany;<br>
 <sup>3</sup>The Medical University of Warsaw, Department of Hematology, Oncology and Internal Diseases, Poland
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 2Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover, Germany;

 3The Medical University of Warsaw, Department of Hematology, Oncology and Internal Diseases, Poland
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	 The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.
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Summary

	 The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.

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                    [TEXT] => <p class="Autor_place_work-Rus"><sup>1</sup>Отдел трансплантации стволовых клеток, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия </p>
<p class="Autor_place_work-Rus"><sup>2</sup>Университетский медицинский центр Гамбург-Эппендорф, Германия</p>
<p class="Autor_place_work-Rus"><sup>3</sup><span class="affiliation">Отдел госпитальной фармации, Университет Тюбинген, Тюбинген, Германия</span></p>
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2Университетский медицинский центр Гамбург-Эппендорф, Германия
3Отдел госпитальной фармации, Университет Тюбинген, Тюбинген, Германия
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                    [TEXT] => <h2>Резюме</h2><p class="Summery_Rus" lang="ru-RU">Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.</p>
<p class="Summery_Rus" lang="ru-RU">Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (<span class="CharOverride-4">Hypericum perforatum</span>), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.</p>
<p class="Summery_Rus" lang="ru-RU">Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов. </p>
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Резюме
Исходы химиотерапии у лиц пожилого возраста зависят от возрастных изменений функций различных органов. Наряду со снижением содержания воды и повышением доли жиров в теле, отмечено снижение нормальной функции органов: сердечного выброса – на 1%, кровотока печени – на 1%, кровотока почек – на 1% ежегодно. Снижение кислотности в желудке и моторики кишечника может приводить к снижению биодоступности многих препаратов. Нарушения краткосрочной памяти ведут к ошибкам дозировки и проблемам с соблюдением режима приема препаратов. Эти нарушения и дефицит когнитивных процессов у лиц пожилого возраста оказывают влияние на терапию и дозировку препаратов. Последствия возрастных различий, в особенности, для исходов химиотерапии, не подвергались систематическому изучению. Существующие исследования указывают, однако, на возрастные различия в клинической фармакокинетике. Однако имеются методические рекомендации международного Общества по гериатрической онкологии по дозировке ряда противораковых препаратов в зависимости от показателей клиренса креатинина у больных. Обсуждается вопрос о кратности приема кардиотоксических препаратов (например, доксорубицина) в зависимости от возраста.
Другие проблемы состоят в возрастающем числе прописанных препаратов, которые часто нужны в старшем возрасте (полифармация) и их взаимодействии с другими, безрецептурными препаратами и средствами комплементарной и альтернативной медицины. Хотя они часто считаются безвредными, так они не требуют рецепта или являются натуральными продуктами, они могут содержать фармакологически активные агенты, влияющие на метаболизм химиотерапевтических препаратов. В качестве примера приводятся препараты зверобоя (Hypericum perforatum), который является индукторами Cyp3A. Его применение совместно с Иматинибом приводит к значительному повышению его клиренса из организма. Миеются также данные о повышении гематотоксического действия этопозида на фоне приема препаратов Эхинацеи Рассматриваются также возможные модифицирующие эффекты зеленого чая, о котором известно, что он предотвращает рак простаты и пременопаузальный рак молочной железы и поэтому часто назначается онкологическим больным. В то же время он содержит эпигаллокатехин-галлат в качестве активной субстанции, которая снижает биодоступность, например, противоракового препарата бортезомиба.
Таким образом, следует учитывать возможные потенцирующие и ингибирующие эффекты многих безрецептурных препаратов на противоопухолевое воздействие многих химиотерапевтических препаратов. Необходимо собирать и систематизировать сведения о соответствующих побочных эффектах от больных пожилого возраста с целью большей адаптации дозировок к возрасту пациентов. На последующем этапе можно включать пожилых больных в клинические исследования и планировать специальные исследования по химиотерапии пациентов старших возрастов. 
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Axel R. Zander1, René J. Hornung2, Hans-Peter Lipp3
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Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany1
University Medical Centre Hamburg-Eppendorf, Hamburg, Germany2
Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany3
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Summary</h2>
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	 Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.
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Summary

	 Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.

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            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 1187
            [VALUE] => 9
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 9
            [~DESCRIPTION] => 
            [~NAME] => PDF ENG
            [~DEFAULT_VALUE] => 
        )

    [NAME_LONG] => Array
        (
            [ID] => 45
            [TIMESTAMP_X] => 2023-04-13 00:55:00
            [IBLOCK_ID] => 2
            [NAME] => Название (для очень длинных заголовков)
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_LONG
            [DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 45
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 80
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Название (для очень длинных заголовков)
            [~DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

        )

)