ISSN 1866-8836
Клеточная терапия и трансплантация
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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). 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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

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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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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.

  

Figure 1. Modelling and treatment of myocardial infarction in rabbits: А – ligation of left anterior descendent coronary artery, B – a view of surgical area, C – topography of intramyocardial injections of marrow cells into the infarcted area; D – a view of surgical area

Detection of labelled cells in the myocardium

Twenty days after the surgical intervention, the subgroups of three rabbits from Groups 3 and 4 (subjected to myocardial injections) were sacrificed (this term was limited by the life-span of detectable fluorochrome in the cells). The hearts were teased in two parts (basal and apical), in order to get sections at the level of arterial ligature perpendicular to long axis of the heart. Apical part of the heart was pulped and treated with trypsin-collagenase enzyme mixture (Sigma, USA). The dissociated cells were collected by centrifugation, placed onto the microscopic slide, and the proportion of labeled cells have been counted.

Electrocardiography (ECG)

ECG was carried out in all animals before surgery, at the days +3, +7, +30, and one year after surgery.The results were evaluated by the 2nd standard lead on an ECG.

Heart ultrasonography

EchoCG was performed with a Sequoia 512 echocardiograph (Acuson, USA), using a linear 13 MGz transducer, according to a standard detection technique. EchoCG was performed in all cases before the surgery, at day +14, and 1 year after the surgery. The procedure was carried out in parallel with ECG recording. The end-diastolic size of left ventricle was registered in M-scanning regimen (EDSLV, mm). Left ventricular systolic function was registered by means of 2D scanning, from the apical access, in four-chamber and two-chamber positions. EF percentage calculations were made by means of a modified Simpson disc method, using the built-in software of the sonographic device .Aortal blood flow velocity was evaluated at the level of aortal valve (VAo, m/sec), using impulse-wave Doppler sonography. Dynamic features of the left ventricular wall were also studied in intervention/ infarction area, e.g., dyskinesia, hypokinesia, akinesia, calcification, or ossification in the areas of transplantation.

Myocardial perfusion evaluation

Perfusion rates were assessed with SPECT technique, using radiopharmaceutical tracer (RP) Myoview (Nycomed, Great Britain) labelled with Tc-99m. RP was injected, at a single dose of 30-50 MBq, into marginal ear vein via a peripheral catheter. 10 to 15 min after injection, a SPECT evaluation was performed by double-detector gamma chamber E.Cam. var (Siemens, Germany). To get quantitative values for myocardial perfusion rates, a ratio of mean RP accumulation in damaged versus reference areas was calculated in every case, as arbitrary units (Fig. 2). Uniformity of perfusion was determined as a minimum-to-maximum ratios (in pixels) for damaged and reference areas. The study was performed before surgical intervention, at day +10, and at 1,5, 6, and 12 months after surgery in all groups of animals.

Figure 2. SPECT visualization of left heart ventricle of rabbit. А, transverse heart projection at the level of ligated left anterior descendent coronary artery; B, a sketch of left ventricle with designation of its walls and localization of damaged and reference areas; C, perfusion SPECT tomography of the left ventricle of rabbit, with indication of reference zone (non-damaged myocardium area) and pathological zone (infarction localization area)

Figure 2. SPECT visualization of left heart ventricle of rabbit. А, transverse heart projection at the level of ligated left anterior descendent coronary artery; B, a sketch of left ventricle with designation of its walls and localization of damaged and reference areas; C, perfusion SPECT tomography of the left ventricle of rabbit, with indication of reference zone (non-damaged myocardium area) and pathological zone (infarction localization area)

Sizing of infarcted area, LV dilatation measurements, histological studies

Dimensions of an experimental IM were determined by means of 2,3,5-triphenyltetrazolium chloride (TTC) staining of the heart sections, thus allowing to discern irreversibly damaged myocardial tissue from viable myocardium. Moreover, a routine histological evaluation was performed. All the animals surviving for 12 months post-surgery were subjected to euthanasia, followed by immediate heart extraction. The organ was rinsed in physiological saline and sectioned transversally with a special device below the ligature level into three segments of equal thickness, i.e., apical (1), middle (2), and basal sections (3), as shown in Fig. 3А.

Figure 3. A scheme of residual myocardial damage  assessment at 12 months post-treatment. А, sectioning of damaged myocardial area into three segments (apical, middle and basal); В, evaluation of post-infarction myocardial scarring  by means of 1,3,5-TTC staining.  Abbreviations: LV, left ventricle; RV,  right heart ventricle

Figure 3. A scheme of residual myocardial damage
assessment at 12 months post-treatment. А, sectioning of damaged myocardial area into three segments (apical, middle and basal); В, evaluation of post-infarction myocardial scarring by means of 1,3,5-TTC staining. Abbreviations: LV, left ventricle; RV, right heart ventricle.

In a half of all animals, the heart segments were then placed to 1% solution of TTC (ICN, USA) for 15 min. at 37ºC, pH 7.4. After development of bright-red color in viable myocardium, the stained heart segments were photographed by digital camera (Olimpus 2020, Japan), and the images were stored and processed by Adobe Photoshop CS2 software (Fig. 3В). For the second half of animals, the heart sections were fixed in 10% formaldehyde solution for 4 days followed by mounting in paraffin and preparing 7-mcm slices, using a routine technique. The histological samples were stained by HE (hematoxylin and eosin) and Mallory dye, thus allowing of discerning various types of connective tissues. Histological examinations were performed with a “BioLam” microscope (Russia). A grade of left ventricular dilatation (LV dilatation index) was determined as a ratio of LV lumen in TTC-positive heart segments to myocardial tissue area in both ventricles. This arbitrary index was calculated for each of three segments, and a mean value was then derived.

Quantitative evaluation of vascularization in damaged myocardial area

We have examined the borderline areas adjacent to the myocardial scars. Each tissue specimen was routinely stained by Mallory, and five consequent microscopic fields were evaluated at a 400x magnification. We performed separate counts of regulated-type vessels, i.e., arterioles, capillaries, venules, as well as non-regulated type-sinusoids, followed by calculating a mean blood vessel number per microscopic field.

Safety evaluation of approaches for angiogenesis stimulation in ischemic myocardium

To assess safety of cell transplantation in the studied groups of animals, we compared some general parameters, e.g., intra- and post-surgical mortality, incidence of arrhythmia and septic/inflammatory complications early after surgery. Condition of heart and internal organs was macroscopically evaluated by pathoanathomical obduction data, looking for occurrence of neoplastic processes, and microscopically evaluated for presence of local pathological changes in the areas of cell injections, in particular, atypically differentiated cells, focal sclerosis, or osteogenesis.

Statistical processing

We used SPSS software for statistical data processing. With small number of observations, the significance of differences was determined by a non-parametric Wilcoxon-Mann-Whitney criterion. All the data were presented as means + SD. The differences by P values of <0.05 were regarded as significant.

Results

Detection of labeled cells in damaged myocardium

Twenty days after treatment, both MFs and MMSCs were detectable as fluorescent cells, at, resp., 13+2% and 11+3% of initial numbers (Fig. 4).

Screen Shot 2015-09-07 at 21.18.20.png

Figure 4. ECG dynamics in studied groups

ECG dynamics in different experimetal groups

All the animals subjected to experimental coronary occlusion, developed typical ECG features of acute MI with distinct typical dynamics. However, all animals from control (placebo-treated), or MF-transplanted groups exhibited ECG signs of transmural MI, whereas MMSCs-transplant animals displayed only subendocardial myocardial damage (Fig. 5). Heart rate disturbances (atrial extrasystoles) in early postoperative period were developing with similar frequency (65%) in all the groups under study, except for MMSC-transplanted animals that showed them 3 times less often (20%). Twelve months after surgery, ECG patterns in MMSC-treated animals returned to the initial state, as compared with scar changes in ECG observed in MF-treated animals (Fig. 5)

Descriptions: MI-associated perfusion defects are shown by arrows; colour scale shows grade of myocardial perfusion from minimal to maximal values.

Figure 5. Typical changes on perfusion tomoscyntigraphy of myocardium in the groups under study, according to SPECT data before surgery, 1.5, and 12 months after surgery.

Initial EchoCG parameters did not differ between the groups under study. After the surgical intervention (coronary occlusion), a significant increase of EDSLV was observed, along with diminished EF, VAo. However, these disruptions were dissimilar for different groups, i.e., minimal for MMSC-treated animals and maximal for MNC-treated animals (Table 1, Fig. 6, 7). One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all cardiological parameters (p<0,05), absence of akinetic areas, that sufficiently differed from appropriate parameters in other groups. In controls and placebo group, the disturbances were long-standing, and a small akinetic area was formed in the apical segment. The most negative changes were detected among animals transplanted with MNC, which revealed drastic decrease in LV systolic function, increased LV size, development of extended akinetic areas, as compared with group 3, controls, and placebo group (p<0,05) (Table 1, Fig. 6, 7).

Groups

Parameters and terms of the study

EF,%

EDSLV, mm

V Ao, m/sec

Initial values

14 days after surgery

12 months after surgery

Initial values

14 days after surgery

12 months after surgery

Initial values

14 days after surgery

12 months after
surgery

1 (controls)

62.2±4.6

45.8±6.1

46.5±6.4

14.4±1.0

17.0±1.4

16.9±0.8

95±4

57±6

71±4

№2 (placebo)

64.9±4.3

46.7±3.5

48.7±3.9

14.1±0.4

16.8±1.2

16.6±0.8

94±3

58±6

73±6

№3 (MMSC)

61.7±4.0

53.1±4.8

58.2±3.1*

14.7±0.9

15.2±0.7

14.9*±1.2

96±4

81±6

89±4*

№4 (MNC)

59.7±3.2

38.8±2.9

28.7*±4.1

14.9±1.2

17.9±0.8

19.8*±0.9

97±5

55±4

45±3*

Abbreviations: LVEF, LV ejection fraction; EDSLV, end LV diastolic size; V Ao- blood flow velocity in ascending aorta; *, differences from control group are significant by p<0,05.

Table 1. Dynamics of LV systolic parameters from EchoCG data (M±m)

Figure 6. Transverse sections (1, apical; 2, median; 3, basal) from infarcted area of the heart wall in different experimental groups (Mallory staining) 12 months after MI modeling/ treatment

Dynamics of myocardial perfusion in the groups under study.

Cumulative findings concerning dynamics of myocardial perfusion in damaged areas are presented in Table 2. Before surgery, the perfusion parameters in all groups were within reference ranges. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, this decrease varied in different groups of animals, i.e., animals treated with MMSC or MNC showed less impaired perfusion rates than in control or placebo groups (p<0,05). At 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged area of myocardium in groups 3 and 4, reaching the pre-surgical rates by 3 months, in group 3 to a greater extent, without subsequent dynamics. In controls and placebo-treated group, the altered perfusion rates remained at similar levels at all the terms of observation.

Figure 7. Numbers of regulated vs. sinusoid-type microvessels per a space unit of MI area 12 months after modelling and treatment in compared groups of experimental animals.

Ordinate, number of microvessels per a IM space unit; abscissa, groups under study.

Groups

TTC accumulation in damaged area (arb.un.), terms of study

Before surgery

10 days after surgery

1.5 months after surgery

6 months after surgery

12 months after surgery

Controls

1.01±0.01

0.57±0.02

0.59±0.04

0.61±0.02

0.61±0.04

Placebo

1.01±0,02

0.59±0.02

0.62±0.02

0.64±0.04

0.61±0.03

MMSC

0.98±0.03

0.81±0.01 *

0.92±0.03 *

0.98±0.02 *

1.02±0.01*

MF

1,00±0.01

0.75±0.03 *

0.89±0.03 *

0.98±0.03 *

0.99±0.01*

Descriptions: arb.units = mean rates of TTC accumulation in damaged area/ mean values of TTC accumulation in reference area;
*- significance of differences as compared to control group (p<0.05)

Table 2. Dynamics of TTC accumulation in damaged myocardial area after treatment of acute MI in the groups under study by perfusion data (SPECT evaluation, M±m).

Morphometric heart studies

12 months after experimental MI modeling/ treatment, general macroscopic appearance of rabbit hearts was similar for control and placebo-treated groups, i.e., enlarged heart size, as compared to healthy hearts (intact animals), along with apical aneurism of LV. Distinct scarring of LV anterior wall was evident for the hearts from MMSC-treated animals, however, without evolving aneurysm, and without sufficient increase of the heart size. Heart dimensions among MF-treated animals did significantly exceed normal size, and appropriate heart parameters of healthy rabbits, and the animals from groups 1,2, and 3. The animals transplanted with MF had extendsive aneurysms at the apex and anterior wall of LV (Fig. 9,10,11). Scarring area and LV dilatation index for control group were, resp., 20.2±1.9%, and 0.19±0.02; 20,8±1.6% and 0.18±0.03 for placebo group; 35.8±1.6% and 0.34±0.03 for MF-transplanted group,. The animals treated with MMSCs exhibited the best characteristics, i.e., 6.0±2.6% and 0.11±0.02 (Fig. 12).

Histological pattern of myocardium

It was shown that intramyocardial MMSC vs. MF transplantation resulted, after 12 months, in the development of principally different heart morphology as compared to control or placebo groups of animals. 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.

Quantitative myocardial vascularization

12 months after MI modeling/treatment, a significant difference was revealed in vascularization patterns of damaged myocardium in the studied groups, i.e., the total microvessel numbers per 1 microscopic field were, resp., 15±3, 13+3, 7±1 and 6±2 for groups treated with MMSCs, MFs, controls and placebo-treated animals. After intramyocardial autotransplantation of bone marrow, the microvessel density in the area was not only increased over controls or placebo groups (p<0.05), but it exhibited a distinct type of microvessels showing a regulated type-wall, whereas control group recovered with development of sinusoid-type microvessels.

Safety evaluation of neoangiogenesis stimulation in ischemic myocardium

Intra- and post-operative mortality in all the studied groups did not significantly differ (a mean of 10±3% и 10±4%). Incidence of septic and inflammatory complications in the intervention area was, in general, significantly lower (p<0.05) among intramyocardially cell-treated animals (1) than in control or placebo group (3). No differences were here noted between MF and MMSC-treated groups. At macroscopic examination one year after surgical intervention, both groups of cell-treated animals did not show any signs of malignant neoplasia. Local examination of myocardium at the locations of cell injections did not reveal any cells with atypical differentiation (osteogenic or chondrogenic tissues).

Discussion

Rabbit model of myocardial infarction induced by ligation of anterior descendent left coronary artery proved to be a convenient and demonstrative technique for evaluation of therapeutic angiogenesis, testing the effects of vascular growth factors and cellular therapy [14]. The results obtained in present study have shown that intramyocardial transplantation of autologous bone marrow cells (MF versus MMSC) into the MI area in rabbits during acute period may considerably change the natural process of MI development and exerts different morpho-functional effects upon the damaged tissues.

MMSC transplantation, as compared to controls and placebo, was associated with definite reduction of the myocardial damage, and later (12 months after MI) this group of animals exhibited normalization of heart systolic function, ECG, myocardial perfusion. Meanwhile, upon morphological examination, the infracted area was represented by fine focal cardiosclerosis, without aneurism formation. The detected changes might have been caused by paracrine effect of transplanted cells and, probably, by their differentiation into various myocardial structures. At the first phase of MI characterized by death of the cardiomyocytes, the transplanted MMSC are able to inhibit apoptosis and produce a cytoprotective effect, thus allowing cardiomyocytes and transplanted cells to survive the ischemic state [6,16,30]. Moreover, the detected changes might be associated with changing degree of inflammatory response, due to effect of the transplant upon the cytokine profile. In the course of inflammation caused by ischemic damage of myocardium, there are two cytokine groups: pro-inflammatory factors (interleukin-1α, 1ß, 6, 8, tumor necrosis factor-α, ß and others) mostly secreted by macrophages and neutrophils, and anti-inflammatory molecules (interleukin-4, 10, transforming growth factor-β and others), mainly released by lymphocytes, monocytes and macrophages. It was shown in vitro that bone marrow MMSC, along with anti-inflammatory cytokines (interleukin-1α, 1ß, 6, 7, 8, tumor necrosis factor-α, ß) produce a broad spectrum of anti-inflammatory cytokines (interleukin-4, 10, transforming growth factor-β), as well as specific receptors for interleukin-1α, 1ß, 1, 3, 4, 6, 7, 8, tumor necrosis factor-α, ß [22]. Moreover, it has been shown that the bone marrow MMSC secrete different chemokines: MCP-1, RANTES, MIP-1alpha [23]. Most probably, such cytokine profile may induce significant populational changes, e.g., quantitative increase of macrophages, lymphocytes and monocytes that are able to secrete anti-inflammatory cytokines. This mechanism allows to reduce the degree of inflammatory response and the damaged area.

Progression of the small-focal myocardial infarction and normalization of systolic functions after BM MMSC transplantation, as shown in our study, can be also explained by potential ability of transplanted cells to differentiate into cardiomyocytes. However, an opportunity of BM MMSCs differentiation into cardiomyocites remains problematic. Most researchers note the ability of bone marrow MMSC to acquire cardiomyocyte-like phenotypes after transplantation into the damaged myocardium, as shown by synthesis of α-actinin, troponin-Т, tropomyosin. However, they have not revealed developing intercellular structures and/or contractile functions [20, 21, 27].

Thus, the changes in myocardial morphology and function after MMSC transplantation may be caused by their cytoprotective activity and ability to reduce the inflammatory response during acute infarction phase. By the contrary, intramyocardial MF transplantation, as compared to control and placebo groups, caused alterations of myocardial contractile function, expanding damage area, resulting into significant left ventricular fibroid aneurysms. Such effect is probably determined by MF ability to intensify inflammatory response, due to changing quantitative and qualitative cytokine profile in the damaged area, following direct massive injections of leukocytes. The bone marrow MFs constitute a heterogeneous population, containing mesenchymal stromal cells, hematopoietic stem cells, progenitor endothelial cells, as well as myeloid and lymphoid cells at different stages of maturation. There is an abundance of mature leukocytes among the bone marrow MF. Apparently, upon entering the ischemic myocardium, the MF start to release a variety of proteolytic enzymes and anti-inflammatory cytokines which attract blood cells to the altered areas, thus intensifying the inflammatory response [8]. The key point of myocardial repair is based on equilibrium between extracellular matrix degradation (needed for cell migration), and its resynthesis by the cells migrating to the damaged area. The proteolytic enzymes released by MF lyse intercellular collagen links and activate matrix metalloproteinases. Extracellular matrix degradation and expansion of infarcted area are caused by a cascade of proteolytic reactions. Moreover, the matrix metalloproteinases are also activated by some cytokines, e.g., as interleukin-1ß и tumor necrosis factor-α, ß [9, 19].

G. Ertl, S. Frantz have shown that dilatation of left ventricle and mortality were less expressed in the mice deficient for interleukin-1ß than in animals with normal cytokine levels [7]. In addition, proteolytic enzymes released by transplanted MF of bone marrow induce massive death of cardiomyocytes. Cardiac myosin released from necrotized myocardium is a proven potent autoantigen. The autoimmune reactions occur via activation of T lymphocytes followed by the secondary T-cell induced damage of cardiomyocytes and altered remodeling of extracellular matrix [2, 28].

Thus, morphological and functional changes revealed in myocardium after bone marrow MF injections may be caused by excessive intensification of inflammatory response during the hyperacute phase of MI.

The results of our study indicate that intramyocardial transplantation of MMSC and MF of bone marrow leads to increased vascularization of damage area. We assume that the angiogenic effect of these cells is accomplished by secretion of vascular growth factors and, probably, by differentiation of transplanted cells into cellular components of the vascular wall. 

MMSCs are able to secrete angiogenic factors, such as VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor), HGF (hepatocyte growth factor), TGF-ß (transforming growth factor), angiopoietin-1 [13, 19]. Tang et al. (2005) demonstrated that the BM MMSC transplantation into the ischemic myocardium results into secretion of cytokine SDF-1 (stromal cell derived factor-1), which is a chemoattractant for endothelial cell progenitors and hematopoietic stem cells [22]. Progenitor endothelial cells migrating from peripheral blood into the damaged area are able to transform into mature endothelial cells and participate in angiogenesis [4, 12, 17]. Another mechanism of MMSCs involvement in post-transplant neoangiogenesis in myocardium is connected with their ability to differentiate into endothelial cells, smooth muscle cells, pericytes, fibroblasts that subsequently become components of the vascular wall, as shown in several studies [4,22]. 

Involvement of bone marrow MF in angiogenesis, according to the literature data, is regulated by several mechanisms. First of all, the MF populations, e.g., mesenchymal stromal cells, hematopoietic stem cells, progenitor endothelial cells, as well as immature cells of myeloid and lymphoid series, are secreting various angiogenic factors (VEGF, bFGF, TGF-ß, PDGF, angiopoietin-1, which stimulate proliferation of vascular endothelium and endothelial progenitors of damaged myocardium [13,25, 30, 31]. Secondly, the MF cells are able to secrete SDF-1 (stromal cell derived factor-1), which is a chemoattractant for progenitor endothelial cells and hematopoietic stem cells [20]. Thirdly, such mesenchymal stromal cells within the MF fraction are able to differentiate into endothelial cells and other vascular structures [22].

Our data differ from other studies that did not show such significant differences after MF and MMSC transplantation to the experimental MI area [6,13,16,21,25,27,31]. A probable explanation is that transplantation of bone marrow cells in these studies was performed either in later terms following MI, or the cells were administered by a different route, e.g., via coronary arteries, or intravenously [1,3,5,10,24,29]. A prolonged observation in our study did not register such complications as ossification or formation of angiomas in the cell transplantation area, as previously described [15], neither any neoplastic processes have been registered.

Conclusions

1. Local intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit, when performed in acute phase of experimental MI, was accompanied by changes in the MI development and resulted into different morphofunctional outcomes. I.e., transplantation of mesenchymal stem cells exerted a pronounced therapeutic effect, causing reduction of myocardial damage area and improvement of systolic functional indices. On the contrary, mononuclear cell transplantation produced negative effects, causing expansion of the damaged area and impairment of systolic indices.

2. Both MMSC and MF intramyocardial transplantation display stimulation of neoangiogenesis and improvement of perfusion in the infarcted area.

Conflict of interest

All the authors have no conflict of interest to declare.

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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.

  

Figure 1. Modelling and treatment of myocardial infarction in rabbits: А – ligation of left anterior descendent coronary artery, B – a view of surgical area, C – topography of intramyocardial injections of marrow cells into the infarcted area; D – a view of surgical area

Detection of labelled cells in the myocardium

Twenty days after the surgical intervention, the subgroups of three rabbits from Groups 3 and 4 (subjected to myocardial injections) were sacrificed (this term was limited by the life-span of detectable fluorochrome in the cells). The hearts were teased in two parts (basal and apical), in order to get sections at the level of arterial ligature perpendicular to long axis of the heart. Apical part of the heart was pulped and treated with trypsin-collagenase enzyme mixture (Sigma, USA). The dissociated cells were collected by centrifugation, placed onto the microscopic slide, and the proportion of labeled cells have been counted.

Electrocardiography (ECG)

ECG was carried out in all animals before surgery, at the days +3, +7, +30, and one year after surgery.The results were evaluated by the 2nd standard lead on an ECG.

Heart ultrasonography

EchoCG was performed with a Sequoia 512 echocardiograph (Acuson, USA), using a linear 13 MGz transducer, according to a standard detection technique. EchoCG was performed in all cases before the surgery, at day +14, and 1 year after the surgery. The procedure was carried out in parallel with ECG recording. The end-diastolic size of left ventricle was registered in M-scanning regimen (EDSLV, mm). Left ventricular systolic function was registered by means of 2D scanning, from the apical access, in four-chamber and two-chamber positions. EF percentage calculations were made by means of a modified Simpson disc method, using the built-in software of the sonographic device .Aortal blood flow velocity was evaluated at the level of aortal valve (VAo, m/sec), using impulse-wave Doppler sonography. Dynamic features of the left ventricular wall were also studied in intervention/ infarction area, e.g., dyskinesia, hypokinesia, akinesia, calcification, or ossification in the areas of transplantation.

Myocardial perfusion evaluation

Perfusion rates were assessed with SPECT technique, using radiopharmaceutical tracer (RP) Myoview (Nycomed, Great Britain) labelled with Tc-99m. RP was injected, at a single dose of 30-50 MBq, into marginal ear vein via a peripheral catheter. 10 to 15 min after injection, a SPECT evaluation was performed by double-detector gamma chamber E.Cam. var (Siemens, Germany). To get quantitative values for myocardial perfusion rates, a ratio of mean RP accumulation in damaged versus reference areas was calculated in every case, as arbitrary units (Fig. 2). Uniformity of perfusion was determined as a minimum-to-maximum ratios (in pixels) for damaged and reference areas. The study was performed before surgical intervention, at day +10, and at 1,5, 6, and 12 months after surgery in all groups of animals.

Figure 2. SPECT visualization of left heart ventricle of rabbit. А, transverse heart projection at the level of ligated left anterior descendent coronary artery; B, a sketch of left ventricle with designation of its walls and localization of damaged and reference areas; C, perfusion SPECT tomography of the left ventricle of rabbit, with indication of reference zone (non-damaged myocardium area) and pathological zone (infarction localization area)

Figure 2. SPECT visualization of left heart ventricle of rabbit. А, transverse heart projection at the level of ligated left anterior descendent coronary artery; B, a sketch of left ventricle with designation of its walls and localization of damaged and reference areas; C, perfusion SPECT tomography of the left ventricle of rabbit, with indication of reference zone (non-damaged myocardium area) and pathological zone (infarction localization area)

Sizing of infarcted area, LV dilatation measurements, histological studies

Dimensions of an experimental IM were determined by means of 2,3,5-triphenyltetrazolium chloride (TTC) staining of the heart sections, thus allowing to discern irreversibly damaged myocardial tissue from viable myocardium. Moreover, a routine histological evaluation was performed. All the animals surviving for 12 months post-surgery were subjected to euthanasia, followed by immediate heart extraction. The organ was rinsed in physiological saline and sectioned transversally with a special device below the ligature level into three segments of equal thickness, i.e., apical (1), middle (2), and basal sections (3), as shown in Fig. 3А.

Figure 3. A scheme of residual myocardial damage  assessment at 12 months post-treatment. А, sectioning of damaged myocardial area into three segments (apical, middle and basal); В, evaluation of post-infarction myocardial scarring  by means of 1,3,5-TTC staining.  Abbreviations: LV, left ventricle; RV,  right heart ventricle

Figure 3. A scheme of residual myocardial damage
assessment at 12 months post-treatment. А, sectioning of damaged myocardial area into three segments (apical, middle and basal); В, evaluation of post-infarction myocardial scarring by means of 1,3,5-TTC staining. Abbreviations: LV, left ventricle; RV, right heart ventricle.

In a half of all animals, the heart segments were then placed to 1% solution of TTC (ICN, USA) for 15 min. at 37ºC, pH 7.4. After development of bright-red color in viable myocardium, the stained heart segments were photographed by digital camera (Olimpus 2020, Japan), and the images were stored and processed by Adobe Photoshop CS2 software (Fig. 3В). For the second half of animals, the heart sections were fixed in 10% formaldehyde solution for 4 days followed by mounting in paraffin and preparing 7-mcm slices, using a routine technique. The histological samples were stained by HE (hematoxylin and eosin) and Mallory dye, thus allowing of discerning various types of connective tissues. Histological examinations were performed with a “BioLam” microscope (Russia). A grade of left ventricular dilatation (LV dilatation index) was determined as a ratio of LV lumen in TTC-positive heart segments to myocardial tissue area in both ventricles. This arbitrary index was calculated for each of three segments, and a mean value was then derived.

Quantitative evaluation of vascularization in damaged myocardial area

We have examined the borderline areas adjacent to the myocardial scars. Each tissue specimen was routinely stained by Mallory, and five consequent microscopic fields were evaluated at a 400x magnification. We performed separate counts of regulated-type vessels, i.e., arterioles, capillaries, venules, as well as non-regulated type-sinusoids, followed by calculating a mean blood vessel number per microscopic field.

Safety evaluation of approaches for angiogenesis stimulation in ischemic myocardium

To assess safety of cell transplantation in the studied groups of animals, we compared some general parameters, e.g., intra- and post-surgical mortality, incidence of arrhythmia and septic/inflammatory complications early after surgery. Condition of heart and internal organs was macroscopically evaluated by pathoanathomical obduction data, looking for occurrence of neoplastic processes, and microscopically evaluated for presence of local pathological changes in the areas of cell injections, in particular, atypically differentiated cells, focal sclerosis, or osteogenesis.

Statistical processing

We used SPSS software for statistical data processing. With small number of observations, the significance of differences was determined by a non-parametric Wilcoxon-Mann-Whitney criterion. All the data were presented as means + SD. The differences by P values of <0.05 were regarded as significant.

Results

Detection of labeled cells in damaged myocardium

Twenty days after treatment, both MFs and MMSCs were detectable as fluorescent cells, at, resp., 13+2% and 11+3% of initial numbers (Fig. 4).

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Figure 4. ECG dynamics in studied groups

ECG dynamics in different experimetal groups

All the animals subjected to experimental coronary occlusion, developed typical ECG features of acute MI with distinct typical dynamics. However, all animals from control (placebo-treated), or MF-transplanted groups exhibited ECG signs of transmural MI, whereas MMSCs-transplant animals displayed only subendocardial myocardial damage (Fig. 5). Heart rate disturbances (atrial extrasystoles) in early postoperative period were developing with similar frequency (65%) in all the groups under study, except for MMSC-transplanted animals that showed them 3 times less often (20%). Twelve months after surgery, ECG patterns in MMSC-treated animals returned to the initial state, as compared with scar changes in ECG observed in MF-treated animals (Fig. 5)

Descriptions: MI-associated perfusion defects are shown by arrows; colour scale shows grade of myocardial perfusion from minimal to maximal values.

Figure 5. Typical changes on perfusion tomoscyntigraphy of myocardium in the groups under study, according to SPECT data before surgery, 1.5, and 12 months after surgery.

Initial EchoCG parameters did not differ between the groups under study. After the surgical intervention (coronary occlusion), a significant increase of EDSLV was observed, along with diminished EF, VAo. However, these disruptions were dissimilar for different groups, i.e., minimal for MMSC-treated animals and maximal for MNC-treated animals (Table 1, Fig. 6, 7). One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all cardiological parameters (p<0,05), absence of akinetic areas, that sufficiently differed from appropriate parameters in other groups. In controls and placebo group, the disturbances were long-standing, and a small akinetic area was formed in the apical segment. The most negative changes were detected among animals transplanted with MNC, which revealed drastic decrease in LV systolic function, increased LV size, development of extended akinetic areas, as compared with group 3, controls, and placebo group (p<0,05) (Table 1, Fig. 6, 7).

Groups

Parameters and terms of the study

EF,%

EDSLV, mm

V Ao, m/sec

Initial values

14 days after surgery

12 months after surgery

Initial values

14 days after surgery

12 months after surgery

Initial values

14 days after surgery

12 months after
surgery

1 (controls)

62.2±4.6

45.8±6.1

46.5±6.4

14.4±1.0

17.0±1.4

16.9±0.8

95±4

57±6

71±4

№2 (placebo)

64.9±4.3

46.7±3.5

48.7±3.9

14.1±0.4

16.8±1.2

16.6±0.8

94±3

58±6

73±6

№3 (MMSC)

61.7±4.0

53.1±4.8

58.2±3.1*

14.7±0.9

15.2±0.7

14.9*±1.2

96±4

81±6

89±4*

№4 (MNC)

59.7±3.2

38.8±2.9

28.7*±4.1

14.9±1.2

17.9±0.8

19.8*±0.9

97±5

55±4

45±3*

Abbreviations: LVEF, LV ejection fraction; EDSLV, end LV diastolic size; V Ao- blood flow velocity in ascending aorta; *, differences from control group are significant by p<0,05.

Table 1. Dynamics of LV systolic parameters from EchoCG data (M±m)

Figure 6. Transverse sections (1, apical; 2, median; 3, basal) from infarcted area of the heart wall in different experimental groups (Mallory staining) 12 months after MI modeling/ treatment

Dynamics of myocardial perfusion in the groups under study.

Cumulative findings concerning dynamics of myocardial perfusion in damaged areas are presented in Table 2. Before surgery, the perfusion parameters in all groups were within reference ranges. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, this decrease varied in different groups of animals, i.e., animals treated with MMSC or MNC showed less impaired perfusion rates than in control or placebo groups (p<0,05). At 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged area of myocardium in groups 3 and 4, reaching the pre-surgical rates by 3 months, in group 3 to a greater extent, without subsequent dynamics. In controls and placebo-treated group, the altered perfusion rates remained at similar levels at all the terms of observation.

Figure 7. Numbers of regulated vs. sinusoid-type microvessels per a space unit of MI area 12 months after modelling and treatment in compared groups of experimental animals.

Ordinate, number of microvessels per a IM space unit; abscissa, groups under study.

Groups

TTC accumulation in damaged area (arb.un.), terms of study

Before surgery

10 days after surgery

1.5 months after surgery

6 months after surgery

12 months after surgery

Controls

1.01±0.01

0.57±0.02

0.59±0.04

0.61±0.02

0.61±0.04

Placebo

1.01±0,02

0.59±0.02

0.62±0.02

0.64±0.04

0.61±0.03

MMSC

0.98±0.03

0.81±0.01 *

0.92±0.03 *

0.98±0.02 *

1.02±0.01*

MF

1,00±0.01

0.75±0.03 *

0.89±0.03 *

0.98±0.03 *

0.99±0.01*

Descriptions: arb.units = mean rates of TTC accumulation in damaged area/ mean values of TTC accumulation in reference area;
*- significance of differences as compared to control group (p<0.05)

Table 2. Dynamics of TTC accumulation in damaged myocardial area after treatment of acute MI in the groups under study by perfusion data (SPECT evaluation, M±m).

Morphometric heart studies

12 months after experimental MI modeling/ treatment, general macroscopic appearance of rabbit hearts was similar for control and placebo-treated groups, i.e., enlarged heart size, as compared to healthy hearts (intact animals), along with apical aneurism of LV. Distinct scarring of LV anterior wall was evident for the hearts from MMSC-treated animals, however, without evolving aneurysm, and without sufficient increase of the heart size. Heart dimensions among MF-treated animals did significantly exceed normal size, and appropriate heart parameters of healthy rabbits, and the animals from groups 1,2, and 3. The animals transplanted with MF had extendsive aneurysms at the apex and anterior wall of LV (Fig. 9,10,11). Scarring area and LV dilatation index for control group were, resp., 20.2±1.9%, and 0.19±0.02; 20,8±1.6% and 0.18±0.03 for placebo group; 35.8±1.6% and 0.34±0.03 for MF-transplanted group,. The animals treated with MMSCs exhibited the best characteristics, i.e., 6.0±2.6% and 0.11±0.02 (Fig. 12).

Histological pattern of myocardium

It was shown that intramyocardial MMSC vs. MF transplantation resulted, after 12 months, in the development of principally different heart morphology as compared to control or placebo groups of animals. 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.

Quantitative myocardial vascularization

12 months after MI modeling/treatment, a significant difference was revealed in vascularization patterns of damaged myocardium in the studied groups, i.e., the total microvessel numbers per 1 microscopic field were, resp., 15±3, 13+3, 7±1 and 6±2 for groups treated with MMSCs, MFs, controls and placebo-treated animals. After intramyocardial autotransplantation of bone marrow, the microvessel density in the area was not only increased over controls or placebo groups (p<0.05), but it exhibited a distinct type of microvessels showing a regulated type-wall, whereas control group recovered with development of sinusoid-type microvessels.

Safety evaluation of neoangiogenesis stimulation in ischemic myocardium

Intra- and post-operative mortality in all the studied groups did not significantly differ (a mean of 10±3% и 10±4%). Incidence of septic and inflammatory complications in the intervention area was, in general, significantly lower (p<0.05) among intramyocardially cell-treated animals (1) than in control or placebo group (3). No differences were here noted between MF and MMSC-treated groups. At macroscopic examination one year after surgical intervention, both groups of cell-treated animals did not show any signs of malignant neoplasia. Local examination of myocardium at the locations of cell injections did not reveal any cells with atypical differentiation (osteogenic or chondrogenic tissues).

Discussion

Rabbit model of myocardial infarction induced by ligation of anterior descendent left coronary artery proved to be a convenient and demonstrative technique for evaluation of therapeutic angiogenesis, testing the effects of vascular growth factors and cellular therapy [14]. The results obtained in present study have shown that intramyocardial transplantation of autologous bone marrow cells (MF versus MMSC) into the MI area in rabbits during acute period may considerably change the natural process of MI development and exerts different morpho-functional effects upon the damaged tissues.

MMSC transplantation, as compared to controls and placebo, was associated with definite reduction of the myocardial damage, and later (12 months after MI) this group of animals exhibited normalization of heart systolic function, ECG, myocardial perfusion. Meanwhile, upon morphological examination, the infracted area was represented by fine focal cardiosclerosis, without aneurism formation. The detected changes might have been caused by paracrine effect of transplanted cells and, probably, by their differentiation into various myocardial structures. At the first phase of MI characterized by death of the cardiomyocytes, the transplanted MMSC are able to inhibit apoptosis and produce a cytoprotective effect, thus allowing cardiomyocytes and transplanted cells to survive the ischemic state [6,16,30]. Moreover, the detected changes might be associated with changing degree of inflammatory response, due to effect of the transplant upon the cytokine profile. In the course of inflammation caused by ischemic damage of myocardium, there are two cytokine groups: pro-inflammatory factors (interleukin-1α, 1ß, 6, 8, tumor necrosis factor-α, ß and others) mostly secreted by macrophages and neutrophils, and anti-inflammatory molecules (interleukin-4, 10, transforming growth factor-β and others), mainly released by lymphocytes, monocytes and macrophages. It was shown in vitro that bone marrow MMSC, along with anti-inflammatory cytokines (interleukin-1α, 1ß, 6, 7, 8, tumor necrosis factor-α, ß) produce a broad spectrum of anti-inflammatory cytokines (interleukin-4, 10, transforming growth factor-β), as well as specific receptors for interleukin-1α, 1ß, 1, 3, 4, 6, 7, 8, tumor necrosis factor-α, ß [22]. Moreover, it has been shown that the bone marrow MMSC secrete different chemokines: MCP-1, RANTES, MIP-1alpha [23]. Most probably, such cytokine profile may induce significant populational changes, e.g., quantitative increase of macrophages, lymphocytes and monocytes that are able to secrete anti-inflammatory cytokines. This mechanism allows to reduce the degree of inflammatory response and the damaged area.

Progression of the small-focal myocardial infarction and normalization of systolic functions after BM MMSC transplantation, as shown in our study, can be also explained by potential ability of transplanted cells to differentiate into cardiomyocytes. However, an opportunity of BM MMSCs differentiation into cardiomyocites remains problematic. Most researchers note the ability of bone marrow MMSC to acquire cardiomyocyte-like phenotypes after transplantation into the damaged myocardium, as shown by synthesis of α-actinin, troponin-Т, tropomyosin. However, they have not revealed developing intercellular structures and/or contractile functions [20, 21, 27].

Thus, the changes in myocardial morphology and function after MMSC transplantation may be caused by their cytoprotective activity and ability to reduce the inflammatory response during acute infarction phase. By the contrary, intramyocardial MF transplantation, as compared to control and placebo groups, caused alterations of myocardial contractile function, expanding damage area, resulting into significant left ventricular fibroid aneurysms. Such effect is probably determined by MF ability to intensify inflammatory response, due to changing quantitative and qualitative cytokine profile in the damaged area, following direct massive injections of leukocytes. The bone marrow MFs constitute a heterogeneous population, containing mesenchymal stromal cells, hematopoietic stem cells, progenitor endothelial cells, as well as myeloid and lymphoid cells at different stages of maturation. There is an abundance of mature leukocytes among the bone marrow MF. Apparently, upon entering the ischemic myocardium, the MF start to release a variety of proteolytic enzymes and anti-inflammatory cytokines which attract blood cells to the altered areas, thus intensifying the inflammatory response [8]. The key point of myocardial repair is based on equilibrium between extracellular matrix degradation (needed for cell migration), and its resynthesis by the cells migrating to the damaged area. The proteolytic enzymes released by MF lyse intercellular collagen links and activate matrix metalloproteinases. Extracellular matrix degradation and expansion of infarcted area are caused by a cascade of proteolytic reactions. Moreover, the matrix metalloproteinases are also activated by some cytokines, e.g., as interleukin-1ß и tumor necrosis factor-α, ß [9, 19].

G. Ertl, S. Frantz have shown that dilatation of left ventricle and mortality were less expressed in the mice deficient for interleukin-1ß than in animals with normal cytokine levels [7]. In addition, proteolytic enzymes released by transplanted MF of bone marrow induce massive death of cardiomyocytes. Cardiac myosin released from necrotized myocardium is a proven potent autoantigen. The autoimmune reactions occur via activation of T lymphocytes followed by the secondary T-cell induced damage of cardiomyocytes and altered remodeling of extracellular matrix [2, 28].

Thus, morphological and functional changes revealed in myocardium after bone marrow MF injections may be caused by excessive intensification of inflammatory response during the hyperacute phase of MI.

The results of our study indicate that intramyocardial transplantation of MMSC and MF of bone marrow leads to increased vascularization of damage area. We assume that the angiogenic effect of these cells is accomplished by secretion of vascular growth factors and, probably, by differentiation of transplanted cells into cellular components of the vascular wall. 

MMSCs are able to secrete angiogenic factors, such as VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor), HGF (hepatocyte growth factor), TGF-ß (transforming growth factor), angiopoietin-1 [13, 19]. Tang et al. (2005) demonstrated that the BM MMSC transplantation into the ischemic myocardium results into secretion of cytokine SDF-1 (stromal cell derived factor-1), which is a chemoattractant for endothelial cell progenitors and hematopoietic stem cells [22]. Progenitor endothelial cells migrating from peripheral blood into the damaged area are able to transform into mature endothelial cells and participate in angiogenesis [4, 12, 17]. Another mechanism of MMSCs involvement in post-transplant neoangiogenesis in myocardium is connected with their ability to differentiate into endothelial cells, smooth muscle cells, pericytes, fibroblasts that subsequently become components of the vascular wall, as shown in several studies [4,22]. 

Involvement of bone marrow MF in angiogenesis, according to the literature data, is regulated by several mechanisms. First of all, the MF populations, e.g., mesenchymal stromal cells, hematopoietic stem cells, progenitor endothelial cells, as well as immature cells of myeloid and lymphoid series, are secreting various angiogenic factors (VEGF, bFGF, TGF-ß, PDGF, angiopoietin-1, which stimulate proliferation of vascular endothelium and endothelial progenitors of damaged myocardium [13,25, 30, 31]. Secondly, the MF cells are able to secrete SDF-1 (stromal cell derived factor-1), which is a chemoattractant for progenitor endothelial cells and hematopoietic stem cells [20]. Thirdly, such mesenchymal stromal cells within the MF fraction are able to differentiate into endothelial cells and other vascular structures [22].

Our data differ from other studies that did not show such significant differences after MF and MMSC transplantation to the experimental MI area [6,13,16,21,25,27,31]. A probable explanation is that transplantation of bone marrow cells in these studies was performed either in later terms following MI, or the cells were administered by a different route, e.g., via coronary arteries, or intravenously [1,3,5,10,24,29]. A prolonged observation in our study did not register such complications as ossification or formation of angiomas in the cell transplantation area, as previously described [15], neither any neoplastic processes have been registered.

Conclusions

1. Local intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit, when performed in acute phase of experimental MI, was accompanied by changes in the MI development and resulted into different morphofunctional outcomes. I.e., transplantation of mesenchymal stem cells exerted a pronounced therapeutic effect, causing reduction of myocardial damage area and improvement of systolic functional indices. On the contrary, mononuclear cell transplantation produced negative effects, causing expansion of the damaged area and impairment of systolic indices.

2. Both MMSC and MF intramyocardial transplantation display stimulation of neoangiogenesis and improvement of perfusion in the infarcted area.

Conflict of interest

All the authors have no conflict of interest to declare.

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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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string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_META_DESCRIPTION"]=> string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_PICTURE_FILE_ALT"]=> string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_PICTURE_FILE_TITLE"]=> string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "sravnitelnye-effekty-vnutrimiokardialnoy-autotransplantatsii-razlichnykh-vidov-kletok-kostnogo-mozga" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(299) "Сравнительные эффекты внутримиокардиальной аутотрансплантации различных видов клеток костного мозга на исходы экспериментального инфаркта миокарда у кроликов" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "sravnitelnye-effekty-vnutrimiokardialnoy-autotransplantatsii-razlichnykh-vidov-kletok-kostnogo-mozga" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "sravnitelnye-effekty-vnutrimiokardialnoy-autotransplantatsii-razlichnykh-vidov-kletok-kostnogo-mozga" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "sravnitelnye-effekty-vnutrimiokardialnoy-autotransplantatsii-razlichnykh-vidov-kletok-kostnogo-mozga" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(1) "2" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) 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string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(3) "894" ["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"]=> 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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(7) { [0]=> string(3) "469" [1]=> string(3) "470" [2]=> 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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. Давыденко<sup>1</sup>, Андрей А. Матюков<sup>1</sup>, Тимур Д. Власов<sup>1</sup>, Наталия В. Цупкина<sup>2</sup>, Анатолий Н. Ялфимов<sup>3</sup>, Георгий П. Пинаев<sup>2</sup>, Халида К. Аминева<sup>1</sup></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"><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>" ["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

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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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"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. 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>" ["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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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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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.
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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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Цандер<sup>1</sup>, Рене Дж. Хорнунг<sup>2</sup>, Ханс П. Липп<sup>3</sup></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"><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>" ["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

" ["TYPE"]=> string(4) "html" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_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) "38" ["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) "101" ["VALUE"]=> array(2) { ["TEXT"]=> string(512) "<p class="Autor_place_work">Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany<sup>1</sup></p><p class="Autor_place_work">University Medical Centre Hamburg-Eppendorf, Hamburg, Germany<sup>2</sup></p> <p class="Autor_place_work">Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany<sup>3</sup></p>" ["TYPE"]=> string(4) "html" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(410) "

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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["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["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) "" ["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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Introduction

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability disorder which occurs worldwide with prevalence among Eastern and Central European population and caused by mutation in NBN gene at 8q21, the most often mutation 657-661delACAAA in 6 exon, named Slavic mutation [1-4]. Except of progressing microcephaly, low birth weight, growth retardation and characteristic bird-like facial features, it is characterized by combined immunodeficiency, radiosensitivity and high predisposition to malignancy development in childhood, mostly of lymphoid origin [5-6]. NBN gene encoding the nibrin protein plays a key role in DNA double-strand break repair and the maintenance of genomic stability. Insufficient function of defective nibrin decreases cellular response to DNA damage and results in genomic instability and finally can lead to cancer, which remains the most common cause of death in patients with NBS [7-8]. Other known causes of death are fatal infections and bone marrow aplasia [8]. Currently, no specific therapy is available for NBS. Substitution therapy with immunoglobulins is indicated in patients with agammaglobulinemia. Antibiotic prophylaxis is considered in patients with recurrent respiratory tract and urinary tract infections. Cancer treatment is accompanied by severe toxic complications and should be adapted to individual risk factors and tolerance [9-13]. The NBS patients are usually not subject to hematopoietic stem cells transplantation (HSCT), owing to concerns about increased toxicity. European experience of HSCT performed with reduced-intensity conditioning regimens in order to correct severe immunodeficiency or to treat refractory or recurring malignancy is limited but quite successful [14-15]. But there is still no consensus on optimal management of NBS patient, and no recommended options about benefits of HSCT and appropriate protocols for individual patients.

The aim of our review article was to share our experience in NBS management and to discuss indications for allo-HSCT performance. We presented here general clinical characteristics, laboratory data, treatment details and clinical outcomes of 19 Belarusian NBS patients.

Patients and Methods

According to data, provided by the Belarusian National Children Registry of primary immune deficiency (PID) diseases, a total of 238 children were diagnosed with PID until December 2014, including 18 cases of NBS. A single adult patient (21 years old) was diagnosed in our center as having NBS. The diagnosis of PID was based on the diagnostic PID criteria, as described in the last classification issued by the International Union of Immunological Societies Expert Committee for Primary Immunodeficiencies, 2013 [16].

To reveal and classify the PID condition, we used immunological criteria as well as genetic studies. Serum concentrations of immunoglobulins IgG, IgA and IgM were measured by immunonephelometry. Analysis of peripheral blood lymphocyte subpopulations was performed by flow cytometry. The blood cells were incubated with specific monoclonal antibodies (MoAbs) against CD45, CD3, CD4, CD8, CD16/CD56, CD19, CD31, CD45RA (obtained from Beckman Coulter and Beckton Dickinson). Recent thymic emigrants (RTE) were determined as CD4+CD45RA+CD31+ T cells.

Quantification of TRECs and KRECs was determined by RT-qPCR. Healthy age-matched donors of peripheral blood lymphocytes (n = 4) were taken as a control. RT-qPCR data were normalized with albumin control gene and calculated by 2-∆Ct [17]. Average values of TREC/KREC expression in healthy control group were taken as 100%, the patients’ results were presented as a percentage of control values. Statistical analysis was performed by Mann-Whitney U test and Spearman rank test.

Mutational analysis of exon 6 of the NBN gene was performed in all patients. Chromosomal instability assays reflecting increased chromosomal breakage in peripheral lymphocytes was evaluated in 5 patients. Chromosomal somatic mutations (translocations and/or inversions involving chromosomes 7 and 14) were revealed in 6 cases by conventional G-banding.

Nine NBS patients were diagnosed as having acute leukemia or non-Hodgkin lymphoma (NHL). Histological classification of haematopoietic neoplasms was performed and revised, according to World Health Organization classification, 2008 [18]. Immunophenotyping was carried out in eight cases by immunohistochemical analysis or by flow cytometry. The NHL staging was based on St.Jude criteria [19]. Chemotherapy was performed according to ALL-BFM 90/2000, ALL-MB 2008 (Moscow-Berlin), AML-MM 2003 (Moscow-Minsk) and NHL-BFM 90/95 regimens with some modifications [20-26]. One patient with peripheral T-cell lymphoma received individual chemotherapy (see below). Clinical data and outcomes are presented as by January l, 2015.

Parents of the patients provided written informed consent for leukemia/lymphoma treatment, as well as for blood sampling and processing for PID diagnostics, in accordance with protocols approved by the local Ethical Committee.

Results

NBS accounted for 8.0% of all the registered PID cases. A specific 657del5 mutation in the NBN gene was found in all 19 patients. Patient characteristics and immunological data are presented in Table 1. NBS occurrence was nearly equal in boys and girls (M:F ratio of 1.1:1). Median age at the NBS diagnosis was 7.1 years. NBS has been revealed only in 4 patients (21%) under 1 year old. In most cases, examination for PID and NBS was performed after recurrent infections or development of autoimmune disease, or in connection with lymphoma or leukemia diagnosis. In four cases the diagnosis of NBS was confirmed only post mortem.

Immunological investigations revealed highly variable immunological features of the NBS patients, without evident correlations between immune markers and degree of clinical immunodeficiency, or malignancy development. Abnormalities in immunoglobulin concentrations were found in 62.5% of examined patients. Just one child with hypogammaglobulinemia who received regular substitution therapy with intravenous immunoglobulin had no severe infections in anamnesis. All other patients had frequent or chronic respiratory infections. All NBS patients with autoimmune pathology, and half of the children with lymphoid malignancies had decreased serum immunoglobulin level. Moreover, two patients from our cohort developed lymphoid neoplasia at the age of 16 and 21 years, despite normal immunoglobulin serum levels and absence of frequent infections in anamnesis. Two other patients (without evidence of malignancy at the age of 3.7 and 5.7 years) had low numbers of CD3+ T cells (<300 cells/µL), thus indicative for pronounced abnormalities of T-cell immunity, similar to severe combined immunodeficiency. Expression of TREC and KREC mRNAs was detected at very low levels in all examined patients, including 5 children without malignancies. Immunophenotyping was performed to 13 NBS patients. A reduction of T- and/or B-cell immunity was revealed in all cases but the majority of patients had normal percentage and absolute number of CD3+ T-lymphocytes. Seven patients with low RTE level were analyzed for TRECs quantity. We found statistically significant decrease of the number of TRECs in NBS patients compared with healthy donors (p = 0.01). And a high correlation between RTE (%) and TRECs’ level was revealed (R = 0.89, p < 0.05).

Lymphoproliferative disorders occurred in 47.4% of all registered NBS patients and in 60.0% patients older than 4 years. The median age at the time of malignancy diagnosis was 10.7 years (ranged from 4 to 21). In 7 of 9 cases, NBS was diagnosed simultaneously or after the lymphoid neoplasm was confirmed. T cell malignancies prevailed in our series (7 out of 8 cases with identified immunophenotype, including one case with mixed phenotype, i.e., early T/myeloid leukemia), being T-mature in half of the cases. Some details of treatment and outcomes are presented in Table 2.

Despite full chemotherapy dosage, a complete remission (CR) was achieved only in 66.7% cases (6 out of 9 cases). Two patients died of infectious complications before CR was achieved, and one patient was lost with sepsis in the 1s CR, while on maintenance therapy. A patient with peripheral T cell lymphoma developed rapid tumor growth after short-term partial clinical response to chemotherapy and died of progression. One girl developed a secondary lymphoma 4.5 years after the treatment of diffuse large B-cell lymphoma. Three patients (two cases of T-mature lymphoblastic lymphoma, and one patient with ETP-ALL) did not respond to standard induction chemotherapy; their blast cells also had poor in vitro sensitivity to most cytostatics, as measured by MTT-test. In these patients, CR was achieved only after intensive chemotherapy (HR-blocks). The patient with ETP-ALL developed early relapse prior HSCT, and two others underwent unrelated HSCT and are alive with no evidence of disease at, resp., 6 and 13 months after transplantation. Overall, only two NBS patients (22.2%) with malignancy are alive in CR1 with a follow-up of 12 and 20 months.

All NBS patients exhibited grade 3 to 4 complications after chemotherapy. Of those, most common were neutropenic infections and hemostatic disorders. Three fatal outcomes were related to first-line treatment, two from sepsis and one patient with invasive aspergillosis and massive pulmonary bleeding. Unrecognized NBS was the main reason for non-reduced dose regimens during induction therapy.

Three patients from this cohort underwent allo-HSCT (HLA-matched sibling donor in one case, and matched unrelated donors in two cases). A graft from sibling donor was transplanted 9.8 years ago to a boy without malignancy, but with infectious and autoimmune disorders (Table 1, patient #4). His sister with NBS died from leukemia ten years earlier. Two other patients developed T-mature ALL/NHL without response to induction chemotherapy, as mentioned above (Table 2, patients #15, 16). They all received reduced-intensity conditioning regimens (Bu 8 mg/kg, FLU 150 mg/m2, ATG 90 mg/kg; MEL 140 mg/m2, FLU 125 mg/m2, ATG 60 mg/kg; MEL 140 mg/m2, FLU 150 mg/m2, ATG 60 mg/kg) that were well tolerated. Every patient experienced acute graft-versus host disease (GvHD) grade II-III. Extensive chronic GvHD developed in 2 patients. Cytomegalovirus infection occurred in 2 patients and adenovirus infection was found in one case.

Currently there are 9 NBS patients under our observation, ranging from 1.1 to 20.7 years of age, who did not undergo HSCT and have no signs of malignant disorders. Unfortunately, there are no data of any living older patients with NBS in Belarus.

Discussion

NBS is a rare disease, but the number of patients identified worldwide is rapidly increasing, probably because physicians are becoming more aware of the disorder. The frequency of NBN gene mutation carriers is rather high in the population of Slavic origin, being estimated as 1 case in 177 newborns [2]. The majority of Belarusian NBS patients are residents of the southwestern part of the country, likely as a result of a founder effect. Etiopathogenesis and clinical manifestations of NBS are well studied, but no specific therapy is available. Early diagnosis of NBS is crucial, in order to avoid even diagnostic irradiation, and to prevent severe and recurrent infections by appropriate management. Increasing number of newly diagnosed NBS cases and high risk of potential complications makes it necessary to develop optimal therapeutic strategies.

Only 21% of Belarusian patients were diagnosed as having NBS at the age less than 1 year. Moreover, 78% of NBS patients who developed lymphoma or leukemia were not recognized as immunodeficient before the malignancy became evident. Their immune status was, therefore, not tested, preventive measures were not complied, and they did not receive timely treatment with intravenous immunoglobulin. As a result, their initial infectious status supposed to be worse and made their management more challenging. Therefore, the most important thing to do is to diagnose NBS as early as possible.

Combined cellular and humoral immunodeficiency is an essential feature of the disease, unless the patients with NBS mutation had variable initial immune status with inevitably increasing immune insufficiency over time [27-28]. Unlike some other combined immunodeficiency syndromes, HSCT is not a recommended therapeutic approach for immune system restoration in NBS patients, due to the high risk of toxic complications. Meanwhile, life-long monitoring of the immune system allows for preventive measures and maintains the patients in good clinical condition for a long time. There are patients with very mild manifestations who do not suffer from frequent infections and do not need immunoglobulin supplementation. In most patients, however, a number of complications increase over time. Chronic infections leading to development of respiratory or renal failure, severe autoimmune pathology, or malignancy cause death of NBS patients in childhood or in younger adults [4, 28-31].

In the presented cohort, combined immunodeficiency was confirmed in all patients, whereas the degree of cellular and/or humoral immunodeficiency varied from very mild to severe with very low CD3+ cells counts or serum immunoglobulin levels, similar to manifestations of severe combined immunodeficiency. Severity of the complications also differed individually. Our adult NBS patient had no particular history of infections before ALL diagnosed at the age of 21 years, and his clinical condition was sufficiently satisfactory to perform full dose chemotherapy treatment and allo-HSCT (Table 2, patient #15). We have also treated another NBS patient who received adequate immunoglobulin supplementation, but multiple infectious and autoimmune complications urged us to limit the intensity of chemotherapy in the first lymphoma episode and made it impossible to perform treatment of the second lymphoma (Table 2, patient #3). This diversity in immune and clinical status implies a personalized therapeutic approach. Obviously, the patients with decreased immunoglobulin concentration need a substitution treatment. But we suppose that HSCT should be taken into consideration both for NBS patients with severe cellular or humoral immunodeficiency prior to the development of malignancies or other serious complications.

Patients with NBS have very high risk of cancer in childhood, mostly lymphoid malignancies, but medulloblastoma, rhabdomyosarcoma and some other tumors have been described as well [11, 32-34]. As reported by the International NBS Study Group and by the Polish NBS Registry, 40 to 60% of NBS patients develop NHL by the age of 20 years [11, 35-36]. We have obtained similar data, with 47% of NBS patients who developed lymphoproliferative disorders. The survival of children with PID-associated NHL is much lower in comparison with immunocompetent patients and ranges from 35 to 58% [9-13]. There are no specific treatment protocols designed for patients with NBS and NHL. Due to the higher risk of treatment-related toxicity, there is a common tendency to modify treatment by reducing dosage of some chemotherapy agents. Complication rate during cancer treatment was high in our cohort of children, thus being consistent with other reports [9, 11-12]. Tolerability of chemotherapy was limited mostly by infectious status rather than toxic side effects. In future, modified chemotherapy schemes combined with monoclonal antibodies should be designed for the treatment of patients with NBS and NHL.

Relapses or refractory cases of NHL occur more often in NBS than in immunocompetent patients and represent a major cause of treatment failure [9, 11-12]. Moreover, the surviving NBS patients are at increased risk for developing a second malignancy, more often, lymphoma [11, 37]. As a result, only few patients survived the whole-scale cancer treatment. There are some data on successful treatment of refractory or relapsed lymphoma with allo-HSCT in NBS patients [15]. Five out of 6 patients have restored T cell immunity and are alive, with a median follow up of 2.2 years. It has been suggested that HSCT should be considered for NBS patients with recurrent or second lymphoma.

In the present group, 87.5% patients (7 out of 8) were suffering from T cell lymphoid malignancies with T-mature immunophenotype in a half of cases, which is different from normal spectrum of ALL/NHL in immunocompetent children, since both T and B cell lymphoid neoplasms have been described, with some prevalence of B-cell lineage and a high recurrent disease rate in T cell malignancies [11-12, 37]. The outcome of our patients was poor with only 2 survivors (22.2%) after allo-HSCT with less than 2 years follow-up term. The reasons for this poor outcome were either infectious complications or treatment failure. More than half of the patients (5 out of 9) with NBS and malignancy did not respond to standard full dose chemotherapy or developed early relapse. Taking into account a case of secondary lymphoma development as a late event in the present cohort, the prognosis for patients with NBS and malignancies seems to be poor initially. However, despite limited tolerability of chemotherapy and a high rate of infectious complications, we demonstrated the possibility of safe allo-HSCT performance using reduced-intensity conditioning regimens.

In spite of small group under observation, we may assume that NBS patients are prone to develop T-ALL/NHL subtypes with limited curative potential. These patients may benefit from allo-HSCT as a consolidation therapy, in order to prevent relapse and to partially restore immune system, seeking to reduce the risk of secondary malignancies.

Conclusion

Our data show that NBS needs to be diagnosed at the early age. Taking into account a progressive immunodeficiency with deteriorating clinical state and extremely high risk of lymphoid malignancy with uncertain curative potential, allogeneic HSCT with reduced-intensity conditioning may be a rational therapeutic option for NBS patients with severe defects of immune function and for any NBS patients with lymphoid malignancy in first remission.

Conflict of interest

All authors have no conflict of interest to declare.

Acknowledgements

Authors gratefully acknowledges Mikhail V. Belevtsev, Chief, Belarusian National Children Registry of PID Diseases who provided information of PID cases; Dr.Svetlana N. Aleshkevich, (patient examination and collection of immunolo­gical data), Maria Stsegantseva, (PCR analysis of mutations), and to the physicians from our Center.

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  23. Burkhardt B, Woessmann W, Zimmermann M et al. Impact of cranial radiotherapy on central nervous system prophylaxix in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 2006, 24: 491-499.
  24. Barovskaya Yu А, Aleinikova ОV. Results of pediatric AML treatment according to the AML-MM 2006 in Belarus. Meditsinsky Journal, 2014, №4: 56-59. (In Russian)
  25. Popov AM, Tsaur GA, Solodivnikov AG et al. Significance of different prognostic factors for occurrence of minimal residual disease in children with acute myeloblastic leukemia after induction therapy by the ALL-MB-2008 protocol. Voprosy Gematologii/Onkologii i Immunopatologii v Pediatrii, 2012; v.11: 20-27. (In Russian)
  26. Conter V, Bartram CR, Valsecchi MC et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010, 115: 3206-14.
  27. Gregorek H, Chrzanowska KH, Michalkiewicz J et al. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: a 8-year follow-up study in a single centre. Clin Exp Immunol 2002, 130: 319-324.
  28. Gregorek H, Chrzanowska KH, Dzierzanowska-Fangrat K et al. Nijmegen breakage syndrome: long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin Immunol 2010, 135: 440-447.
  29. Resnick I, Kondratenko I, Togoev O et al. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr 2002, 140: 355-361.
  30. Kondratenko I, Paschenko O, Plyakov A et al. Nijmegen breakage syndrome. Adv Exp Med Biol 2007, 601: 61-67.
  31. Kostyuchenko L, Makuch H, Kitsera N et al. Nijmegen breakage syndrome in Ukraine: diagnostics and follow-up. Centr Eur J Immunol 2009, 34: 46-52.
  32. Distel L, Neubauer S, Varon R et al. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol 2003, 41: 44-48.
  33. Bakhshi S, Cerosaletti KM, Concannon P et al. Medulloblastoma with adverse reaction to radiation therapy in Nijmegen breakage syndrome. J Pediatr Hematol Oncol 2003, 25: 248-251.
  34. Meyer S, Kingston H, Taylor A et al. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet. 2004; 154: 169-174.
  35. Chrzanowska KH, Digweed M, Sperling K et al. DNA-repair deficiency and cancer: Lessons from lymphoma. Hereditary tumors. From genes to clinical consequences. Edited by: Allgayer H., Rehder H., Fulda S. Weinheim: WILEY-VH; 2009: 377-391.
  36. International Nijmegen breakage syndrome study group. Nijmegen breakage syndrome. Arch Dis Child 82: 400-406, 2000.
  37. Gładkowska-Dura M, Dzierzanowska-Fangrat K, Dura WT et al. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation.
    J Pathol. 2008, 216: 337-44.

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Introduction

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability disorder which occurs worldwide with prevalence among Eastern and Central European population and caused by mutation in NBN gene at 8q21, the most often mutation 657-661delACAAA in 6 exon, named Slavic mutation [1-4]. Except of progressing microcephaly, low birth weight, growth retardation and characteristic bird-like facial features, it is characterized by combined immunodeficiency, radiosensitivity and high predisposition to malignancy development in childhood, mostly of lymphoid origin [5-6]. NBN gene encoding the nibrin protein plays a key role in DNA double-strand break repair and the maintenance of genomic stability. Insufficient function of defective nibrin decreases cellular response to DNA damage and results in genomic instability and finally can lead to cancer, which remains the most common cause of death in patients with NBS [7-8]. Other known causes of death are fatal infections and bone marrow aplasia [8]. Currently, no specific therapy is available for NBS. Substitution therapy with immunoglobulins is indicated in patients with agammaglobulinemia. Antibiotic prophylaxis is considered in patients with recurrent respiratory tract and urinary tract infections. Cancer treatment is accompanied by severe toxic complications and should be adapted to individual risk factors and tolerance [9-13]. The NBS patients are usually not subject to hematopoietic stem cells transplantation (HSCT), owing to concerns about increased toxicity. European experience of HSCT performed with reduced-intensity conditioning regimens in order to correct severe immunodeficiency or to treat refractory or recurring malignancy is limited but quite successful [14-15]. But there is still no consensus on optimal management of NBS patient, and no recommended options about benefits of HSCT and appropriate protocols for individual patients.

The aim of our review article was to share our experience in NBS management and to discuss indications for allo-HSCT performance. We presented here general clinical characteristics, laboratory data, treatment details and clinical outcomes of 19 Belarusian NBS patients.

Patients and Methods

According to data, provided by the Belarusian National Children Registry of primary immune deficiency (PID) diseases, a total of 238 children were diagnosed with PID until December 2014, including 18 cases of NBS. A single adult patient (21 years old) was diagnosed in our center as having NBS. The diagnosis of PID was based on the diagnostic PID criteria, as described in the last classification issued by the International Union of Immunological Societies Expert Committee for Primary Immunodeficiencies, 2013 [16].

To reveal and classify the PID condition, we used immunological criteria as well as genetic studies. Serum concentrations of immunoglobulins IgG, IgA and IgM were measured by immunonephelometry. Analysis of peripheral blood lymphocyte subpopulations was performed by flow cytometry. The blood cells were incubated with specific monoclonal antibodies (MoAbs) against CD45, CD3, CD4, CD8, CD16/CD56, CD19, CD31, CD45RA (obtained from Beckman Coulter and Beckton Dickinson). Recent thymic emigrants (RTE) were determined as CD4+CD45RA+CD31+ T cells.

Quantification of TRECs and KRECs was determined by RT-qPCR. Healthy age-matched donors of peripheral blood lymphocytes (n = 4) were taken as a control. RT-qPCR data were normalized with albumin control gene and calculated by 2-∆Ct [17]. Average values of TREC/KREC expression in healthy control group were taken as 100%, the patients’ results were presented as a percentage of control values. Statistical analysis was performed by Mann-Whitney U test and Spearman rank test.

Mutational analysis of exon 6 of the NBN gene was performed in all patients. Chromosomal instability assays reflecting increased chromosomal breakage in peripheral lymphocytes was evaluated in 5 patients. Chromosomal somatic mutations (translocations and/or inversions involving chromosomes 7 and 14) were revealed in 6 cases by conventional G-banding.

Nine NBS patients were diagnosed as having acute leukemia or non-Hodgkin lymphoma (NHL). Histological classification of haematopoietic neoplasms was performed and revised, according to World Health Organization classification, 2008 [18]. Immunophenotyping was carried out in eight cases by immunohistochemical analysis or by flow cytometry. The NHL staging was based on St.Jude criteria [19]. Chemotherapy was performed according to ALL-BFM 90/2000, ALL-MB 2008 (Moscow-Berlin), AML-MM 2003 (Moscow-Minsk) and NHL-BFM 90/95 regimens with some modifications [20-26]. One patient with peripheral T-cell lymphoma received individual chemotherapy (see below). Clinical data and outcomes are presented as by January l, 2015.

Parents of the patients provided written informed consent for leukemia/lymphoma treatment, as well as for blood sampling and processing for PID diagnostics, in accordance with protocols approved by the local Ethical Committee.

Results

NBS accounted for 8.0% of all the registered PID cases. A specific 657del5 mutation in the NBN gene was found in all 19 patients. Patient characteristics and immunological data are presented in Table 1. NBS occurrence was nearly equal in boys and girls (M:F ratio of 1.1:1). Median age at the NBS diagnosis was 7.1 years. NBS has been revealed only in 4 patients (21%) under 1 year old. In most cases, examination for PID and NBS was performed after recurrent infections or development of autoimmune disease, or in connection with lymphoma or leukemia diagnosis. In four cases the diagnosis of NBS was confirmed only post mortem.

Immunological investigations revealed highly variable immunological features of the NBS patients, without evident correlations between immune markers and degree of clinical immunodeficiency, or malignancy development. Abnormalities in immunoglobulin concentrations were found in 62.5% of examined patients. Just one child with hypogammaglobulinemia who received regular substitution therapy with intravenous immunoglobulin had no severe infections in anamnesis. All other patients had frequent or chronic respiratory infections. All NBS patients with autoimmune pathology, and half of the children with lymphoid malignancies had decreased serum immunoglobulin level. Moreover, two patients from our cohort developed lymphoid neoplasia at the age of 16 and 21 years, despite normal immunoglobulin serum levels and absence of frequent infections in anamnesis. Two other patients (without evidence of malignancy at the age of 3.7 and 5.7 years) had low numbers of CD3+ T cells (<300 cells/µL), thus indicative for pronounced abnormalities of T-cell immunity, similar to severe combined immunodeficiency. Expression of TREC and KREC mRNAs was detected at very low levels in all examined patients, including 5 children without malignancies. Immunophenotyping was performed to 13 NBS patients. A reduction of T- and/or B-cell immunity was revealed in all cases but the majority of patients had normal percentage and absolute number of CD3+ T-lymphocytes. Seven patients with low RTE level were analyzed for TRECs quantity. We found statistically significant decrease of the number of TRECs in NBS patients compared with healthy donors (p = 0.01). And a high correlation between RTE (%) and TRECs’ level was revealed (R = 0.89, p < 0.05).

Lymphoproliferative disorders occurred in 47.4% of all registered NBS patients and in 60.0% patients older than 4 years. The median age at the time of malignancy diagnosis was 10.7 years (ranged from 4 to 21). In 7 of 9 cases, NBS was diagnosed simultaneously or after the lymphoid neoplasm was confirmed. T cell malignancies prevailed in our series (7 out of 8 cases with identified immunophenotype, including one case with mixed phenotype, i.e., early T/myeloid leukemia), being T-mature in half of the cases. Some details of treatment and outcomes are presented in Table 2.

Despite full chemotherapy dosage, a complete remission (CR) was achieved only in 66.7% cases (6 out of 9 cases). Two patients died of infectious complications before CR was achieved, and one patient was lost with sepsis in the 1s CR, while on maintenance therapy. A patient with peripheral T cell lymphoma developed rapid tumor growth after short-term partial clinical response to chemotherapy and died of progression. One girl developed a secondary lymphoma 4.5 years after the treatment of diffuse large B-cell lymphoma. Three patients (two cases of T-mature lymphoblastic lymphoma, and one patient with ETP-ALL) did not respond to standard induction chemotherapy; their blast cells also had poor in vitro sensitivity to most cytostatics, as measured by MTT-test. In these patients, CR was achieved only after intensive chemotherapy (HR-blocks). The patient with ETP-ALL developed early relapse prior HSCT, and two others underwent unrelated HSCT and are alive with no evidence of disease at, resp., 6 and 13 months after transplantation. Overall, only two NBS patients (22.2%) with malignancy are alive in CR1 with a follow-up of 12 and 20 months.

All NBS patients exhibited grade 3 to 4 complications after chemotherapy. Of those, most common were neutropenic infections and hemostatic disorders. Three fatal outcomes were related to first-line treatment, two from sepsis and one patient with invasive aspergillosis and massive pulmonary bleeding. Unrecognized NBS was the main reason for non-reduced dose regimens during induction therapy.

Three patients from this cohort underwent allo-HSCT (HLA-matched sibling donor in one case, and matched unrelated donors in two cases). A graft from sibling donor was transplanted 9.8 years ago to a boy without malignancy, but with infectious and autoimmune disorders (Table 1, patient #4). His sister with NBS died from leukemia ten years earlier. Two other patients developed T-mature ALL/NHL without response to induction chemotherapy, as mentioned above (Table 2, patients #15, 16). They all received reduced-intensity conditioning regimens (Bu 8 mg/kg, FLU 150 mg/m2, ATG 90 mg/kg; MEL 140 mg/m2, FLU 125 mg/m2, ATG 60 mg/kg; MEL 140 mg/m2, FLU 150 mg/m2, ATG 60 mg/kg) that were well tolerated. Every patient experienced acute graft-versus host disease (GvHD) grade II-III. Extensive chronic GvHD developed in 2 patients. Cytomegalovirus infection occurred in 2 patients and adenovirus infection was found in one case.

Currently there are 9 NBS patients under our observation, ranging from 1.1 to 20.7 years of age, who did not undergo HSCT and have no signs of malignant disorders. Unfortunately, there are no data of any living older patients with NBS in Belarus.

Discussion

NBS is a rare disease, but the number of patients identified worldwide is rapidly increasing, probably because physicians are becoming more aware of the disorder. The frequency of NBN gene mutation carriers is rather high in the population of Slavic origin, being estimated as 1 case in 177 newborns [2]. The majority of Belarusian NBS patients are residents of the southwestern part of the country, likely as a result of a founder effect. Etiopathogenesis and clinical manifestations of NBS are well studied, but no specific therapy is available. Early diagnosis of NBS is crucial, in order to avoid even diagnostic irradiation, and to prevent severe and recurrent infections by appropriate management. Increasing number of newly diagnosed NBS cases and high risk of potential complications makes it necessary to develop optimal therapeutic strategies.

Only 21% of Belarusian patients were diagnosed as having NBS at the age less than 1 year. Moreover, 78% of NBS patients who developed lymphoma or leukemia were not recognized as immunodeficient before the malignancy became evident. Their immune status was, therefore, not tested, preventive measures were not complied, and they did not receive timely treatment with intravenous immunoglobulin. As a result, their initial infectious status supposed to be worse and made their management more challenging. Therefore, the most important thing to do is to diagnose NBS as early as possible.

Combined cellular and humoral immunodeficiency is an essential feature of the disease, unless the patients with NBS mutation had variable initial immune status with inevitably increasing immune insufficiency over time [27-28]. Unlike some other combined immunodeficiency syndromes, HSCT is not a recommended therapeutic approach for immune system restoration in NBS patients, due to the high risk of toxic complications. Meanwhile, life-long monitoring of the immune system allows for preventive measures and maintains the patients in good clinical condition for a long time. There are patients with very mild manifestations who do not suffer from frequent infections and do not need immunoglobulin supplementation. In most patients, however, a number of complications increase over time. Chronic infections leading to development of respiratory or renal failure, severe autoimmune pathology, or malignancy cause death of NBS patients in childhood or in younger adults [4, 28-31].

In the presented cohort, combined immunodeficiency was confirmed in all patients, whereas the degree of cellular and/or humoral immunodeficiency varied from very mild to severe with very low CD3+ cells counts or serum immunoglobulin levels, similar to manifestations of severe combined immunodeficiency. Severity of the complications also differed individually. Our adult NBS patient had no particular history of infections before ALL diagnosed at the age of 21 years, and his clinical condition was sufficiently satisfactory to perform full dose chemotherapy treatment and allo-HSCT (Table 2, patient #15). We have also treated another NBS patient who received adequate immunoglobulin supplementation, but multiple infectious and autoimmune complications urged us to limit the intensity of chemotherapy in the first lymphoma episode and made it impossible to perform treatment of the second lymphoma (Table 2, patient #3). This diversity in immune and clinical status implies a personalized therapeutic approach. Obviously, the patients with decreased immunoglobulin concentration need a substitution treatment. But we suppose that HSCT should be taken into consideration both for NBS patients with severe cellular or humoral immunodeficiency prior to the development of malignancies or other serious complications.

Patients with NBS have very high risk of cancer in childhood, mostly lymphoid malignancies, but medulloblastoma, rhabdomyosarcoma and some other tumors have been described as well [11, 32-34]. As reported by the International NBS Study Group and by the Polish NBS Registry, 40 to 60% of NBS patients develop NHL by the age of 20 years [11, 35-36]. We have obtained similar data, with 47% of NBS patients who developed lymphoproliferative disorders. The survival of children with PID-associated NHL is much lower in comparison with immunocompetent patients and ranges from 35 to 58% [9-13]. There are no specific treatment protocols designed for patients with NBS and NHL. Due to the higher risk of treatment-related toxicity, there is a common tendency to modify treatment by reducing dosage of some chemotherapy agents. Complication rate during cancer treatment was high in our cohort of children, thus being consistent with other reports [9, 11-12]. Tolerability of chemotherapy was limited mostly by infectious status rather than toxic side effects. In future, modified chemotherapy schemes combined with monoclonal antibodies should be designed for the treatment of patients with NBS and NHL.

Relapses or refractory cases of NHL occur more often in NBS than in immunocompetent patients and represent a major cause of treatment failure [9, 11-12]. Moreover, the surviving NBS patients are at increased risk for developing a second malignancy, more often, lymphoma [11, 37]. As a result, only few patients survived the whole-scale cancer treatment. There are some data on successful treatment of refractory or relapsed lymphoma with allo-HSCT in NBS patients [15]. Five out of 6 patients have restored T cell immunity and are alive, with a median follow up of 2.2 years. It has been suggested that HSCT should be considered for NBS patients with recurrent or second lymphoma.

In the present group, 87.5% patients (7 out of 8) were suffering from T cell lymphoid malignancies with T-mature immunophenotype in a half of cases, which is different from normal spectrum of ALL/NHL in immunocompetent children, since both T and B cell lymphoid neoplasms have been described, with some prevalence of B-cell lineage and a high recurrent disease rate in T cell malignancies [11-12, 37]. The outcome of our patients was poor with only 2 survivors (22.2%) after allo-HSCT with less than 2 years follow-up term. The reasons for this poor outcome were either infectious complications or treatment failure. More than half of the patients (5 out of 9) with NBS and malignancy did not respond to standard full dose chemotherapy or developed early relapse. Taking into account a case of secondary lymphoma development as a late event in the present cohort, the prognosis for patients with NBS and malignancies seems to be poor initially. However, despite limited tolerability of chemotherapy and a high rate of infectious complications, we demonstrated the possibility of safe allo-HSCT performance using reduced-intensity conditioning regimens.

In spite of small group under observation, we may assume that NBS patients are prone to develop T-ALL/NHL subtypes with limited curative potential. These patients may benefit from allo-HSCT as a consolidation therapy, in order to prevent relapse and to partially restore immune system, seeking to reduce the risk of secondary malignancies.

Conclusion

Our data show that NBS needs to be diagnosed at the early age. Taking into account a progressive immunodeficiency with deteriorating clinical state and extremely high risk of lymphoid malignancy with uncertain curative potential, allogeneic HSCT with reduced-intensity conditioning may be a rational therapeutic option for NBS patients with severe defects of immune function and for any NBS patients with lymphoid malignancy in first remission.

Conflict of interest

All authors have no conflict of interest to declare.

Acknowledgements

Authors gratefully acknowledges Mikhail V. Belevtsev, Chief, Belarusian National Children Registry of PID Diseases who provided information of PID cases; Dr.Svetlana N. Aleshkevich, (patient examination and collection of immunolo­gical data), Maria Stsegantseva, (PCR analysis of mutations), and to the physicians from our Center.

References

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  23. Burkhardt B, Woessmann W, Zimmermann M et al. Impact of cranial radiotherapy on central nervous system prophylaxix in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 2006, 24: 491-499.
  24. Barovskaya Yu А, Aleinikova ОV. Results of pediatric AML treatment according to the AML-MM 2006 in Belarus. Meditsinsky Journal, 2014, №4: 56-59. (In Russian)
  25. Popov AM, Tsaur GA, Solodivnikov AG et al. Significance of different prognostic factors for occurrence of minimal residual disease in children with acute myeloblastic leukemia after induction therapy by the ALL-MB-2008 protocol. Voprosy Gematologii/Onkologii i Immunopatologii v Pediatrii, 2012; v.11: 20-27. (In Russian)
  26. Conter V, Bartram CR, Valsecchi MC et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010, 115: 3206-14.
  27. Gregorek H, Chrzanowska KH, Michalkiewicz J et al. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: a 8-year follow-up study in a single centre. Clin Exp Immunol 2002, 130: 319-324.
  28. Gregorek H, Chrzanowska KH, Dzierzanowska-Fangrat K et al. Nijmegen breakage syndrome: long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin Immunol 2010, 135: 440-447.
  29. Resnick I, Kondratenko I, Togoev O et al. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr 2002, 140: 355-361.
  30. Kondratenko I, Paschenko O, Plyakov A et al. Nijmegen breakage syndrome. Adv Exp Med Biol 2007, 601: 61-67.
  31. Kostyuchenko L, Makuch H, Kitsera N et al. Nijmegen breakage syndrome in Ukraine: diagnostics and follow-up. Centr Eur J Immunol 2009, 34: 46-52.
  32. Distel L, Neubauer S, Varon R et al. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol 2003, 41: 44-48.
  33. Bakhshi S, Cerosaletti KM, Concannon P et al. Medulloblastoma with adverse reaction to radiation therapy in Nijmegen breakage syndrome. J Pediatr Hematol Oncol 2003, 25: 248-251.
  34. Meyer S, Kingston H, Taylor A et al. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet Cytogenet. 2004; 154: 169-174.
  35. Chrzanowska KH, Digweed M, Sperling K et al. DNA-repair deficiency and cancer: Lessons from lymphoma. Hereditary tumors. From genes to clinical consequences. Edited by: Allgayer H., Rehder H., Fulda S. Weinheim: WILEY-VH; 2009: 377-391.
  36. International Nijmegen breakage syndrome study group. Nijmegen breakage syndrome. Arch Dis Child 82: 400-406, 2000.
  37. Gładkowska-Dura M, Dzierzanowska-Fangrat K, Dura WT et al. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation.
    J Pathol. 2008, 216: 337-44.

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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<sup>st</sup> 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 1st 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 1st 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 1st 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 3rd 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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  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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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 3rd 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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  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<sup> </sup></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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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) "241" ["VALUE"]=> array(2) { ["TEXT"]=> string(497) "<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>" ["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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