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1. Numbers of early CD34+ progenitors of bone marrow hematopoiesis in patients with diffuse large B-cell lymphoma

Author

E I Dorokhina, A U Magomedova, I V Galtseva, V N Dvirnyk, S A Glinkina, S M Kulikov, and S K Kravchenko

Subjects
myelotoxicity, high-dose chemotherapy, mnhl-bfm-90, cd34+, diffuse large b-cell lymphoma, Medicine
Abstract

Aim. To estimate the number of early progenitors of bone marrow (BM) hematopoiesis in patients with diffuse large B-cell lymphoma (DLBCL) in the late period after high-dose chemotherapy (HDCT) according to the mNHL-BFM-90 program. Subjects and methods. The investigators analyzed the results of BM immunophenotypic and histological studies in 40 patients (median age, 57 years) with DLBCL who received HDCT according to the mNHL-BFM-90 program at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), in the period 2002 to 2009. A comparison group consisted of 19 patients (median age, 70 years) treated according to the CHOP/R-CHOP program at HRC, MHRF, in the same period. The median follow-up period was 6 years. The results of BM examination were analyzed before and 5—10 years after the end of HDCT. Immunophenotypic study determined the number of early CD34+ hematopoietic progenitors. BM cellularity, the size of erythroid, granulocytic and megakaryocytic lineages, their ratio, the presence of dysplasia signs, and secondary stromal changes were histologically determined. The BM toxic injury signs found for the first time were evaluated as manifestations of late myelotoxicity. Results. At 5-to-10-year follow-ups after the end of HDCT according to the mNHL-BFM-90 program, the patients showed a smaller number of early CD34+ progenitors of BM hematopoiesis in 31 (78%) cases than those treated according to the CHOP/R-CHOP-21 program (n=8 (2%)) (p=0.005). Myelopoiesis with decreased CD34+ cell count was characterized by hypocellularity in 8 (26%) patients (p=0.07), the narrowing of megakaryocytic lineage in 14 (45%) (p=0.006), erythroid one in 7 (23%) (p=0.01), and granulocytic one in 8 (26%) (p=0.92), pronounced secondary stromal changes in 15 (48%) (p=0.03), and grade 1 thrombocytopenia in 13 (42%); p=0.02). Conclusion. There is evidence that the number of early CD34+ progenitors of BM hematopoiesis decreased in patients with DLBCL in the late period after HDCT. The investigation shows the relationship of the reduction in the number of early CD34+ progenitors of BM hematopoiesis in the late follow-up period to the presence of pronounced secondary changes in the BM stroma (p=0.02). There was no statistically significant relationship of the decreased number of CD34+ cells to the age younger or older than 60 years, to the period after the end of chemotherapy, to gender or presence of specific BM injury.

Published
2017
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2. Late myelotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma

Author

E I Dorokhina, A U Magomedova, V N Dvirnyk, I V Galtseva, S A Glinkina, S M Kulikov, T N Obukhova, and S K Kravchenko

Subjects
late myelotoxicity, myelotoxicity, high-dose chemotherapy, mnhl-bfm-90, diffuse large b-cell lymphoma, Medicine
Abstract

Aim. To evaluate late myelotoxicity (MT) relate to high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) program in adult patients with diffuse large B-cell lymphoma (DLBCL). Subjects and methods. The results of a complex clinical, laboratory, and instrumental examination, including cytologic, histologic, and routine cytogenetic studies of the bone marrow (BM), were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the National Research Center for Hematology (NRCH), Ministry of Health of the Russian Federation (MHRF), in 2002 to 2009; among them, there were 20 men and 20 women (median age, 57 years). A comparison group consisted of 19 patients who had received high-dose СНОР/R-СНОР-21 CT in HRC, MHRF, in the same period of time; out of them, there were 8 men and 11 women (median age, 70 years). The median posttherapy follow-up period was 6 years. The results of BM studies were analyzed before and 5-10 years after treatment in complete remission. The cytological and histological studies of BM determined its cellularity, the sizes of erythroid, granulocytic, and megakaryocytic lineages, their ratios, the signs of dysplasia, and stromal dysplastic changes. Routine BM cytogenetic study was conducted to identify karyological problems. Only myelopoietic changes that had been revealed for the first time 5-10 years after completion of CT were kept in mind as late MT. Cases of baseline and post-CT changes and those of baseline and no post-CT changes were not taken into account. Results. Cytopenic syndromes (having no signs of myelopoietic lineage dysplasia or needing no blood component replacement transfusions) were revealed in 52% of the patients in the high-dose CT; thrombocytopenia amounted to 46%. In the late follow-up period, the patient group after high-dose mNHL-BFM-90 CT were found to have BM hypocellularity in 15 (38%) cases, a narrowing of erythroid and megakaryocytic lineages in 13 (33%) and 19 (48%) cases, respectively, and obvious secondary stromal changes in 17 (43%). The first 6 patients underwent routine BM cytogenetic study; all the patients were ascertained to have a normal karyotype; in this connection further BM study was stopped. Conclusion. The late MT of high-dose mNHL-BFM 90 CT is statistically significantly higher than that of the standard CHOP/R-CHOP-21 therapy. However, signs of myelodysplastic syndromes and those of cytopenia requiring blood component transfusions were observed in none patient.

Published
2016

3. Late cardiotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma

Author

E I Dorokhina, A U Magomedova, A A Shevelev, S M Kulikov, M K Gitis, A V Vedernikov, A I Vorobyev, and S K Kravchenko

Subjects
diffuse large b-cell lymphoma, mnhl-bfm 90 protocol, late toxicity, cardiotoxicity, Medicine
Abstract

Aim. To evaluate the late cardiotoxicity (CT) of high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) protocol in adult patients with diffuse large B-cell lymphoma (DLBCL). Subjects and methods. The results of electrocardiography (ECG) and echocardiography (echoCG) were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the Hematology Research Center (HRC), Russian Academy of Medical Sciences (RAMS), in 2002 to 2009. A study group consisted of 20 men and 20 women whose age was 31 to 76 years; median age was 56.5 years at the time of their examination and the median follow-up time after therapy was 6 years. The individual cumulative dose of doxorubicin was 150-300 mg/m2. A comparison group included 19 patients receiving СНОР/R-СНОР CT in HRC, RAMS, in 2002 to 2009. Out of them, there were 8 men and 11 women whose age was 39 to 78 years median age was 70 years at the time of their examination. The individual cumulative dose of doxorubicin was 200—400 mg/m2. ECG and echoCG were carried out before and 5 years or more after CT. Results. Out of the 40 patients with DLBCL, the signs of subclinical cardiomyopathy (CMP) were detected in 24 (60%) patients; no clinical manifestations of congestive heart failure (CHF) were found in any patient. In the comparison group of 19 patients receiving СНОР/R-СНОР CT, 14 (74%) patients were found to have signs of subclinical CMP and no clinical signs of CHF. The summary toxicity index significantly depended on age (p=0.03) and a history of heart disease (p=0.3); it was significantly higher after CHOP/R-CHOP CT (p=0.05). There was a statistically significant relationship of the risk of subclinical CMP to the history of heart diseases (p=0.05). Conclusion. Late cardiotoxicity of the mNHL-BFM-90 program does not exceed the toxicity of standard CHOP/R-CHOP therapy. Post-CT Echo-CG and ECG findings showed that the patients with the most marked subclinical signs of CMP in both groups had cardiotoxicity risk factors, such as coronary heart disease, hypertensive disease, or diabetes in their history. No clinically significant CHF was identified in any patient.

Published
2015

4. THE MORPHOLOGICAL SUBSTRATE AND IMMUNOHYSTOARCHITECTURAL PATTERNS IN NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA

Author

I. A. Shupletsova, A. M. Kovrigina, T. N. Moiseeva, and E. I. Dorokhina

Subjects
нодулярная лимфома ходжкина с лимфоидным преобладанием, морфология, иммунофенотип, иммуногистоархитектоника, Medicine
Abstract

The aim of the study is to compare the tumour growth pattern with immunohystoarchitectural patterns in patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in the debut of the disease. Material and methods. The diagnosis of NLPHL in the debut of the disease was established in 60 patients (male/female ratio is 3.6:1, median age – 37 (range 17–68)) using morphology an expanded immunohistochemical study. The tumor growth pattern was determined by morphological study and immunohistochemical patterns (WHO 2017) – using antibodies to CD20 and clinical stages (Ann Arbor). Results and discussion. All patients were divided into 3 immunohystoarchitectural patterns (subject to immunohystoarchitectonics in reaction with antibodies to CD20): A – LP cells are located within B cell nodules; B – LP cells are located intra- and extranodular with the preservation of B cell nodules or in the presence of a border of B-lymphocytes; C – predominant (> 50 % of section area) diffuse or large-focal discrete arrangement of LP cells without the presence of a B cell border. Concerning to the immunohystoarchitectural patterns, all the patients were divided into three groups: I (immunohistochemical pattern A – 17 cases, 28 %, stage – I–II 82 %, stage III – 18 %, nodular growth – 100 %), II (immunohistochemical pattern B – 30 cases, 50 %, stage I–II – 40 %, stage III–IV – 60 %, nodular growth – 3 %, nodular growth with a significant number of extranodular LP cells – 43 %, nodular-diffuse growth – 53 % cases), III (immunohistochemical pattern C – 12 patients, 20 %; II stage – 8 %, tumor cell-rich case, stage III–IV – 92 %; nodular-diffuse growth – 75 % cases, mainly diffuse growth – 25 % cases), 1 case with transformation in DLBCL (2 %, IV stage). Conclusions. NLPHL is characterized by variable morphological immunohistochemical patterns among which we’ve revealed 4 morphological variants and 3 immunohistochemical patterns considered as sign of immunohistochemical transformation within the continuum of the same entity of NLHLP. The immunohistochemical patterns are not always a predictor of the clinical course of the disease. «Tumor cell-rich» cases require further detailed research.

Published
2019
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5. Numbers of early CD34+ progenitors of bone marrow hematopoiesis in patients with diffuse large B-cell lymphoma

Author

Svetlana A. Glinkina, Sergei M. Kulikov, Aminat U. Magomedova, E I Dorokhina, S K Kravchenko, V N Dvirnyk, and Irina V. Galtseva

Subjects
0301 basic medicine, History, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, CD34, lcsh:Medicine, Antigens, CD34, mnhl-bfm-90, CHOP, Gastroenterology, cd34+, 03 medical and health sciences, myelotoxicity, Bone Marrow, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, Aged, Chemotherapy, Hematology, business.industry, lcsh:R, Antineoplastic Protocols, General Medicine, Middle Aged, Hematopoietic Stem Cells, medicine.disease, Hematopoiesis, Lymphoma, diffuse large b-cell lymphoma, 030104 developmental biology, Hypocellularity, medicine.anatomical_structure, Lymphoma, Large B-Cell, Diffuse, Bone marrow, Family Practice, business, Diffuse large B-cell lymphoma, high-dose chemotherapy, Follow-Up Studies
Abstract

To estimate the number of early progenitors of bone marrow (BM) hematopoiesis in patients with diffuse large B-cell lymphoma (DLBCL) in the late period after high-dose chemotherapy (HDCT) according to the mNHL-BFM-90 program.The investigators analyzed the results of BM immunophenotypic and histological studies in 40 patients (median age, 57 years) with DLBCL who received HDCT according to the mNHL-BFM-90 program at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), in the period 2002 to 2009. A comparison group consisted of 19 patients (median age, 70 years) treated according to the CHOP/R-CHOP program at HRC, MHRF, in the same period. The median follow-up period was 6 years. The results of BM examination were analyzed before and 5-10 years after the end of HDCT. Immunophenotypic study determined the number of early CD34+ hematopoietic progenitors. BM cellularity, the size of erythroid, granulocytic and megakaryocytic lineages, their ratio, the presence of dysplasia signs, and secondary stromal changes were histologically determined. The BM toxic injury signs found for the first time were evaluated as manifestations of late myelotoxicity.At 5-to-10-year follow-ups after the end of HDCT according to the mNHL-BFM-90 program, the patients showed a smaller number of early CD34+ progenitors of BM hematopoiesis in 31 (78%) cases than those treated according to the CHOP/R-CHOP-21 program (n=8 (2%)) (p=0.005). Myelopoiesis with decreased CD34+ cell count was characterized by hypocellularity in 8 (26%) patients (p=0.07), the narrowing of megakaryocytic lineage in 14 (45%) (p=0.006), erythroid one in 7 (23%) (p=0.01), and granulocytic one in 8 (26%) (p=0.92), pronounced secondary stromal changes in 15 (48%) (p=0.03), and grade 1 thrombocytopenia in 13 (42%); p=0.02).There is evidence that the number of early CD34+ progenitors of BM hematopoiesis decreased in patients with DLBCL in the late period after HDCT. The investigation shows the relationship of the reduction in the number of early CD34+ progenitors of BM hematopoiesis in the late follow-up period to the presence of pronounced secondary changes in the BM stroma (p=0.02). There was no statistically significant relationship of the decreased number of CD34+ cells to the age younger or older than 60 years, to the period after the end of chemotherapy, to gender or presence of specific BM injury.Цель исследования. Оценка количества ранних предшественников кроветворения в костном мозге (КМ) больных диффузной В-крупноклеточной лимфомой (ДВККЛ) в отдаленном периоде после высокодозной химиотерапии (ВДХТ) по программе mNHL-BFM-90. Материалы и методы. Проанализированы результаты иммунофенотипического и гистологического исследований КМ 40 больных ДBККЛ, которым выполнена ВДХТ по программе mNHL-BFM-90 в ГНЦ МЗ РФ в период с 2002 по 2009 г., медиана возраста 57 лет. Группу сравнения составили 19 пациентов, которым проведена терапия по программе СНОР/R-СНОР в ГНЦ МЗ РФ в тот же период, медиана возраста 70 лет. Медиана срока наблюдения после окончания лечения 6 лет. Анализировали результаты исследования КМ до начала ВДХТ и через 5-10 лет после окончания лечения. При иммунофенотипическом исследовании определяли количество ранних предшественников кроветворения CD34+. При гистологическом исследовании определяли клеточность КМ, величину эритроидного, гранулоцитарного и мегакариоцитарного ростков, их соотношение, наличие признаков дисплазии, а также вторичные изменения стромы. В качестве проявлений отдаленной миелотоксичности оценивали впервые выявленные признаки токсического поражения КМ. Результаты. У больных ДВККЛ после высокодозной терапии по программе mNHL-BFM-90 при сроке наблюдения от 5 до 10 лет после окончания химиотерапии выявлено снижение количества ранних предшественников кроветворения CD34+ в КМ в 31 (78%) случае, в отличие от 8 (42%) больных после терапии СНОР/R-СНОР-21 (р=0,005). Миелопоэз со сниженным количеством клеток CD34+ характеризовался гипоклеточностью у 8 (26%; р=0,07), сужением мегакариоцитарного ростка у 14 (45%; р=0,006), эритроидного у 7 (23%; р=0,01) и гранулоцитарного у 8 (26%; р=0,92), выраженными вторичными изменениями стромы у 15 (48%; р=0,03), тромбоцитопенией I степени у 13 (42%; р=0,02) больных. Заключение. Доказано уменьшение количества ранних предшественников кроветворения CD34+ в КМ у больных ДВККЛ в отдаленном периоде после ВДХТ. Показана зависимость снижения количества ранних предшественников кроветворения CD34+ в КМ в отдаленном периоде наблюдений от наличия выраженных вторичных изменений стромы КМ (р=0,02). Статистически значимой зависимости уменьшения количества клеток CD34+ от возраста моложе или старше 60 лет, срока после окончания химиотерапии, пола, наличия специфического поражения КМ не выявлено.Цель исследования. Оценка количества ранних предшественников кроветворения в костном мозге (КМ) больных диффузной В-крупноклеточной лимфомой (ДВККЛ) в отдаленном периоде после высокодозной химиотерапии (ВДХТ) по программе mNHL-BFM-90. Материалы и методы. Проанализированы результаты иммунофенотипического и гистологического исследований КМ 40 больных ДBККЛ, которым выполнена ВДХТ по программе mNHL-BFM-90 в ГНЦ МЗ РФ в период с 2002 по 2009 г., медиана возраста 57 лет. Группу сравнения составили 19 пациентов, которым проведена терапия по программе СНОР/R-СНОР в ГНЦ МЗ РФ в тот же период, медиана возраста 70 лет. Медиана срока наблюдения после окончания лечения 6 лет. Анализировали результаты исследования КМ до начала ВДХТ и через 5—10 лет после окончания лечения. При иммунофенотипическом исследовании определяли количество ранних предшественников кроветворения CD34+. При гистологическом исследовании определяли клеточность КМ, величину эритроидного, гранулоцитарного и мегакариоцитарного ростков, их соотношение, наличие признаков дисплазии, а также вторичные изменения стромы. В качестве проявлений отдаленной миелотоксичности оценивали впервые выявленные признаки токсического поражения КМ. Результаты. У больных ДВККЛ после высокодозной терапии по программе mNHL-BFM-90 при сроке наблюдения от 5 до 10 лет после окончания химиотерапии выявлено снижение количества ранних предшественников кроветворения CD34+ в КМ в 31 (78%) случае, в отличие от 8 (42%) больных после терапии СНОР/R-СНОР-21 (р=0,005). Миелопоэз со сниженным количеством клеток CD34+ характеризовался гипоклеточностью у 8 (26%; р=0,07), сужением мегакариоцитарного ростка у 14 (45%; р=0,006), эритроидного у 7 (23%; р=0,01) и гранулоцитарного у 8 (26%; р=0,92), выраженными вторичными изменениями стромы у 15 (48%; р=0,03), тромбоцитопенией I степени у 13 (42%; р=0,02) больных. Заключение. Доказано уменьшение количества ранних предшественников кроветворения CD34+ в КМ у больных ДВККЛ в отдаленном периоде после ВДХТ. Показана зависимость снижения количества ранних предшественников кроветворения CD34+ в КМ в отдаленном периоде наблюдений от наличия выраженных вторичных изменений стромы КМ (р=0,02). Статистически значимой зависимости уменьшения количества клеток CD34+ от возраста моложе или старше 60 лет, срока после окончания химиотерапии, пола, наличия специфического поражения КМ не выявлено.

Published
2017
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6. Late cardiotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma

Author

E I Dorokhina, A A Shevelev, A I Vorobyev, Kravchenko Sk, A V Vedernikov, M K Gitis, Sergei M. Kulikov, and Aminat U. Magomedova

Subjects
Adult, Male, History, medicine.medical_specialty, Time Factors, Endocrinology, Diabetes and Metabolism, cardiotoxicity, lcsh:Medicine, CHOP, Gastroenterology, Russia, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Asparaginase, Humans, Medicine, mnhl-bfm 90 protocol, Survival rate, Aged, Retrospective Studies, Cytopenia, Hematology, Dose-Response Relationship, Drug, business.industry, Incidence, Myelodysplastic syndromes, Daunorubicin, lcsh:R, General Medicine, Middle Aged, Prognosis, medicine.disease, Surgery, Survival Rate, diffuse large b-cell lymphoma, Hypocellularity, Vincristine, Dysplasia, Prednisone, Female, Lymphoma, Large B-Cell, Diffuse, Family Practice, business, Diffuse large B-cell lymphoma, late toxicity, Follow-Up Studies
Abstract

To evaluate the late cardiotoxicity (CT) of high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) protocol in adult patients with diffuse large B-cell lymphoma (DLBCL).The results of electrocardiography (ECG) and echocardiography (echoCG) were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the Hematology Research Center (HRC), Russian Academy of Medical Sciences (RAMS), in 2002 to 2009. A study group consisted of 20 men and 20 women whose age was 31 to 76 years; median age was 56.5 years at the time of their examination and the median follow-up time after therapy was 6 years. The individual cumulative dose of doxorubicin was 150-300 mg/M2. A comparison group included 19 patients receiving CHOP/R-CHOP CT in HRC, RAMS, in 2002 to 2009. Out of them, there were 8 men and 11 women whose age was 39 to 78 years median age was 70 years at the time of their examination. The individual cumulative dose of doxorubicin was 200-400 mg/M2. ECG and echoCG were carried out before and 5 years or more after CT.Out of the 40 patients with DLBCL, the signs of subclinical cardiomyopathy (CMP) were detected in 24 (60%) patients; no clinical manifestations of congestive heart failure (CHF) were found in any patient. In the comparison group of 19 patients receiving CHOP/R-CHOP CT, 14 (74%) patients were found to have signs of subclinical CMP and no clinical signs of CHF. The summary toxicity index significantly depended on age (p=0.03) and a history of heart disease (p=0.3); it was significantly higher after CHOP/R-CHOP CT (p=0.05). There was a statistically significant relationship of the risk of subclinical CMP to the history of heart diseases (p=0.05).Late cardiotoxicity of the mNHL-BFM-90 program does not exceed the toxicity of standard CHOP/R-CHOP therapy. Post-CT Echo-CG and ECG findings showed that the patients with the most marked subclinical signs of CMP in both groups had cardiotoxicity risk factors, such as coronary heart disease, hypertensive disease, or diabetes in their history. No clinically significant CHF was identified in any patient.Цель исследования. Оценка отдаленной кардиотоксичности (КТ) высокодозной химиотерапии по модифицированной программе NHL-BFM-90 (mNHL-BFM-90) у взрослых больных диффузной В-крупноклеточной лимфомой (ДВККЛ). Материалы и методы. Проанализированы результаты электро- и эхокардиографии (ЭхоКГ) у 40 больных ДBККЛ, получивших терапию по программе mNHL-BFM-90 в ГНЦ РАМН в период с 2002 по 2009 г. Основную группу составили 20 мужчин, 20 женщин в возрасте от 31 года до 76 лет, медиана возраста 56,5 года на момент обследования, медиана срока наблюдения после окончания терапии - 6 лет. Индивидуальная кумулятивная доза доксорубицина достигала 150-300 мг/м2. Группу сравнения составили 19 пациентов, получивших химиотерапию (ХТ) по программе СНОР/R-СНОР в ГНЦ РАМН в период с 2002 по 2009 г. Из них 8 мужчин и 11 женщин в возрасте от 39 до 78 лет, медиана 70 лет на момент обследования. Индивидуальная кумулятивная доза доксорубицина - 200-400 мг/м2. Электрокардиографию и ЭхоКГ проводили перед началом и через 5 лет и более после окончания ХТ. Результаты. Из 40 больных ДBККЛ признаки субклинической кардиомиопатии (КМП) обнаружены у 24 (60%), клинических проявлений застойной сердечной недостаточности (ЗСН) ни у одного пациента не выявлено. В группе сравнения из 19 пациентов, получивших ХТ по программе СНОР/R-СНОР, признаки субклинической КМП выявлены у 14 (74%) без клинических признаков ЗСН. Суммарный показатель токсичности достоверно зависел от возраста (p=0,03), наличия заболеваний сердца в анамнезе (р=0,03), и был достоверно выше (р=0,05) после ХТ СНОР/R-СНОР. Выявлена статистически значимая (р=0,05) зависимость риска развития субклинической КМП от наличия заболеваний сердца в анамнезе. Заключение. Отдаленная КТ программы mNHL-BFM-90 не превышает токсичность стандартной терапии СНОР/R-СНОР. У пациентов с наиболее выраженными субклиническими признаками КМП после ХТ по данным ЭхоКГ и электрокардиографии в обеих группах имелись факторы риска КТ - ишемическая болезнь сердца, гипертоническая болезнь, сахарный диабет в анамнезе. Клинически значимой застойной сердечной недостаточности ни у одного пациента не выявлено.

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