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Факторы прогноза у больных с диссеминированными гастроинтестинальными стромальными опухолями
Архири П.П., Стилиди И.С., Поддубная И.В. и др. Факторы прогноза у больных с диссеминированными гастроинтестинальными стромальными опухолями. Современная Онкология. 2016; 18 (2): 67–71.
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Arkhiri P.P., Stilidi I.S., Poddubnaya I.V. et al. Prognostic factors in patients with disseminated gastrointestinal stromal tumors. Journal of Modern Oncology. 2016; 18 (2): 67–71.
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Аннотация
В отличие от локализованных форм заболевания, основным методом лечения больных с метастатической болезнью является таргетная терапия тирозинкиназными ингибиторами. Эффективность и продолжительность эффективности таргентной терапии являются определяющими факторами, влияющими на прогноз больных с метастатическими гастроинтестинальными стромальными опухолями (ГИСО). Среди больных, у которых таргетная терапия неэффективна, медиана выживаемости составляет всего лишь 12–19 мес, тогда как в случаях эффективного лечения медиана выживаемости несопоставимо выше и составляет 60–72 мес. У больных с первичными локализованными гастроинтестинальными стромальными опухолями наиболее значимыми прогностическими факторами являются: размер первичной опухоли, митотический индекс, локализация опухоли, мутационный статус и морфологический вариант клеточного строения ГИСО. Учитывая, что у больных с диссеминированными ГИСО основным методом лечения является лекарственный, прогностическое значение некоторых перечисленных факторов теряется и, наоборот, укрепляется значимость других, таких как мутационный статус, тип клеточного строения опухоли, количество и в меньшей степени размер и локализация метастатических узлов.
Ключевые слова: гастроинтестинальные стромальные опухоли, таргетная терапия, тирозинкиназные ингибиторы, KIT, PDGFRA, дикий тип, иматиниб, сунитиниб, регорафениб.
Ключевые слова: гастроинтестинальные стромальные опухоли, таргетная терапия, тирозинкиназные ингибиторы, KIT, PDGFRA, дикий тип, иматиниб, сунитиниб, регорафениб.
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The main method of treatment of patients with metastatic GIST is targeted therapy using tyrosine kinase inhibitors in contrast to localized forms of the disease. The efficiency and the duration of targeted therapy efficiency are the main prognostic factors in patients with metastatic gastrointestinal stromal tumors (GIST). Targeted therapy was ineffective among patients with the median survival of only 12–19 months, whereas in cases of effective targeted therapy the median survival was incomparably higher – 60–72 months. The main prognostic factors in patients with primary localized gastrointestinal stromal tumors are: the size of the primary tumor, mitotic index, the localization of tumors, mutation status and morphological characteristics of GIST. Taking into consideration that the main method of treatment in patients with disseminated GIST is drug therapy, the predictive values of several mentioned factors have lost the value, but other factors such as mutation status, morphological characteristics, the number and size of tumors and the localization of metastatic nodes have become more important.
Key words: gastrointestinal stromal tumors, targeted therapy, tyrosine kinase inhibitors, KIT, PDGFRA, wild type, imatinib, sunitinib, regorafenib.
Полный текст
Список литературы
1. Fletcher CD, Berman JJ, Corless C et al Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002; 33 (5): 459–65.
2. Miettinen M, Lasota J. Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001; 438 (1): 1–12.
3. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23 (2): 70–83.
4. Rutkowski P, Nowecki Z, Nyckowski P et al. Surgical treatment of Patients with initially inoperable and/or metastatic gastrointestinal Stromal tumors(GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
5. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23: 91–1.
6. Miettinen M, Lasota J. Gastrointestinal Stromal Tumors. Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis. Arch Pathol Lab Med 2006; 130: 1466–76.
7. Casali PG, Jost L, Reichardt P et al. ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment anf follow-up. Ann Oncol 2008; 19 (Suppl. 2): 35–8.
8. Blanke CD, Demetri GD, von Mehren M et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26 (4): 620–5.
9. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1640 patients. J Clin Oncol 2010; 28 (7): 1247–53.
10. Joensuu H, Eriksson M, Hatrmann J et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (18, suppl): abstract LBA1.
11. Blay JY. A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev 2011; 37 (5): 373–84.
12. Antonescu CR, Besmer P, Tianhua G et al. Acquired Resistance to Imatinib in Gastrointestinal StromalTumor Occurs Through Secondary Gene Mutation. Clin Cancer Res 2005; 1: 4182–90.
13. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863): 295–302.
14. Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–38.
15. Стилиди И.С., Архири П.П., Никулин М.П. Хирургическое лечение больных с первичными локализованными и местнораспространенными гасроинтестинальными стромальными опухолями. Вестн. РОНЦ им. Н.Н.Блохина РАМН. 2010; 21 (1): 77–82. / Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s pervichnymi lokalizovannymi i mestnorasprostranennymi gasrointestinal'nymi stromal'nymi opukholiami. Vestn. RONTs im. N.N.Blokhina RAMN. 2010; 21 (1): 77–82. [in Russian]
16. Stilidi I, Arhiri P, Nikulin M, Bokhyan V. Surgical treatment of patients with recurrent and/or metastatic gastrointestinal stromal tumors (GISTs). Eur J Surg Oncol 2010; 9 (36): 927. Special Issue 15th Congress of the European Society of Surgical Oncology, abstract book.
17. Mudan SS, Conlon KC, Woodruff JM. Salvage surgery for patients with recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Canсer 2000; 88: 66–74.
18. Raut CP, Posner M, Desai J et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24 (15): 2325–31.
19. Rutkowski P, Nowecki Z, Nyckowski P. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
20. Архири П.П., Цымжитова Н.Ц., Стилиди И.С. и др. Клиническое и прогностическое значение мутационного статуса у больных гастроинтестинальными стромальными опухолями. Саркомы костей, мягких тканей и опухоли кожи. 2013; 1: 42–6. / Arkhiri P.P., Tsymzhitova N.Ts., Stilidi I.S. i dr. Klinicheskoe i prognosticheskoe znachenie mutatsionnogo statusa u bol'nykh gastrointestinal'nymi stromal'nymi opukholiami. Sarkomy kostei, miagkikh tkanei i opukholi kozhi. 2013; 1: 42–6. [in Russian]
21. Стилиди И.С., Архири П.П., Никулин М.П. Хирургическое лечение больных с рецидивными и метастатическими стромальными опухолями желудочно-кишечного тракта. Вопр. онкологии. 2011; 57 (4): 508–12. / Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s retsidivnymi i metastaticheskimi stromal'nymi opukholiami zheludochno-kishechnogo trakta. Vopr. onkologii. 2011; 57 (4): 508–12. [in Russian]
22. Le Cesne A, Ray-Coquard I, Bui BN et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010; 11 (10): 942–9.
23. De Matteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: 51–8.
24. Heinrich MC, Owzar K, Corless CL et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26 (33): 5360–7.
25. Debiec-Rychter M, Sciot R, Le Cesne A et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42 (8): 1093–103.
2. Miettinen M, Lasota J. Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001; 438 (1): 1–12.
3. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23 (2): 70–83.
4. Rutkowski P, Nowecki Z, Nyckowski P et al. Surgical treatment of Patients with initially inoperable and/or metastatic gastrointestinal Stromal tumors(GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
5. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23: 91–1.
6. Miettinen M, Lasota J. Gastrointestinal Stromal Tumors. Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis. Arch Pathol Lab Med 2006; 130: 1466–76.
7. Casali PG, Jost L, Reichardt P et al. ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment anf follow-up. Ann Oncol 2008; 19 (Suppl. 2): 35–8.
8. Blanke CD, Demetri GD, von Mehren M et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26 (4): 620–5.
9. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1640 patients. J Clin Oncol 2010; 28 (7): 1247–53.
10. Joensuu H, Eriksson M, Hatrmann J et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (18, suppl): abstract LBA1.
11. Blay JY. A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev 2011; 37 (5): 373–84.
12. Antonescu CR, Besmer P, Tianhua G et al. Acquired Resistance to Imatinib in Gastrointestinal StromalTumor Occurs Through Secondary Gene Mutation. Clin Cancer Res 2005; 1: 4182–90.
13. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863): 295–302.
14. Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–38.
15. Стилиди И.С., Архири П.П., Никулин М.П. Хирургическое лечение больных с первичными локализованными и местнораспространенными гасроинтестинальными стромальными опухолями. Вестн. РОНЦ им. Н.Н.Блохина РАМН. 2010; 21 (1): 77–82. / Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s pervichnymi lokalizovannymi i mestnorasprostranennymi gasrointestinal'nymi stromal'nymi opukholiami. Vestn. RONTs im. N.N.Blokhina RAMN. 2010; 21 (1): 77–82. [in Russian]
16. Stilidi I, Arhiri P, Nikulin M, Bokhyan V. Surgical treatment of patients with recurrent and/or metastatic gastrointestinal stromal tumors (GISTs). Eur J Surg Oncol 2010; 9 (36): 927. Special Issue 15th Congress of the European Society of Surgical Oncology, abstract book.
17. Mudan SS, Conlon KC, Woodruff JM. Salvage surgery for patients with recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Canсer 2000; 88: 66–74.
18. Raut CP, Posner M, Desai J et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24 (15): 2325–31.
19. Rutkowski P, Nowecki Z, Nyckowski P. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
20. Архири П.П., Цымжитова Н.Ц., Стилиди И.С. и др. Клиническое и прогностическое значение мутационного статуса у больных гастроинтестинальными стромальными опухолями. Саркомы костей, мягких тканей и опухоли кожи. 2013; 1: 42–6. / Arkhiri P.P., Tsymzhitova N.Ts., Stilidi I.S. i dr. Klinicheskoe i prognosticheskoe znachenie mutatsionnogo statusa u bol'nykh gastrointestinal'nymi stromal'nymi opukholiami. Sarkomy kostei, miagkikh tkanei i opukholi kozhi. 2013; 1: 42–6. [in Russian]
21. Стилиди И.С., Архири П.П., Никулин М.П. Хирургическое лечение больных с рецидивными и метастатическими стромальными опухолями желудочно-кишечного тракта. Вопр. онкологии. 2011; 57 (4): 508–12. / Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s retsidivnymi i metastaticheskimi stromal'nymi opukholiami zheludochno-kishechnogo trakta. Vopr. onkologii. 2011; 57 (4): 508–12. [in Russian]
22. Le Cesne A, Ray-Coquard I, Bui BN et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010; 11 (10): 942–9.
23. De Matteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: 51–8.
24. Heinrich MC, Owzar K, Corless CL et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26 (33): 5360–7.
25. Debiec-Rychter M, Sciot R, Le Cesne A et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42 (8): 1093–103.
________________________________________________
1. Fletcher CD, Berman JJ, Corless C et al Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002; 33 (5): 459–65.
2. Miettinen M, Lasota J. Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001; 438 (1): 1–12.
3. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23 (2): 70–83.
4. Rutkowski P, Nowecki Z, Nyckowski P et al. Surgical treatment of Patients with initially inoperable and/or metastatic gastrointestinal Stromal tumors(GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
5. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23: 91–1.
6. Miettinen M, Lasota J. Gastrointestinal Stromal Tumors. Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis. Arch Pathol Lab Med 2006; 130: 1466–76.
7. Casali PG, Jost L, Reichardt P et al. ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment anf follow-up. Ann Oncol 2008; 19 (Suppl. 2): 35–8.
8. Blanke CD, Demetri GD, von Mehren M et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26 (4): 620–5.
9. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1640 patients. J Clin Oncol 2010; 28 (7): 1247–53.
10. Joensuu H, Eriksson M, Hatrmann J et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2011; 29 (18, suppl): abstract LBA1.
11. Blay JY. A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev 2011; 37 (5): 373–84.
12. Antonescu CR, Besmer P, Tianhua G et al. Acquired Resistance to Imatinib in Gastrointestinal StromalTumor Occurs Through Secondary Gene Mutation. Clin Cancer Res 2005; 1: 4182–90.
13. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863): 295–302.
14. Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–38.
15. Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s pervichnymi lokalizovannymi i mestnorasprostranennymi gasrointestinal'nymi stromal'nymi opukholiami. Vestn. RONTs im. N.N.Blokhina RAMN. 2010; 21 (1): 77–82. [in Russian]
16. Stilidi I, Arhiri P, Nikulin M, Bokhyan V. Surgical treatment of patients with recurrent and/or metastatic gastrointestinal stromal tumors (GISTs). Eur J Surg Oncol 2010; 9 (36): 927. Special Issue 15th Congress of the European Society of Surgical Oncology, abstract book.
17. Mudan SS, Conlon KC, Woodruff JM. Salvage surgery for patients with recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Canсer 2000; 88: 66–74.
18. Raut CP, Posner M, Desai J et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24 (15): 2325–31.
19. Rutkowski P, Nowecki Z, Nyckowski P. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11.
20. Arkhiri P.P., Tsymzhitova N.Ts., Stilidi I.S. i dr. Klinicheskoe i prognosticheskoe znachenie mutatsionnogo statusa u bol'nykh gastrointestinal'nymi stromal'nymi opukholiami. Sarkomy kostei, miagkikh tkanei i opukholi kozhi. 2013; 1: 42–6. [in Russian]
21. Stilidi I.S., Arkhiri P.P., Nikulin M.P. Khirurgicheskoe lechenie bol'nykh s retsidivnymi i metastaticheskimi stromal'nymi opukholiami zheludochno-kishechnogo trakta. Vopr. onkologii. 2011; 57 (4): 508–12. [in Russian]
22. Le Cesne A, Ray-Coquard I, Bui BN et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010; 11 (10): 942–9.
23. De Matteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: 51–8.
24. Heinrich MC, Owzar K, Corless CL et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26 (33): 5360–7.
25. Debiec-Rychter M, Sciot R, Le Cesne A et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42 (8): 1093–103.
Авторы
П.П.Архири*1,2, И.С.Стилиди1,2, И.В.Поддубная2, С.Н.Неред1,2, М.П.Никулин1, О.Б.Абу-Хайдар1
1 ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23;
2 ГБОУ ДПО Российская медицинская академия последипломного образования Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1
*arhiri@mail.ru
1 ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23;
2 ГБОУ ДПО Российская медицинская академия последипломного образования Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1
*arhiri@mail.ru
________________________________________________
P.P.Arkhiri*1,2, I.S.Stilidi1,2, I.V.Poddubnaya2, S.N.Nered1,2, M.P.Nikulin1, O.B.Abu-Khaydar1
1 N.N.Blokhin Russian Cancer Reseach Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23;
2 Russian Medical Academy of Postgraduate Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1
*arhiri@mail.ru
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