原发性纵隔大B细胞淋巴瘤治疗及研究新进展_West China Medical Journal

Authors：

 张雅坤 ,  邹立群

四川大学华西医院肿瘤中心（成都 610041）;

Corresponding author：

邹立群, Email: hxlcyxy@163.com

Keywords：

原发性纵隔大B细胞淋巴瘤; 治疗; 预后; 研究; 进展

DOI：

10.7507/1002-0179.20150451

Video：

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Abstract Full text Figures/Tables Video References Cited by

原发性纵隔大B细胞淋巴瘤（PMBL）是一种非霍奇金淋巴瘤的独特亚型，好发于青年女性，起源于胸腺髓质B细胞，主要表现为前上纵隔巨大肿块，患者症状与肿瘤的胸腔内浸润和压迫邻近器官有关。病理学表现为中等到大体积的肿瘤细胞弥漫增生，肿瘤细胞周围常有不同程度的纤维化和（或）硬化。PMBL表达多重成熟B细胞抗原和B细胞转录因子，但存在缺陷的免疫球蛋白产生。细胞遗传学涉及JAK2基因和c-REL基因的扩增。由于缺乏前瞻性的随机临床试验，目前尚未见PMBL患者治疗的最佳方案。推荐以蒽环类药物为基础的方案化学治疗（化疗），化疗结束后正电子发射计算机断层显像-CT评估是否辅助放射治疗（放疗）。推荐使用剂量调整后的依托泊苷+多柔比星+环磷酰胺+长春新碱+泼尼松+利妥昔单抗（DA-EPOCH-R）方案或利妥昔单抗+环磷酰胺+多柔比星+长春新碱+泼尼松+异环磷酰胺+卡铂+依托泊苷（RCHOP-ICE）方案化疗，可减少巩固放疗及其带来的远期副反应。患者预后与2个或以上的结外病变以及所接受的初始治疗关系密切。现就PMBL的最新治疗进展加以综述。

Citation： 张雅坤, 邹立群. 原发性纵隔大B细胞淋巴瘤治疗及研究新进展. West China Medical Journal, 2015, 30(8): 1571-1576. doi: 10.7507/1002-0179.20150451 Copy

1.	Lichtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal lymphoma in adults[J]. Am J Med, 1980, 68(4):509-514.
2.	Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma[J]. Blood, 2011, 118(10):2659-2669.
3.	Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms:a proposal from the International Lymphoma Study Group[J]. Blood, 1994, 84(5):1361-1392.
4.	Carbone A, Gloghini A, Aiello A, et al. B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology[J]. Hum Pathol, 2010, 41(5):621-631.
5.	Popov SW, Moldenhauer G, Wotschke B, et al. Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma[J]. Cancer Res, 2007, 67(14):6555-6564.
6.	Banks PM, Warnke R. Mediastinal (thymic) large B-cell lymphoma[M]//Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumors. Lyon:IARC Press, 2001:175-176.
7.	Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues[M]. Lyon:International Agency for Research on Cancer, 2008:250-251.
8.	Hutchinson CB, Mediastinal WP. Large b-cell lymphoma:a short review with brief discussion of mediastinal gray zone lymphoma[J]. Arch Pathol Lab Med, 2011, 135(3):394-398.
9.	NCCN. NCCN clinical practice guidelines in oncology, non-hodgkin's lymphomas, Version 3. 2014[EB/OL]. (2014-07-18)[2014-12-01]. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.
10.	Pileri SA, Zinzani PL, Gaidano G, et al. Pathobiology of primary mediastinal B-cell lymphoma[J]. Leuk Lymphoma, 2003, 44(Suppl 3):S21-S26.
11.	Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma[J]. Blood, 2003, 102(12):3871-3879.
12.	Frick M, Dörken B, Lenz G. The molecular biology of diffuse large B-cell lymphoma[J]. Ther Adv Hematol, 2011, 2(6):369-379.
13.	Van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma:a review of pathology and management[J]. J Clin Oncol, 2001, 19(6):1855-1864.
14.	Bhatt VR, Mourya R, Shrestha R, et al. Primary mediastinal large B-cell lymphoma[J]. Cancer Treat Rev, 2015, 68(3):256-263.
15.	Boleti E, Johnson PW. Primary mediastinal B-cell lymphoma[J]. Hematol Oncol, 2007, 25(4):157-163.
16.	Savage KJ. Primary mediastinal large B-Cell lymphoma[J]. Oncologist, 2006, 11(5):488-495.
17.	Pileri SA, Gaidano G, Zinzani PL, et al. Primary mediastinal B-cell lymphoma:high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, Bob.1, and PU.1 in the absence of immunoglobulins[J]. Am J Pathol, 2003, 162(1):243-253.
18.	Ritz O, Leithäuser F, Hasel C, et al. Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line[J]. J Pathol, 2005, 205(3):336-348.
19.	Higgins JP, Warnke RA. CD30 expression is common in mediastinal large B-cell lymphoma[J]. Am J Clin Pathol, 1999, 112(2):241-247.
20.	De Leval L, Ferry JA, Falini B, et al. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma:evidence for derivation from germinal center B cells?[J]. Am J Surg Pathol, 2001, 25(10):1277-1282.
21.	Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma[J]. J Exp Med, 2003, 198(6):851-862.
22.	Attias D, Hodgson D, Weitzman S. Primary mediastinal B-cell lymphoma in the pediatric patient:can a rational approach to therapy be based on adult studies?[J]. Pediatr Blood Cancer, 2009, 52(5):566-570.
23.	Reiter A, Klapper W. Recent advances in the understanding and management of diffuse large B-cell lymphoma in children[J]. Br J Haematol, 2008, 142(3):329-347.
24.	Ahn HJ, Yoon DH, Kim S, et al. Primary mediastinal large B-cell lymphoma:a single-center experience in Korea[J]. Blood Res, 2014, 49(1):36-41.
25.	Hamlin PA. Evolving treatment paradigms for primary mediastinal diffuse large B-cell lymphoma[J]. J Clin Oncol, 2014, 32(17):1751-1753.
26.	Cheah CY, Hofman MS, Seymour JF, et al. The utility and limitations of PET-CT in patients with primary mediastinal B-cell lymphoma:single institution experience and literature review[J]. Leuk Lymphoma, 2015, 56(1):49-56.
27.	Rieger M, Osterborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab:results of the Mabthera International Trial Group study[J]. Ann Oncol, 2011, 22(3):664-670.
28.	Lazzarino M, Orlandi E, Paulli M, et al. Primary mediastinal B-cell lymphoma with sclerosis:an aggressive tumor with distinctive clinical and pathologic features[J]. J Clin Oncol, 1993, 11(12):2306-2313.
29.	Lazzarino M, Orlandi E, Paulli M, et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma:a multicenter study of 106 patients[J]. J Clin Oncol, 1997, 15(4):1646-1653.
30.	Zinzani PL, Martelli M, Bertini M, et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis:a retrospective multinational study on 426 previously untreated patients[J]. Haematologica, 2002, 87(12):1258-1264.
31.	Avigdor A, Sirotkin T, Kedmi M, et al. The impact of R-VACOP-B and interim FDG-PET/CT on outcome in primary mediastinal large B cell lymphoma[J]. Ann Hematol, 2014, 93(8):1297-1304.
32.	Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy[J]. Blood, 2013, 121(2):278-285.
33.	Avilés A, Neri N, Fernández R, et al. Randomized clinical trial to assess the efficacy of radiotherapy in primary mediastinal large B-lymphoma[J]. Int J Radiat Oncol Biol Phys, 2012, 83(4):1227-1231.
34.	Pugh TJ, Ballonoff A, Rusthoven KE, et al. Cardiac mortality in patients with stage Ⅰ and Ⅱ diffuse large B-cell lymphoma treated with and without radiation:a surveillance, epidemiology, and end-results analysis[J]. Int J Radiat Oncol Biol Phys, 2010, 76(3):845-849.
35.	Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma[J]. N Engl J Med, 2013, 368(15):1408-1416.
36.	Moskowitz C, Hamlin J, Maragulia JA, et al. Sequential Dose-Dense RCHOP followed by ICE consolidation (MSKCC protocol 01-142) without radiotherapy for patients with primary mediastinal large B cell lymphoma[J]. Blood, 2010, 116(21):187-188.
37.	Melzner I, Bucur AJ, Bruderlein S, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phosphor JAK2 action in the MedB-1 mediastinal lymphoma line[J]. Blood, 2005, 105(6):2535-2542.
38.	Melzner I, Weniger MA, Bucur AJ, et al. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein[J]. Int J Cancer, 2006, 118(8):1941-1944.
39.	Quintás-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond[J]. Nat Rev Drug Discov, 2011, 10(2):127-140.
40.	Gebauer N, Hardel TT, Gebauer J, et al. Activating mutations affecting the NF-kappa B pathway and EZH2-mediated epigenetic regulation are rare events in primary mediastinal large B-cell lymphoma[J]. Anticancer Res, 2014, 34(10):5503-5507.
41.	Wessendorf S, Barth TF, Viardot A, et al. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas:an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH)[J]. Leukemia, 2007, 21(12):2463-2469.
42.	Lam LT, Davis RE, Pierce J, et al. Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling[J]. Clin Cancer Res, 2005, 11(1):28-40.
43.	Poiré X, Van Besien K. Autologous transplant for primary mediastinal B-cell lymphoma[J]. Expert Rev Hematol, 2009, 2(1):31-36.
44.	Kuruvilla J, Pintilie M, Tsang R, et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma[J]. Leuk Lymphoma, 2008, 49(7):1329-1336.
45.	Popat U, Przepiork D, Champlin R, et al. High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma:mediastinal localization predicts for a favorable outcome[J]. J Clin Oncol, 1998, 16(1):63-69.
46.	Sehn LH, Antin JH, Shulman LN, et al. Primary diffuse large B-cell lymphoma of the mediastinum:outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation[J]. Blood, 1998, 91(2):717-723.
47.	Ratei R, Matylis A, Krahl D, et al. Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8[J]. Leuk Lymphoma, 2000, 40(1/2):133-140.
48.	Nath SV, Seymour JF. Cure of a patient with profoundly chemotherapy-refractory primary mediastinal large B-cell lymphoma:role of rituximab, high-dose therapy, and allogeneic stem cell transplantation[J]. Leuk Lymphoma, 2005, 46(7):1075-1079.

1. Lichtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal lymphoma in adults[J]. Am J Med, 1980, 68(4):509-514.
2. Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma[J]. Blood, 2011, 118(10):2659-2669.
3. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms:a proposal from the International Lymphoma Study Group[J]. Blood, 1994, 84(5):1361-1392.
4. Carbone A, Gloghini A, Aiello A, et al. B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology[J]. Hum Pathol, 2010, 41(5):621-631.
5. Popov SW, Moldenhauer G, Wotschke B, et al. Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma[J]. Cancer Res, 2007, 67(14):6555-6564.
6. Banks PM, Warnke R. Mediastinal (thymic) large B-cell lymphoma[M]//Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumors. Lyon:IARC Press, 2001:175-176.
7. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues[M]. Lyon:International Agency for Research on Cancer, 2008:250-251.
8. Hutchinson CB, Mediastinal WP. Large b-cell lymphoma:a short review with brief discussion of mediastinal gray zone lymphoma[J]. Arch Pathol Lab Med, 2011, 135(3):394-398.
9. NCCN. NCCN clinical practice guidelines in oncology, non-hodgkin's lymphomas, Version 3. 2014[EB/OL]. (2014-07-18)[2014-12-01]. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.
10. Pileri SA, Zinzani PL, Gaidano G, et al. Pathobiology of primary mediastinal B-cell lymphoma[J]. Leuk Lymphoma, 2003, 44(Suppl 3):S21-S26.
11. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma[J]. Blood, 2003, 102(12):3871-3879.
12. Frick M, Dörken B, Lenz G. The molecular biology of diffuse large B-cell lymphoma[J]. Ther Adv Hematol, 2011, 2(6):369-379.
13. Van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma:a review of pathology and management[J]. J Clin Oncol, 2001, 19(6):1855-1864.
14. Bhatt VR, Mourya R, Shrestha R, et al. Primary mediastinal large B-cell lymphoma[J]. Cancer Treat Rev, 2015, 68(3):256-263.
15. Boleti E, Johnson PW. Primary mediastinal B-cell lymphoma[J]. Hematol Oncol, 2007, 25(4):157-163.
16. Savage KJ. Primary mediastinal large B-Cell lymphoma[J]. Oncologist, 2006, 11(5):488-495.
17. Pileri SA, Gaidano G, Zinzani PL, et al. Primary mediastinal B-cell lymphoma:high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, Bob.1, and PU.1 in the absence of immunoglobulins[J]. Am J Pathol, 2003, 162(1):243-253.
18. Ritz O, Leithäuser F, Hasel C, et al. Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line[J]. J Pathol, 2005, 205(3):336-348.
19. Higgins JP, Warnke RA. CD30 expression is common in mediastinal large B-cell lymphoma[J]. Am J Clin Pathol, 1999, 112(2):241-247.
20. De Leval L, Ferry JA, Falini B, et al. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma:evidence for derivation from germinal center B cells?[J]. Am J Surg Pathol, 2001, 25(10):1277-1282.
21. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma[J]. J Exp Med, 2003, 198(6):851-862.
22. Attias D, Hodgson D, Weitzman S. Primary mediastinal B-cell lymphoma in the pediatric patient:can a rational approach to therapy be based on adult studies?[J]. Pediatr Blood Cancer, 2009, 52(5):566-570.
23. Reiter A, Klapper W. Recent advances in the understanding and management of diffuse large B-cell lymphoma in children[J]. Br J Haematol, 2008, 142(3):329-347.
24. Ahn HJ, Yoon DH, Kim S, et al. Primary mediastinal large B-cell lymphoma:a single-center experience in Korea[J]. Blood Res, 2014, 49(1):36-41.
25. Hamlin PA. Evolving treatment paradigms for primary mediastinal diffuse large B-cell lymphoma[J]. J Clin Oncol, 2014, 32(17):1751-1753.
26. Cheah CY, Hofman MS, Seymour JF, et al. The utility and limitations of PET-CT in patients with primary mediastinal B-cell lymphoma:single institution experience and literature review[J]. Leuk Lymphoma, 2015, 56(1):49-56.
27. Rieger M, Osterborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab:results of the Mabthera International Trial Group study[J]. Ann Oncol, 2011, 22(3):664-670.
28. Lazzarino M, Orlandi E, Paulli M, et al. Primary mediastinal B-cell lymphoma with sclerosis:an aggressive tumor with distinctive clinical and pathologic features[J]. J Clin Oncol, 1993, 11(12):2306-2313.
29. Lazzarino M, Orlandi E, Paulli M, et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma:a multicenter study of 106 patients[J]. J Clin Oncol, 1997, 15(4):1646-1653.
30. Zinzani PL, Martelli M, Bertini M, et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis:a retrospective multinational study on 426 previously untreated patients[J]. Haematologica, 2002, 87(12):1258-1264.
31. Avigdor A, Sirotkin T, Kedmi M, et al. The impact of R-VACOP-B and interim FDG-PET/CT on outcome in primary mediastinal large B cell lymphoma[J]. Ann Hematol, 2014, 93(8):1297-1304.
32. Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy[J]. Blood, 2013, 121(2):278-285.
33. Avilés A, Neri N, Fernández R, et al. Randomized clinical trial to assess the efficacy of radiotherapy in primary mediastinal large B-lymphoma[J]. Int J Radiat Oncol Biol Phys, 2012, 83(4):1227-1231.
34. Pugh TJ, Ballonoff A, Rusthoven KE, et al. Cardiac mortality in patients with stage Ⅰ and Ⅱ diffuse large B-cell lymphoma treated with and without radiation:a surveillance, epidemiology, and end-results analysis[J]. Int J Radiat Oncol Biol Phys, 2010, 76(3):845-849.
35. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma[J]. N Engl J Med, 2013, 368(15):1408-1416.
36. Moskowitz C, Hamlin J, Maragulia JA, et al. Sequential Dose-Dense RCHOP followed by ICE consolidation (MSKCC protocol 01-142) without radiotherapy for patients with primary mediastinal large B cell lymphoma[J]. Blood, 2010, 116(21):187-188.
37. Melzner I, Bucur AJ, Bruderlein S, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phosphor JAK2 action in the MedB-1 mediastinal lymphoma line[J]. Blood, 2005, 105(6):2535-2542.
38. Melzner I, Weniger MA, Bucur AJ, et al. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein[J]. Int J Cancer, 2006, 118(8):1941-1944.
39. Quintás-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond[J]. Nat Rev Drug Discov, 2011, 10(2):127-140.
40. Gebauer N, Hardel TT, Gebauer J, et al. Activating mutations affecting the NF-kappa B pathway and EZH2-mediated epigenetic regulation are rare events in primary mediastinal large B-cell lymphoma[J]. Anticancer Res, 2014, 34(10):5503-5507.
41. Wessendorf S, Barth TF, Viardot A, et al. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas:an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH)[J]. Leukemia, 2007, 21(12):2463-2469.
42. Lam LT, Davis RE, Pierce J, et al. Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling[J]. Clin Cancer Res, 2005, 11(1):28-40.
43. Poiré X, Van Besien K. Autologous transplant for primary mediastinal B-cell lymphoma[J]. Expert Rev Hematol, 2009, 2(1):31-36.
44. Kuruvilla J, Pintilie M, Tsang R, et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma[J]. Leuk Lymphoma, 2008, 49(7):1329-1336.
45. Popat U, Przepiork D, Champlin R, et al. High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma:mediastinal localization predicts for a favorable outcome[J]. J Clin Oncol, 1998, 16(1):63-69.
46. Sehn LH, Antin JH, Shulman LN, et al. Primary diffuse large B-cell lymphoma of the mediastinum:outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation[J]. Blood, 1998, 91(2):717-723.
47. Ratei R, Matylis A, Krahl D, et al. Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8[J]. Leuk Lymphoma, 2000, 40(1/2):133-140.
48. Nath SV, Seymour JF. Cure of a patient with profoundly chemotherapy-refractory primary mediastinal large B-cell lymphoma:role of rituximab, high-dose therapy, and allogeneic stem cell transplantation[J]. Leuk Lymphoma, 2005, 46(7):1075-1079.

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West China Medical Journal

原发性纵隔大B细胞淋巴瘤治疗及研究新进展

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