Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma

Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.     

弥漫大B细胞淋巴瘤的一线治疗

 短疗程化疗联合受累野局部放疗(IFRT)是治疗局限期(Ⅰ～Ⅱ期) 弥漫大B细胞淋巴瘤患者的重要方法,但对于放疗的价值,目前存在争议。含蒽环类药物的联合化疗虽然使部分患者有可能被治愈,但依然有患者面临死亡。于是,研究者努力尝试通过提高化疗剂量密度或强度来提高患者的生存,但对老年患者,则试图减少剂量或使用毒性低的药物来进一步提高患者的生存。另外放射免疫疗法、生物靶向治疗等多方面的研究也取得了一定进展。     

Differentiation of low-grade gastric MALT lymphoma and high-grade gastric MALT lymphoma: the clinical value of Ga-67 citrate scintigraphy--a pilot study

Ga-67 citrate scintigraphy has been routinely and extensively used to evaluate non-Hodgkin's lymphoma (NHL) for more than 20 years. Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is by far the most common extranodal primary NHL. Gastric MALT lymphoma can be classified as low-grade (LG) or high-grade (HG). Low-grade gastric MALT lymphoma can be cured by eradication of Helicobacter pylori; but radiotherapy and/or chemotherapy and/or surgery are the major methods of treatment for the HG gastric MALT lymphoma. However, it is difficult to differentiate these two groups by clinical parameters and endoscopic findings. The purpose of this study was to determine whether Ga-67 citrate scintigraphy can distinguish the LG gastric MALT lymphoma from the HG gastric MALT lymphoma. Twenty-one patients (11 men and 10 women ranging in age from 38 to 83 years) with histologically confirmed gastric MALT lymphoma were enrolled. Twelve patients had LG and nine patients had HG. All 21 patients underwent Ga-67 citrate scintigraphy before treatment. The results of Ga-67 citrate scintigraphy were classified as positive or negative. In the LG group, nine patients had negative results and three patients had positive results. In the HG group of nine patients, all patients had positive results. Among the three patients who had positive results in the LG group, the uptake of gastric MALT lymphoma was lower than that of the liver. The Ga-67 citrate scintigraphy is of good clinical value for the differentiation of the LG gastric MALT lymphoma and the HG gastric MALT lymphoma. We think that the major value of Ga-67 citrate scintigraphy will be in following the patients with HG gastric MALT lymphoma after treatment to assess response of therapy and to detect possible recurrence and perhaps in determining transformation from the LG to HG gastric MALT lymphoma. However, further investigation is needed to understand the relationship between the uptake of Ga-67 citrate in gastric MALT lymphoma and transformation.     

弥漫大B细胞淋巴瘤的分子靶向治疗

 弥漫大B细胞淋巴瘤（DLBCL）是最常见的成人非霍奇金淋巴瘤。现阶段利妥昔单抗与CHOP方案的联合应用已显著改善了DLBCL的预后,约50%的DLBCL可以治愈。然而由于肿瘤的异质性,对于难治、复发的DLBCL仍然缺乏行之有效的治疗方法。随着基因表达谱(GEP)的运用以及对淋巴瘤细胞内活化信号途径的深入研究,发现了很多潜在的治疗靶点。     

Emerging prognostic factors in diffuse large B cell lymphoma

PURPOSE OF REVIEW: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype, characterized by marked clinical and biologic heterogeneity. Gene expression studies together with new monoclonal antibody production are playing an increasing role in determining important prognostic factors/biomarkers predictive of outcome. Despite these technical advances, much confusion exists in the literature as to what constitutes the important biomarkers for determining patient outcome. The purpose of this review is to highlight recent advances in our understanding of novel biomarkers in DLBCL and how these might be incorporated into current risk-adjustment models for prognosis. RECENT FINDINGS: Microarray gene expression analyses have revolutionized our approach to biomarkers in non-Hodgkin lymphomas. Thousands of genes can now be simultaneously analyzed for individual patients, creating a wealth of new data. This has resulted in an improved understanding of the basic biology, as well as the development of new outcome predictors. Monoclonal antibody reagents for some of these biomarkers already exist, allowing for their rapid validation at the level of protein expression and potential clinical translation. SUMMARY: A molecular classification of DLBCL is a current reality, and together with routine morphology, immunophenotype, and molecular cytogenetics, has allowed us to more accurately subclassify DLBCL and determine clinically relevant subgroups. The time is right to begin to consider how these novel biomarkers should be incorporated into current prognostic models to move beyond the clinically based International Prognostic Index     

来那度胺治疗弥漫大B细胞淋巴瘤的进展

来那度胺作为免疫调节药物已被广泛应用于多发性骨髓瘤的治疗,其不仅能直接诱导肿瘤细胞凋亡,还通过炎症因子、NK细胞、调节T细胞等发挥重要的免疫调节作用。此外,多项基础及临床研究均证实来那度胺在弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma,DLBCL）治疗中也可起到非常重要的作用,无论对初诊还是复发/难治DLBCL患者,来那度胺单药或联合R-CHOP等方案均取得较好的治疗效果。本文旨在综述来那度胺在治疗DLBCL的进展。     

Gastric diffuse large B cell lymphoma presenting as paraneoplastic cerebellar degeneration: Case report and review of literature

Paraneoplastic cerebellar degeneration (PCD) is a type of paraneoplastic neurological disorder (PND) that is associated with many solid tumors, Hodgkin’s lymphoma (HL) and very rarely with non-Hodgkin’s lymphoma (NHL). We report a case of PCD associated with gastric diffuse large B-cell lymphoma (DLBCL) in a patient who presented with acute onset of giddiness and double vision and had complete remission of the gastric lesion and marked improvement of cerebellar syndrome with rituximab-based combination chemotherapy. A brief review of the literature is also presented.     

Primary diffuse large B cell lymphoma of the base of tongue

Primary non-Hodgkin's lymphoma of tongue is very rare. We report a case of an elderly female who presented with a mass lesion and pain primarily involving the tongue and was diagnosed with diffuse large B cell lymphoma. Computed tomography revealed a 3-cm enhanced mass localized to the right tongue base. The patient was treated with three cycles of combination rituximab and CHOP chemotherapy, followed by external beam radiotherapy. The patient had a complete response after treatment, and three years following treatment, the patient has no signs of recurrence.     

CD20阴性的弥漫大B细胞淋巴瘤的研究进展

CD20阴性的弥漫大B细胞淋巴瘤是一种罕见的异质性淋巴增生性疾病。其以化学免疫治疗耐药性及低生存率为特点,表现为不典型的细胞形态和侵袭性的临床行为,因此CD20阴性弥漫大B细胞淋巴瘤的诊疗都是个难题。本综述分别对不同类型CD20阴性弥漫大B细胞淋巴瘤的临床特征、预后及治疗进行介绍,以提高临床医生对于此类恶性肿瘤的认识,从而提升其疗效。     

弥漫性大B细胞淋巴瘤预后因素的研究进展

弥漫性大B细胞淋巴瘤（diffuse large B cell lymphema,DLBCL）在形态学、临床表现及其治疗反应上都表现出异质性，明确DLBCL的预后影响因素有利于实施个体化治疗。根据免疫表型分组，DLBCL分为GCB组和非GCB组，GCB组患者预后明显优于非GCB组，其分组的准确性甚至优于基因检测；相关免疫表型如bcl2、 bcl6对于不同组的预后影响不同，利妥昔单抗的应用减少了细胞来源和相关免疫表型对于预后的不良影响。特定转录因子可以作为预后预测因子，如FOXP1阴性组预后好于阳性组、LMO2高表达的患者具有较高生存率等。抑制PI3K/AKT通路可使淋巴瘤细胞发生凋亡，且pAKT阴性组预后较阳性组好。谷胱甘肽过氧化物酶1（GXP1）低表达组预后较好；而在GXP1低表达组中，ABC转运体MDR1低表达组预后明显好于高表达组。此外，EB病毒感染、骨髓浸润的一致性、肿瘤大小、肿瘤血管形成均同预后有关，都有可能作为预后预测因子。     

老年弥漫大B细胞淋巴瘤的疗效分析

目的:探讨影响老年弥漫大B细胞淋巴瘤治疗与预后的相关因素。方法:选取我院肿瘤科2008年7月至2014年7月收治的20例年龄大于65岁的弥漫大B细胞淋巴瘤病人,观察影响疗效及总生存率的各种变量,分析导致死亡的最主要因素。结果:16例病人接受治疗,4例病人未接受治疗。接受治疗的16例病人2年生存率为40%,中位生存时间为15个月。其中分期早、白蛋白高、IPI值2分以下、完成治疗的病人2年生存率高、预后好。利用COX比例风险回归模型分析感染、有无完成治疗是影响患者总生存期的因素。结论:感染是导致生存率下降的危险因素,也是导致死亡最主要的因素。     

弥漫性大B细胞淋巴瘤侵犯骨髓的病理学观察

 目的　探讨弥漫性大B细胞淋巴瘤（DLBCL）侵犯骨髓的病理学特点、诊断与鉴别诊断。方法　对24例DLBCL侵犯骨髓的骨髓活检HE染色切片进行形态学观察,20例免疫组化（IHC）法进行免疫表型分析。将其中10例髓外部位原发的NHL患者的骨髓与髓外部位瘤细胞的形态学进行对比观察。结果　DLBCL侵犯骨髓的方式依次为：弥漫型14 例,间质型 6例,混合型2例,结节型1 例,窦内型1例。侵犯程度为重度15例,中度4例,轻度5例。瘤细胞形态学类型为中心母细胞型21 例,免疫母细胞型3例。瘤细胞表达CD20、CD45RA、Pax5等一种或多种B细胞的标记。不表达CD3、CD45RO、CD5、CD10、TdT、CyclinD1、CD38、CD68、MPO。10例髓外原发淋巴瘤患者的骨髓与其髓外部位瘤细胞形态一致。结论　DLBCL侵犯骨髓多具有特殊的骨髓病理学特点。少数轻度、间质型浸润以及混有较多小淋巴细胞者, 免疫组化有助于鉴别诊断。骨髓活检对于DLBCL侵犯骨髓的诊断具有重要意义。     

The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma

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Sequential development of peripheral t-cell lymphoma post immunochemotherapy of diffuse large B cell lymphoma

Reports of sequential occurrence of two or more types of lymphoma are rare, especially when they involve different cell lineages. Herein, we report a rare case of sequential development of peripheral t-cell lymphoma following treatment of diffuse large B cell lymphoma. In a 73-year-old Chinese male patient, diffuse large B-cell lymphoma (DLBCL) was diagnosed in September 2011 based on the result of a tongue biopsy. Afterwards, he received rituximab combined with chemotherapy and local radiotherapy. Though he achieved completed remission, he had a new symptom of one enlarged left inguinal lymph node in November of 2015. A new biopsy was then performed. Immunohistochemistry and polymerase chain reaction (PCR) for gene rearrangements proved monoclonal T-cell lymphoma. We didn't detect EBV infection in either of two biopsies, nor any evidence of immune dysfunction complications. Sequential development of B-cell and T-cell malignancy in this patient maybe an example of treatment-related secondary lymphoma.     

弥漫性大B细胞淋巴瘤中Bcl-2/IgH易位的初步研究

目的研究弥漫性大B细胞淋巴瘤中染色体Bcl-2/IgH易位及其与Bcl-2蛋白表达的关系。方法用PCR方法检测42例原发性DLBCL患者的Bcl-2/IgH易位,免疫组化方法检测Bcl-6和CD10的共表达（确认生发中心表型的标志）以及Bcl-2蛋白的表达。结果在42例DLBCL患者中13例为GC亚型病例;Bcl-2/IgH易位检出率为11.9%（5/42）,其中4例属于GC亚型,1例属于非GC亚型;5例易位阳性中3例有Bcl-2蛋白的表达。结论原发性DLBCL的Bcl-2/IgH易位率为11.9%,代表了一类由滤泡中心细胞起源的亚类,Bcl-2/IgH易位与Bcl-2蛋白表达无关。     

Clinicopathologic evaluation of subgroups of diffuse large B cell lymphoma by immunohistochemistry

Diffuse large B cell lymphoma (DLBCL) has become an emerging epidemic in recent years. Striking heterogeneity in its clinical, biological and treatment responses prompted us to identify variation in our study group. The aim was to classify the DLBCL into prognosis-based subgroups according to the WHO classification and to evaluate their relation to clinical parameters (age, gender, anatomic location and B symptoms), as well as bcl 2 and Ki 67 status. Patients and Methods: A cross sectional study was carried out on 42 DLBCL patients, classified histologically and immunophenotypically into germinal center B cell like (GCB) or non-GCB type. Immunohistochemistry (IHC) was performed using antibodies against CD 10, MUM-1 and bcl 6; additionally anti-apoptotic protein bcl 2 and proliferative marker Ki 67 (using cutoff value of 70%) were also assayed by IHC. Results: Of the total 27/42 (64%) were males and 15/42 (36%) females, with a mean age of 44.1±15 years. 15/42 (36%) cases were of GCB type as compared to 27/42 (64%) of non GCB type. Extranodal involvement and B symptoms were seen in 18/27 (66.6%) and 20/27(74%) of the non GCB type, whereas bcl 2 protein expression and Ki 67 proliferative index (PI) <70% were each noted in 22/27 (81.4%). Conclusion: We document an astonishingly high number of non-GCB type DLBCL in our population. It is alarming to see such an aggressive tumor proliferating in our region. Significant association of non-GCB type with extranodal origin, B symptoms and low Ki 67 PI (<70%) is another concern.