Prognostic impact of C-REL expression in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) phenotype is believed to confer a better prognosis than DLBCL with an activated B-cell (ABC) phenotype. Previous studies have suggested that nuclear factor-κB (NF-κB) activation plays an important role in the ABC subtype of DLBCL, whereas c-REL amplification is associated with the GCB subtype. Using immunohistochemical techniques, we examined 68 newly diagnosed de novo DLBCL cases (median follow-up 44 months, range 1 to 142 months) for the expression of c-REL, BCL-6, CD10, and MUM1/IRF4. Forty-four (65%) cases demonstrated positive c-REL nuclear expression. In this cohort of patients, the GCB phenotype was associated with a better overall survival (OS) than the non-GCB phenotype (Kaplan–Meier survival (KMS) analysis, p = 0.016, Breslow–Gehan–Wilcoxon test). In general, c-REL nuclear expression did not correlate with GCB vs. non-GCB phenotype, International Prognostic Index score, or OS. However, cases with a GCB phenotype and negative nuclear c-REL demonstrated better OS than cases with a GCB phenotype and positive nuclear c-REL (KMS analysis, p = 0.045, Breslow–Gehan–Wilcoxon test), whereas in cases with non-GCB phenotype, the expression of c-REL did not significantly impact the prognosis. These results suggest that c-REL nuclear expression may be a prognostic factor in DLBCL and it may improve patient risk stratification in combination with GCB/non-GCB phenotyping.     

利妥昔单抗联合化疗治疗弥漫型大B细胞淋巴瘤患者的临床研究

目的:探讨利妥昔单抗与化疗相结合治疗弥漫型大B细胞淋巴瘤(diffuse large Bcelllymphoma,DLBCL)患者的可行性。方法:选取2002年1月至2011年5月我院收治的84例CD20阳性的DLBCL患者,采用利利妥昔单抗与化疗相结合的方法治疗,对其疗效及安全性进行评价,并对其影响因素进行分析。结果:有56例患者治疗艹6个周期,占66.67%;有28例患者治疗6个周期,占33.33%。84例患者治疗的总有效率为83.33%。其中,初治组的总有效率为91.67%,明显高于复治组的62.5%,差异有统计学意义(P0.05)。红细胞沉降率、国际预后指数评分、是否为初治、是否存在B症状以及利妥昔单抗的治疗周期等变量成为影响治疗效果的独立危险因素(P0.05)。随访5年,治疗后第l年、2年、3年和5年患者的生存率分别为88.1%(74/84)、72.62%(61/84)、60.71%(51/84)、60.71%(51/84)。国际预后指数评分、利妥昔单抗的治疗周期以及治疗效果等变量是影响患者生存的独立危险因素(P0.05)。结论:对于弥漫型大B细胞淋巴瘤患者尤其是对初治患者而言,利妥昔单抗联合化疗治疗具有更好的治疗效果,临床应用时不会加重患者的不良反应。     

Immunofluorescent labeling of CD20 tumor marker with quantum dots for rapid and quantitative detection of diffuse large B-cell non-Hodgkin's lymphoma

Fluorescent semiconductor quantum dots (QDs) are newfound nanocrystal probes which have been used in bioimaging filed in recent years. The purpose of this study is to evaluate the diagnostic value of specific QDs coupled to rituximab monoclonal antibody against CD20 tumor markers for patients with diffuse large B-cell lymphoma (DLBCL). In current study rituximab-conjugated quantum dots (QDs-rituximab) were prepared against CD20 tumor markers for detection of CD20-positive cells (human Raji cell line) using flowcytometry. A total of 27 tumor tissue samples were collected from patients with DLBCL and 27 subjects with negative pathological tests as healthy ones, which stained by QD-rituximab. The detection signals were obtained from QDs using fluorescence microscopy. The flowcytometry results demonstrated a remarkable difference in fluorescent intensity and FL2-H + (CD20-positive cells percentage) between two groups. Both factors were significantly higher in Raji in comparison with K562 cell line (P < 0.05). Lot of green fluorescence signals was observed due to the selectively binding of QD-rituximab to CD20 tumor markers which overexpressed in tumor tissues and a few signals observed on the defined healthy ones. Based on these observations the cut-off point was 46.8 dots and the sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 89.5%, 91.3%, and 100%, respectively (LR+, 9.52; LR−, 0). The QD - rituximab could be beneficial as a bioimaging tool with high sensitivity to provide an accurate molecular imaging technique for identifying CD20 tumor markers for early diagnosis of the patients with DLBCL.     

利妥昔单抗维持治疗弥漫大B 细胞淋巴瘤的初步研究

目的:对弥漫大B细胞淋巴瘤患者进行利妥昔单抗维持治疗(Maintenance Rituximab,MR)的安全性及疗效的研究和探讨.方法:38例患者诱导治疗结束后根据患者及家属意见和经济条件分为MR组和观察组.每组19例.诱导治疗阶段两组患者均接受6～8个疗程R-CHOP(每3周)或R-EPOCH方案治疗.维持阶段,利妥昔单抗在诱导治疗完成后4-8周开始,375mg/m2,每3个月1次共2年(8次)或直至疾病复发、进展、死亡.维持前均经影像学检查证实无复发.结果与结论:MR对R-EPOCH或R-CHOP的诱导治疗后达到CRu/CR初治DLBCL病人,有很好的近期疗效,能提高其DFS率,但OS率无改善,而且其毒副反应小,可以耐受.     

Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma

MicroRNAs are naturally occurring small RNA species that regulate gene expression and are frequently abnormally expressed in cancers. However, the role of microRNAs in lymphoma is poorly understood. Therefore, we undertook a comprehensive study of microRNA expression in two of the most common lymphomas: diffuse large B-cell lymphoma (DLBCL) ( n = 80) and follicular lymphoma (FCL) ( n = 18) using microarrays containing probes for 464 human microRNAs. Unsupervised cluster analysis revealed distinct expression patterns between these two lymphomas and specific microRNA signatures (including members of the miR-17–92 cluster) were derived that correctly predicted lymphoma type in >95% of cases. Furthermore, we identified microRNAs in de novo DLBCL ( n = 64) associated with germinal centre-like and non-germinal centre-like immunophenotypes, international prognostic index status and event-free survival in CHOP and rituximab (R)-CHOP treated patients. Despite the indolent nature of FCL a significant proportion of cases undergo high-grade transformation to more aggressive DLBCL. In order to see if transformation is associated with changes in microRNA expression we compared transformed DLBCL cases ( n = 16) with de novo DLBCL, as well as FCL cases that underwent subsequent transformation ( n = 7) with FCL cases that had not transformed at a median follow-up of 60 months ( n = 11). Differential expression of 12 microRNAs correctly predicted >85% of transformed versus de novo DLBCL cases; six microRNAs ( miR-223, 217, 222 , 221 and let-7i and 7b) were found which could similarly predict or transformation in FCL ( P < 0.05). These data suggest that microRNAs have potential as diagnostic and prognostic markers in these lymphomas and may be used to identify FCL patients at risk of high-grade transformation.     

Genotypic and Phenotypic Differences between Nodal and Extranodal Diffuse Large B-Cell Lymphomas

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases that have diverse clinical, pathological, and biological features. Here, it is shown that primary nodal and extranodal DLBCLs differ genomically and phenotypically. Using conventional comparative genomic hybridization (CGH), the authors assessed the chromosomal aberrations in 18 nodal, 13 extranodal, and 5 mixed DLBCLs. The results demonstrate significantly distinct chromosomal aberrations exemplified by gains of chromosomal arms 1p, 7p, 12q24.21-12q24.31, and 22q and chromosome X and loss of chromosome 4, 6q, and 18q22.3-23 in extranodal compared with nodal DLBCLs. Nodal DLBCLs showed an increased tendency for 18q amplification and BCL2 protein overexpression compared with extranodal and mixed tumors. Using a panel of five antibodies against GCET1, MUM1, CD10, BCL6, and FOXP1 proteins to subclassify DLBCLs according to the recent Choi algorithm, the authors showed that the genomic profiles observed between the nodal and extranodal DLBCLs were not due to the different proportions of GCB vs ABC in the two groups. Further delineation of these genomic differences was illuminated by the use of high-resolution 21K BAC array CGH performed on 12 independent new cases of extranodal DLBCL. The authors demonstrated for the first time a novel genome and proteome-based signatures that may differentiate the two lymphoma types.     

Commentary on the WHO classification of tumors of lymphoid tissues (2008): ��Gray zone�� lymphomas overlapping with Burkitt lymphoma or classical Hodgkin lymphoma

The 2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues has introduced two new categories of high-grade B-cell lymphomas: entities in which features of diffuse large B-cell lymphoma (DLBCL) overlap with Burkitt lymphoma (DLBCL/BL) or classical Hodgkin lymphoma (DLBCL/HL). The DLBCL/BL category encompasses cases that resemble Burkitt lymphoma morphologically, but have one or more immunophenotypic or molecular genetic deviations that would exclude it from the BL category; conversely, some cases have immunophenotypic and/or genetic features of BL, but display cytologic variability unacceptable for BL. Many of the cases in the DLBCL/BL category contain a translocation of MYC as well as either BCL2 or BCL6 (so-called double-hit lymphomas) and have a very aggressive clinical behavior. The DLBCL/HL category encompasses lymphomas that exhibit the morphology of classical Hodgkin lymphoma but the immunophenotype of DLBCL, or vice versa. Most DLBCL/HL cases described present as mediastinal masses, but this category is not limited to mediastinal lymphomas. These new categories acknowledge the increasing recognition of cases that display mixed features of two well-established diseases. Whether the existence of such cases reflects shortcomings of our current diagnostic armamentarium or a true disease continuum in which such hybrid or intermediate neoplasms actually exist remains to be determined.     

外周血NETs、TP53、STAT3表达与弥漫性大B细胞淋巴瘤临床病理及预后的关系分析

摘要 目的：探究外周血中性粒细胞胞外诱捕网（NETs）、TP53、信号转导与转录因子3（STAT3）表达与弥漫性大B细胞淋巴瘤（DLBCL）临床病理及预后的关系。方法：选取2020年3月-2021年12月收治的71例DLBCL患者作为研究对象,抽取患者外周静脉血,采用R-CHOP方案进行治疗,记录患者外周血NETs、TP53、STAT3表达情况并分析DLBCL患者外周血NETs、TP53、STAT3表达与其临床病理及预后的关系。结果：髓细胞组织增生蛋白（MYC）阳性在TP53阳性中的占比显著高于TP53阴性,差异有统计学意义（x²=28.844,P＜0.001）;Hans分型生发中心B细胞（GCB）在STAT3阳性中的占比显著高于STAT3阴性（x²=4.331,P=0.037）,其余差异无统计学意义（P>0.05）;随访截止至2022年6月,随访时长8~28个月,71例患者中共53例缓解DLBCL患者,其余18例为R/R DLBCL患者;NETs阳性、TP53阳性、STAT3阳性患者无进展生存期（PFS）显著低于NETs阴性、TP53阴性、STAT3阴性患者,差异有统计学意义（P<0.05）且NETs阳性、TP53阳性、STAT3阳性患者存活率均低于NETs阴性、TP53阴性、STAT3阴性患者（P<0.05）;单因素分析结果显示Ann Arbor分期、NETs、TP53、STAT3为DLBCL患者的影响因素（P<0.05）;以患者预后情况（R/R DLBCL=1,缓解DLBCL=0）为因变量,将Ann Arbor分期、NETs、TP53、STAT3单因素分析有统计学意义的因素纳入COX回归模型中,结果显示：NETs、TP53、STAT3为DLBCL患者预后的危险因素（P<0.05）。结论：TP53、STAT3表达与DLBCL临床病理存在一定相关性,临床应对DLBCL患者TP53、STAT3表达情况引起重视;NETs、TP53、STAT3表达为DLBCL预后的危险因素,可作为DLBCL患者不良预后的预测指标。     

Survival and consolidative radiotherapy in patients living with HIV and treated for diffuse large B-cell lymphoma

ObjectivesCurrent guidelines tend to treat HIV positive (HIV+) patients as their seronegative counterparts with diffuse large B-cell lymphoma (DLBCL) but little is known about their radiotherapy responses differences.Patients and MethodsA retrospective cohort of all consecutive HIV+ DBCL patients treated with chemotherapy between 2004 and 2018 was assessed. All patients had biopsy-proven lymphomas. They were included if the proposed radical treatment was done without progression or death during chemotherapy and had at least 6 months of follow-up or were followed until death.ResultsFifty-three (53) patients were selected, with a median age at diagnosis of 41.39 years (20–65 years). Median follow-up of 35.16 months (1.4–178.7 months). Male patients accounted for 54.7% and most had a good performance in the ECOG scale at diagnoses (81.1% are ECOG 0−1). Median overall survival was not reached. Mean OS was 41.5 months with 16 deaths. Age had an impact on OS, with patients older than 60 years at more risk (p = 0.044), as did longtime use of HAART, with those that started antiretroviral therapy within the diagnose of the lymphoma at greatest risk (p = 0.044). RT did not have an impact on OS (p = 0.384) or PFS (p = 0.420), although survival curves show better OS in the radiotherapy group. Toxicities were rare, since none of the patients had grade 3 or superior toxicity.ConclusionRT did not impact survival or progression in our limited sample, but a longer OS may occur after the first-year post RT. RT should be tested in prospective data in the HIV+ population with DLBCL.     

Hyper-CVAD/MA治疗复发或难治性弥漫大B 细胞淋巴瘤的临床研究

目的:探讨Hyper-CVAD/MA方案治疗复发或难治弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的疗效及安全性。方法:观察26例经系统化疗后复发或难治的DLBCL患者接受Hyper-CVAD/MA方案化疗,21-28天为1周期,连续2个周期评价疗效及安全性,分析生存情况。结果:全组26例患者中,总有效率为46.15%,其中完全缓解(complete remission,CR)3例(11.54%),部分缓解(partial remission,PR)9例(34.61%),全组患者中位生存时间为10(2-25)个月,1年和2年总生存率分别为28.57%、14.29%。不良反应主要表现为III-IV度骨髓抑制及继发的肺部感染,其他包括胃肠道反应、口腔炎、肝功能异常等。结论:Hyper-CVAD/MA治疗复发难治DLBCL有一定的疗效,且患者可耐受,可作为二线方案的一个选择。     

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identi?ed that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL.     

Immunological microenvironment gene expression in patients with diffuse large B cell non Hodgkin lymphoma

BackgroundNon Hodgkin lymphoma (NHL) is one of the immune system cancers. The occurrence and progression of malignant lymphomas depends on cellular pathways deregulation. Understanding the relationship between the immune system at the genetic level and malignant transformation is critical to reach its etiology.ObjectiveThe aim of this work is to evaluate the expression of five immune related genes (PD-1, FOXP3, GrA, GrB and CD11c) in patients with diffuse large B cell non Hodgkin lymphoma (DLBCL).Materials and methodsThis study was conducted on fifty patients with DLBCL and fifty sex and age matched apparently healthy subjects. The participants were subjected to these laboratory investigations: complete blood count, serum lactate dehydrogenase and β2microglobulin (β₂M) levels and determination of PD-1, FOXP3, GrA, GrB and CD11c gene expressions.ResultsThe results of this study revealed that PD-1, FOXP3, GrA, GrB and CD11c gene expressions were significantly increased in DLBCL patients.ConclusionPatients with DLBCL have variablePD-1, FOXP3,GrA, GrB and CD11cgene expressions levels, which are correlated with the overall survival (OS) indicating that they can be good predictors of outcome in these patients.     

Long non-coding RNA as a novel biomarker and therapeutic target in aggressive B-cell non-Hodgkin lymphoma: A systematic review

Cancer initiation and progression have been associated with dysregulated long non-coding RNA (lncRNA) expression. However, the lncRNA expression profile in aggressive B-cell non-Hodgkin lymphoma (NHL) has not been comprehensively characterized. This systematic review aims to evaluate the role of lncRNAs as a biomarker to investigate their future potential in the diagnosis, real-time measurement of response to therapy and prognosis in aggressive B-cell NHL. We searched PubMed, Web of Science, Embase and Scopus databases using the keywords “long non-coding RNA”, “Diffuse large B-cell lymphoma”, “Burkitt's lymphoma” and “Mantle cell lymphoma”. We included studies on human subjects that measured the level of lncRNAs in samples from patients with aggressive B-cell NHL. We screened 608 papers, and 51 papers were included. The most studied aggressive B-cell NHL was diffuse large B-cell lymphoma (DLBCL). At least 79 lncRNAs were involved in the pathogenesis of aggressive B-cell NHL. Targeting lncRNAs could affect cell proliferation, viability, apoptosis, migration and invasion in aggressive B-cell NHL cell lines. Dysregulation of lncRNAs had prognostic (e.g. overall survival) and diagnostic values in patients with DLBCL, Burkitt's lymphoma (BL), or mantle cell lymphoma (MCL). Furthermore, dysregulation of lncRNAs was associated with response to treatments, such as CHOP-like chemotherapy regimens, in these patients. LncRNAs could be promising biomarkers for the diagnosis, prognosis and response to therapy in patients with aggressive B-cell NHL. Additionally, lncRNAs could be potential therapeutic targets for patients with aggressive B-cell NHL like DLBCL, MCL or BL.     

CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4⁺ T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19⁺ cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19⁺ cells than patients who did not show recurrence. Examining cytotoxic CD4⁺ T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4⁺ T cells. Also, frequency of cytotoxic CD4⁺ T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4⁺ T cells against autologous CD19⁺ cells was investigated. We found that the cytotoxic potential of CD4⁺ T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19⁺ cells presented a significant reduction after longer incubation with cytotoxic CD4⁺ T cells, suggesting that cytotoxic CD4⁺ T cells preferentially eliminated MHC II-expressing CD19⁺ cells. Blocking MHC II on CD19⁺ cells significantly reduced the cytolytic capacity of CD4⁺ T cells. Despite these discoveries, the frequency of cytotoxic CD4⁺ T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4⁺ T cells presented an MHC II-dependent cytotoxic potential against autologous CD19⁺ cells and could potentially represent a future treatment option for DLBCL.     

中枢神经系统弥漫大B 细胞淋巴瘤相关microRNAs 的研究进展

中枢神经系统(central nervous system,CNS)复发是弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的一种不常见的严重的并发症,新诊断的患者2年内易于发生,最常见于非霍奇金淋巴瘤弥漫大B细胞型(non-Hodgkin diffuse large B-cell lymphoma-,NHL-DLBCL),目前,对于初始治疗后出现中枢复发其发病机制并不清楚。microRNA(miRNA)是一类新发现的非编码小分子RNA,通过抑制靶基因翻译或降解靶miRNA调控基因表达,参与细胞分化、增殖、调亡等生命活动。miRNA在淋巴瘤的发生发展中有重要作用。近年来大量研究已证实miRNA与肿瘤的组织来源、进展、转移预后与耐药都密切相关,既可作为抑癌基因,也可作为癌基因。淋巴瘤是一种血液免疫系统肿瘤,与淋巴瘤相关的miRNA已成为当前研究热点之一。microRNAs的功能紊乱如何导致DLBCL发生的机制目前还没有得到很好的证明,但DLBCL患者中464种miRNAs显示microRNA(包括miRNA-17-92簇)预测淋巴瘤的准确率达95%,为淋巴瘤研究提供了新依据。     

The relationship among primary anatomic subsite and risk and distribution of second malignant neoplasms in patients with stage I/II diffuse large B-cell lymphoma: An analysis of the surveillance,epidemiology, and end results database

BackgroundRecent studies have reported that diffuse large B-cell lymphoma (DLBCL) involving different primary extranodal sites have distinct clinicopathological characteristics and prognosis. However, the risk of secondary malignant neoplasms (SMNs) in DLBCL survivors with different primary extranodal sites are unknown.MethodsA total of 40,714 patients diagnosed with stage I/II DLBCL were included from the Surveillance, Epidemiology, and End Results (SEER) database from 1983 to 2015.The standardized incidence ratio (SIR) and absolute excess risk (AER) were used to assess the risk of SMNs.ResultsThe results show that the risk of SMN was significantly higher in extranodal DLBCL than in the US general population (SIR, 1.18; 95% CI, 1.11–1.26), and the risk of developing SMN remains significantly elevated with increased latency. Moreover, there were multiple site-specific risk patterns. There was a 22%, 44%, 66%, 123% and 151% increased risk of SMN 10 years after primary gastrointestinal tract, head/neck, skeletal, lung and liver/pancreas DLBCL diagnosis, respectively. There was a significant decrease risk of SMN with increasing age at diagnosis for primary gastrointestinal tract and skeletal DLBCL. In addition, DLBCL patients with primary sites in the gastrointestinal tract, thyroid and liver/pancreas had the highest incidences of secondary stomach cancer, second thyroid cancer, and second hepatobiliary cancer, respectively, which indicated that the initial site of DLBCL may predict the type of SMN.ConclusionsThe strategies for cancer surveillance after extranodal DLBCL diagnosis may need to be individualized according to the subsite of extranodal DLBCL.     

2-12烷基-6-甲氧基环己基-2,5-二烯-1,4-二酮(DMDD)抗弥漫大B淋巴瘤的作用及机制*

目的:探讨2-12烷基-6-甲氧基环己基-2,5-二烯-1,4-二酮(DMDD)抗弥漫大B淋巴瘤(DLBCL)的作用及分子机制。方法:动物实验取4周龄BALB/C小鼠,分5组,20只/组,腹股沟注射DLBCL细胞株OCI-LY19细胞1 × 10⁷ cells/ml 每只0.1 ml,两天后分别灌胃0、1、5、25、125 mg/kg剂量的DMDD,1次/2天,给药的第18日,杀10只小鼠,取瘤组织称重,记录剩余小鼠的生存期。细胞实验取OCI-LY19细胞加入96孔培养板,每孔100 μl 1×10⁵ cells/ml,分别加入100 μl DMDD使其终浓度分别为0、1、5、25和125 μmol/L,作用0、24、48和72 h,设三复孔,MTS法检测细胞增殖活性;根据细胞增殖实验结果,选择0 μmol/L、5 μmol/L和25 μmol/L的DMDD作为后续用药浓度作用OCI-LY19细胞24 h,流式细胞仪分析凋亡率,hoechst染色观察细胞核型,JC-1染色观察线粒体膜电位,LDH释放实验评估药物细胞毒性,qPCR、Western blot分析基因转录和表达水平。结果:动物实验表明:与0 mg/kg用药组比,1～125 mg/kg DMDD能抑制小鼠瘤组织生长并延长其生存期(P＜0.01)。细胞实验表明:DMDD用药组OCI-LY19细胞增殖活性明显降低、凋亡水平显著增加(P＜0.01),细胞核出现碎裂、凝集和凋亡小体及线粒体膜电位下降,LDH释放率显著增加(P＜0.01),细胞内caspase-3和bax基因的转录表达和IκBα的磷酸化水平显著上调,bcl-2、bcl-xL、jak2和stat3基因的转录和蛋白表达水平明显受抑(P＜0.01)。结论:DMDD通过抑制JAK2/STAT3和NF-κB信号通路中JAK2、STAT3和p-IκBα的表达,下调BCL-2/BAX、活化Caspase-3,最终激活OCI-LY19细胞线粒体凋亡的内源性通路而促进了DLBCL细胞凋亡,抑制了OCI-LY19细胞增殖,具有抗DLBCL的作用。     

90例弥漫性大B细胞淋巴瘤的分子遗传学及预后意义初探

目的：分析90例弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）的临床病理学特征及其临床意义。方法：收集90例DLBCL石蜡包埋组织标本及预后资料,采用免疫组织化学技术及间期荧光原位杂交（Fluorescence in situ Hybridization,FISH）技术研究其免疫表型和分子遗传学特征。结果：本组病例中,70例原发于淋巴结外,20例原发于淋巴结。根据Hans模型,42.2%（38/90）的DLBCL起源于生发中心B细胞（GC）,57.8%（52/90）起源于非生发中心B细胞（Non-GC）。IGH、bcl-6、bcl-2及c-myc基因易位的阳性率分别为33.3%（30/90）、22.2%（20/90）、4.4%（4/90）和3.3%（3/90）;bcl-2、bcl-6、c-myc及IGH基因多拷贝的阳性率分别为51.1%（46/90）,40%（36/90）、30%（27/90）和14.4%（13/90）。20例bcl-6基因易位的DLBCL中,14例为Non-GC起源,6例为GC起源;4例bcl-2基因易位的病例中,3例为GC起源,1例为Non-GC起源;3例c-myc基因易位的病例中,2例为GC起源,1例为Non-GC起源。结外DLBCL的IGH基因易位的阳性率高于结内者（P〈0.05）;结内DLBCL的c-myc基因多拷贝的阳性率高于结外者（P〈0.05）。本组29例有随访结果的病例显示,IGH、bcl-6、bcl-2及c-myc基因易位及多拷贝与预后无明显相关（P〉0.05）。结论：本组DLBCL总的分子遗传学异常率（包括因易位及拷贝数的异常）为82.2%,其中以bcl2多拷贝（51.1%）最为多见。不存在IGH、bcl-6、bcl-2及c-myc基因异常,不能除外DLBCL的诊断。少部分DLBCL中存在Burrkitt淋巴瘤特征性的c-myc基因易位。IGH、bcl-2、bcl-6及c-myc基因易位及拷贝数的异常在DLBCL中不具有的预后判定意义。     

Commentary on the WHO classification of tumors of lymphoid tissues (2008): aggressive B-cell lymphomas

In the novel WHO classification 2008, the classification of aggressive B-cell lymphoma has been revised for several categories with the aim to define “clean” entities. Within large B-cell lymphoma, a few distinct clinico-pathological entities have been recognized with more clinically defined entities than pathologically defined ones. The majority of known morphological variations were not considered to merit more than classification as a variant of DLBCL, not otherwise specified. Specifically, a biological subgrouping of DLBCL on the basis of molecular (activated B-cell versus germinal center B-cell) or immunophenotypic (CD5+) features was felt to be too immature to include at this stage. The role of EBV in aggressive B-cell lymphoma has been explored in more depth with the recognition of several novel and re-defined clinico-pathological entities. Also, in these diseases, clinical definitions play a very dominant role in the WHO classification 2008.