The biological and clinical significance of the KI-67 growth fraction in multiple myeloma

We tested the significance of the Ki-67 plasma cell growth fraction in 49 bone marrow samples from 42 patients with multiple myeloma (MM). As a new approach to study myeloma cell proliferation, strong positivity of the CD38 antigen as plasma cell related feature was simultaneously evaluated with nuclear Ki-67 expression in a flow cytometric double immunofluorescence assay. Mean Ki-67 values were significantly higher in MM at relapse (22·4 per cent ± 10·4) as compared with MM at diagnosis (11·9 per cent ± 8·4, p < 0·005) and plateau-phase (10·0 per cent ± 5·5, p < 0·001), respectively. Serial observations in six patients confirmed this change in cell kinetic behaviour during the course of the disease. Elevated Ki-67 values correlated significantly with stage III (versus stage I, p < 0·05), beta-2-microglobulin serum levels > 6 (p < 0·001), plasmablastic morphology (p < 0·001), and diploid myeloma cell DNA-content (p < 0·005). No correlation was found between Ki-67 and immunoglobulin isotypes as well as immunophenotypic features (expression of CD10, CD33, and CD56) of myeloma cells. Clinically, six of seven patients with Ki-67 > 14 per cent at diagnosis had an unfavourable course (primary resistant disease or early relapse), and three of four patients with elevated Ki-67 values at plateau-phase relapsed within 3 months. Our results demonstrate the usefulness of Ki-67 in determining proliferative activity in MM and emphasize its value in the evaluation of the risk profile of MM patients.     

112例淋巴系统恶性肿瘤骨髓免疫表型分析

背景与目的:淋巴细胞白血病和淋巴瘤骨髓侵犯的诊断以细胞形态学为基础,而免疫分型可通过获得肿瘤细胞分化和发育阶段的信息使淋巴系统恶性肿瘤的诊断更为准确,为临床合理治疗和预后判断提供重要的科学依据.本研究应用多参数流式细胞术(flow cytometry,FCM)探讨淋巴细胞白血病和非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)骨髓侵犯的免疫表型特点.方法:收集112例病理确诊NHL并伴骨髓侵犯和淋巴细胞白血病患者的骨髓标本.应用FCM检测肿瘤细胞的免疫表型.结果:45例前驱B淋巴母细胞白血病/淋巴瘤(precursor B lymphoblastic lymphoma/leukemia,B-ALL/LBL)主要表达CD19、CD10、TdT、CD34、HLA-DR和CD20;32例前驱T淋巴母细胞白血病/淋巴瘤(precursor T lymphoblastic lymphoma/leukemia,T-ALL/LBL)主要表达胞内CD3(cytoplasmic CD3,CyCD3)、CD7、CD5、TdT、膜表面CD3(surface CD3,sCD3)和HLA-DR.77例前驱淋巴细胞肿瘤中,28例(36%)有髓系抗原CD13、CD33的表达;9例(20%)B-ALL/LBL病例有CD20与CD34共同表达,28例(87.5%)T-ALL/LBL病例有CyCD3与TdT共同表达.成熟淋巴细胞肿瘤35例,其中17例慢性淋巴细胞白血病/小淋巴细胞淋巴瘤主要表达CD19、CD20、CD5和HLA-DR,并有CD19与CD5共同表达.4例弥漫大B细胞性淋巴瘤主要表达CD19、CD20、CD10和HLA-DR.3例伯基特淋巴瘤主要表达CD19、CD10、CD20、SIgM.1例套细胞淋巴瘤表达CD5、CD19、CD20、HLA-DR.5例外周T细胞淋巴瘤(PTCL)主要表达sCD3、CD5、CD7、CD4或CD8.1例间变性大细胞淋巴瘤主要表达sCD3、HLA-DR.4例NK/T细胞肿瘤表达CD56、HLA-DR,也表达CD7或CD4或CD8.成熟淋巴细胞肿瘤不表达早期抗原如CD34、TdT.成熟淋巴细胞肿瘤可伴有髓系抗原CD13、CD33的表达.结论:淋巴系统恶性肿瘤侵犯骨髓采用形态学结合FCM免疫学分型可获得T、B细胞来源、肿瘤细胞分化阶段和异常抗原表达等参数,有助于临床诊断和微小残留病灶的检测.     

Prognostic correlation of HLA-DR expression in large cell lymphoma as determined by LN3 antibody staining. An Eastern Cooperative Oncology Group (ECOG) study.

Several previous studies employing surface-marker techniques suggest that HLA-DR antigen expression may correlate with prognosis in diffuse large cell lymphoma. Control studies in the authors' laboratory indicated that LN3 positivity in paraffin-embedded tissue correlates well with HLA-DR antigen expression. Accordingly they examined 212 cases of diffuse large cell lymphoma from one of Eastern Cooperative Oncology Group's (ECOG) high-grade malignant lymphoma treatment protocols. All patients studied had careful clinical follow-up of between 5 and 11 1/2 years from diagnosis and initiation of therapy. There was no correlation of strongly positive, positive, weakly positive, equivocal, or negative staining with survival. Cases that were LN3 negative had a median survival of 18.8 months versus a median survival of 39.4 months for all LN3-positive cases. However this difference was not statistically significant when using a log-rank test. The authors were unable to confirm that HLA-DR antigen expression, as defined by LN3, is prognostically valuable in diffuse large cell lymphoma in a multi-institutional study.     

Epstein-Barr virus-associated antibody pattern in untreated non-Hodgkin lymphoma patients. Relationship to clinical variables and lymphocyte functions

Sera from 296 unselected and untreated patients with non-Hodgkin lymphoma (NHL) classified according to the Rappaport and the Kiel systems were analzyed for antibodies to Epstein-Barr virus (EBV). The aim of the study was to determine whether antibody spectra and liters to EBV-coded antigens correlated to clinical and immunological variables and whether the liters were of any prognostic significance. Increased antibody titers to EB viral capsid antigen (VCA) and slightly raised titers to early antigens (EA) of the diffuse (D) and restricted (R) types were noted frequently. Anti-VCA antibody titers correlated to clinical stage and age of the patients but not to histological. subgroups according to the Rappaport or the Kiel classification systems. However, and-VCA titers ? 1:2560 were seen only in diffuse lymphomas according to the Rappaport and in non-follicle cell-derived lymphomas according to the Kiel classifications. Patients with complement-receptor-positive diffuse lymphomas had higher anti-VGA titers than complement-receptor-positive nodular cases. Anti-VCA titers also correlated positively to serum IgG levels (p <0.01). Total number of lymphocytes separated from peripheral blood and mitogen induced (ConA, PWM) DNA synthesis were recorded before treatment in 54 of the patients. The patients exhibited a significant lymphocytopenia as well as a significantly reduced lymphocyte response to mitogens (p <0.001) compared to healthy controls. Elevated anti-VCA titers and anti-EA titers correlated to a good mitogen-induced lymphocyte response (p <0.05). Only anti-D 1:40 at diagnosis predicted a poor prognosis.     

LACE‐conditioned autologous stem cell transplantation for relapsed or refractory diffuse large B‐cell lymphoma: treatment outcome and risk factor analysis from a single centre

High‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed diffuse large B‐cell lymphoma. We have analysed 51 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara‐C), cyclophosphamide, etoposide) conditioning for relapsed (n = 34, 67%) or primary refractory (n = 17, 33%) diffuse large B‐cell lymphoma. With a median follow‐up of 60 months (range 2–216) the probabilities of overall survival (OS) and progression‐free survival (PFS) at 5 years were 47 and 42%, respectively. The cumulative treatment‐related mortality was 10% (n = 5). Probabilities for OS and PFS at 5 years were 56 and 50% for patients with chemosensitive and 29 and 27% for patients with chemorefractory disease. In multivariate analysis abnormal pre‐ASCT levels of C‐reactive protein (>5 mg/L) were identified as a risk factor for worse OS, whereas abnormal pre‐ASCT levels of C‐reactive protein and chemoresistance predicted inferior PFS. LACE followed by ASCT is an effective treatment for approximately half of patients with chemosensitive relapsed diffuse large B‐cell lymphoma, and a proportion of chemorefractory patients also benefit. Copyright © 2010 John Wiley & Sons, Ltd.     

Prognostic significance of Ki-67 nuclear proliferative antigen, bcl-2 protein, and p53 expression in follicular and diffuse large B-cell lymphoma

We analyzed 104 patients with non-Hodgkin’s lymphoma, follicular or diffuse large-B-cell-type lymphoma, in order to evaluate the correlation between clinical characteristics and immunohistochemical parameters. Immunostaining was performed by means of monoclonal antibodies against Ki-67, bcl-2, and p53 expression. Forty-nine of the patients showed follicular lymphoma. A high expression of bcl-2 was found in 93%, high expression of p53 in 57%, and low expression of Ki-67 in 96%. Follicular lymphoma grade III showed a p53 expression (p=0.07) slightly higher than follicular lymphoma grades I and II, not reaching statistical significance. Follicular lymphoma grades I and II tended to express lower Ki-67 and higher levels of bcl-2 expression than grade III (p=0.06). Fifty-five cases showed diffuse large-B-cell lymphoma. Among them, bcl-2 was absent in 39%, whereas p53 and Ki-67 expression were high in 38%. In the diffuse large-B-cell lymphomas, a high bcl-2 expression correlated with stages III and IV (p=0.03) and involvement of more than one extranodal area (p=0.03). High Ki-67 expression was also associated to extranodal involvement of more than one area (p=0.03). Overall survival of patients did not show statistically significant differences regarding Ki-67, bcl-2, and p53 tumoral expression. Prognostic factors for overall survival in the multivariate analysis were age (p=0.02) and LDH (p=0.003). Time to progression was worse among follicular lymphoma with high p53 expression than with mild/moderate p53 expression (p=0.009).     

A Novel B Cell Line Established from Ki-1-positive Diffuse Large Cell Lymphoma

A novel cell line, designated KIS-1, was established from a patient with Ki-1-positive diffuse large cell lymphoma. Multiple phenotypic analysis of the KIS-1 cells was carried out with a total of 22 monoclonal antibodies defining hematopoietic cell subsets and lineages. The KIS-1 cells were positive for Ki-1, B4, HLA-DR, and 2D1 (common leucocyte) antigens, but were negative for the antigens reportedly specific for T cells, natural killer cells, granulocytes, monocytes, interdigitating reticulum cells and dendritic reticulum cells. The genomic analysis of the KIS-1 cells showed not only the rearrangement of JH and Jk genes but also the probable rearrangement of Cγ genes. Moreover, the cells produced immunoglobulin γ chains. Thus, KIS-1 was considered to be of B-cell lineage. The lymphoma-cell derivation of KIS-1 was based on the following facts. The cytochemical, immunologic, cytogenetic properties and the results of the molecular genomic analysis in the KIS-1 cells were essentially the same as those of the original tumor cells, and the KIS-1 cells were negative for Epstein-Barr virus-associated nuclear antigen. KIS-1 is the only known B-cell line derived from Ki-1-positive diffuse large cell lymphoma, and should be useful for defining the biological implications of Ki-1 antigen.     

Association between atl and non-hematopoietic neoplasms

A high incidence of multiple primary neoplasms has been observed in our patients with ATL in comparison to persons with other forms of hematologic malignancy who we have observed during the past 23 years (1963–1985). Five of 15 patients with ATL (33·3 per cent) have had at least one other associated neoplasm in comparison to only 44 of 1156 patients with other forms of hematological malignancy (3·8 per cent). The incidence figures for secondary neoplasms associated with the other hematologic malignancies were 4·3 per cent (16/370) for acute non-lymphocytic leukemia (ANLL), 2·2 per cent (2/90) for acute lymphocytic leukemia (ALL), 4·8 per cent (1/21) for acute unclassifiable leukemia, 2·2 per cent (5/225) for chronic myelogenous leukemia, 4·7 per cent (2/43) for chronic lymphocytic leukemia, 5·9 per cent (8/136) for malignant monoclonal gammopathy and 3·7 per cent (10/271) for malignant lymphoma. The incidence of multiple neoplasms in patients with ATL in comparison to those with other hematological malignancies was statistically significant (p<0·01 or p<0·001). The neoplasms associated with ATL have been adenocarcinoma of the thyroid or stomach, and squamous cell carcinoma of the larynx, lip or lung. We identified ATL-derived factor (ADF) in the cytoplasm of the secondary neoplasms of the ATL patients by means of indirect immunofluoroscopy and immunohistochemical techniques utilizing anti-ADF antibody. We also identified ras p21 products in these neoplasms by means of p21 ras monoclonal antibody studies. The possibility that HTLV-I was the cause of the secondary neoplasms thus was investigated. HTLV-I provirus genome was not found in all the six cases of non-ATL leukemic cells of the patients with anti-HTLV-I antibodies as determined by means of Southern blot analysis utilizing pX DNA probe. These findings suggest that there is some association between ATL cells and pre-malignant cells through ADF or other unknown factors in the activation of ras oncogenes. Subsequent suppression of host immune defence mechanisms in ATL patients permits evolution of the secondary neoplasms.     

Immunocompetence and malignant lymphoma: immunologic status before therapy

One-hundred-eighty-six previously untreated patients with malignant lymphoma were evaluated for immunocompetence by means of several tests of immune function: total circulating lymphocytes, T cells (E-rosettes), B cells (EAC-rosettes), delayed hypersensitivity to six recall antigens, serum immunoglobulins, mixed lymphocyte culture, and lymphocyte mitogenic response to phytohemagglutinin and pokeweed mitogen. The results were correlated with histology, stage, and clinical features. Diffuse lymphomas, especially diffuse histiocytic (large cell) (DHL), were associated with decreased absolute lymphocytes and E-rosette forming cells. Skin test reactivity varied with both histology and stage. For example, only one of six tests was impaired in diffuse lymphocytic well differentiated (DLWD) lymphoma in contrast to two of six in localized DHL and five of six in advanced DHL. Patients with nodular lymphoma exhibited depressed mean levels of IgA and IgG, while only IgA was significantly decreased in diffuse lymphoma. Mitogen stimulation was depressed in all groups, although mixed lymphocyte cultures did not differ significantly from controls. In summary, there is a spectrum of immunodeficiency of both B and T cell type in patients with malignant lymphoma that correlated with histology and stage. Implications and possible mechanisms of these observations are discussed.     

Bcl-1 gene rearrangements in B cell lymphoma

We analyzed 50 B cell lymphoma samples by Southern blot analysis, using the bcl-1 and heavy chain immunoglobulin (JH) probes with two or more restriction endonucleases. All samples showed JH rearrangement, and three samples (two diffuse small lymphocytic lymphomas and one diffuse large cell lymphoma probably transformed from a diffuse small lymphocytic lymphoma) demonstrated rearranged bcl-1 sequences. The three samples showed the t(11;14)(q13;q32) chromosome translocation, and all three contained rearranged JH fragments that comigrated with the rearranged bcl-1 fragment. The breakpoint of the translocation occurred within a 1.6-kb region on chromosome 11 in the three cases. Two of the three patients had primary refractory disease. Two of the three patients had gastrointestinal involvement. Bcl-1 rearrangement may identify an unusual subset of patients with primary refractory disease with gastrointestinal involvement. It may also describe a unique subset of large cell lymphoma patients transformed from diffuse small cell histology.     

miR-155在弥漫性大B细胞淋巴瘤预后预测中的应用价值

目的:探讨miR-155在弥漫性大B细胞淋巴瘤预后预测中的应用价值。方法:选取我院收治的120例弥漫性大B细胞淋巴瘤作为研究对象,采用qRT-PCR检测所有患者癌组织miR-155的相对表达水平,根据miR-155的表达水平将所有患者分成miR-155高表达组（n=72）和miR-155低表达组（n=48）,比较两组患者的临床病理资料、生存率,采用 Cox比例风险回归模型对弥漫性大B细胞淋巴瘤患者的预后进行单因素和多因素分析,并分析miR-155对弥漫性大B细胞淋巴瘤细胞增殖和迁移能力的影响。结果:miR-155高表达组患者结外侵犯比例显著高于miR-155低表达组（P＜0.05）;miR-155高表达组患者3年无进展生存率（29.2%）及总体生存率（40.3%）均显著低于miR-155低表达组（81.3%和83.3%）;单因素和多因素分析结果均显示miR-155表达水平是DLBCL无进展生存期和总体生存期的影响因素;miR-155低表达组细胞划痕愈合速度(0.53±0.04)显著低于对照组细胞（1.0±0.03）(P＜0.05),miR-155低表达组细胞在培养的3、4 d的吸光度值显著低于对照组（0.38±0.01 vs 0.56±0.03;0.56±0.02 vs 0.76±0.02）（P＜0.05）。结论:弥漫性大B细胞淋巴瘤患者的miR-155表达水平显著影响患者的预后,其可能机制是通过影响弥漫性大B细胞淋巴瘤细胞的增殖和迁移能力,提示miR-155可能是弥漫性大B细胞淋巴瘤新的和可靠的预后生物标志物,值得进一步深入研究。     

A Collaborative Nationwide Lymphoma Study in Lebanon: Incidence of Various Subtypes and Analysis of Associations with Viruses

Incidence of various Hodgkin (HL) and non-Hodgkin lymphoma (NHL) subtypes and association with viruses in Lebanon are not known. We undertook a nationwide study of 272 patients diagnosed with lymphoma in 2007. HL comprised 32.7 % (n?=?89) of cases while NHL represented 67.3 % (n?=?183). Consistent with the literature, nodular sclerosis was the most predominant HL subtype (n?=?57/89). Among NHL, B-cell NHL represented 88 % (n?=?161/183), T-cell NHL 9 % (n?=?17/183), whereas in 2.7 % it was not classifiable. The B-cell NHL comprised predominantly diffuse large B-cell lymphoma (46 %) and follicular lymphoma (23 %). 81 cases were reviewed by a panel of pathologists with 87.6 % concordance rate. Serology was negative for hepatitis C in 122 tested cases. HIV was positive in 2 cases. Two adult T-cell leukemia/lymphoma were HTLV-I positive. EBV IgG were positive in 88.5 % of cases. 38 EBV seropositive cases [27 NHL (24 B-cell, 3 T-cell) and 11 HL] were studied for EBV genome expression using EBV-encoded RNA (EBER)-in situ hybridization. EBER expression was positive in 8 (21 %) cases (6 HL, 2 T-cell NHL). The distribution of lymphoma subtypes in Lebanon appears similar to that of Western countries. The high rate of EBV positivity in HL and T-cell lymphoma by EBER deserves further investigation.     

Clinical significance and prognosis of MYC translocation in diffuse large B-cell lymphoma

Recent studies have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B‐cell lymphoma (DLBCL). However, there have been few reports on MYC translocation in Chinese patients. One hundred and six cases of DLBCLs were analyzed using interphase fluorescent in situ hybridization. Immunophenotyping analysis (CD20, CD3, CD10, Bcl‐6, Mum‐1) was also performed. MYC translocation was identified in 13 (12.3%) out of 106 cases. All MYC⁺ DLBCLs showed a non‐germinal center B‐cell type. MYC⁺ DLBCLs showed significantly poorer overall survival (OS) and progression‐free survival, with a median OS and progression‐free survival time of 4.7 and 3.2 months, respectively (p < 0.001). Multivariate analysis using a Cox proportional hazard model confirmed that MYC⁺ (for OS, Hazards ratio 5.254; 95% CI, 2.354–11.723, p < 0.001) was the strongest independent predictor. DLBCL with MYC translocation is a subgroup of non‐germinal center B‐cell DLBCL with poor outcome. This may be a clinical characteristic that is specific to Chinese patients. Because only a few patients received rituximab, its usefulness could not be assessed. Future studies with larger numbers of patients are required. Copyright © 2011 John Wiley & Sons, Ltd.     

Cellular (FLICE) like inhibitory protein (cFLIP) expression in diffuse large B-cell lymphoma identifies a poor prognostic subset, but fails to predict the molecular subtype

Immunohistochemistry can sub‐classify diffuse large B‐cell lymphoma (DLBCL) into germinal centre B‐cell like (GCB) and non‐GCB subtypes. The latter consists predominately of the activated B‐cell like subgroup in which nuclear factor kappa‐B activation is its characteristic. Expression of cellular caspase 8 (FLICE)‐like inhibitory protein (cFLIP), a caspase 8 homologue, is regulated by nuclear factor kappa‐B signalling, and it is the main inhibitor of Fas ligand activated apoptosis. To determine if cFLIP expression was confined to non‐GCB subtype, we studied 66 cases of DLBCL. cFLIP expression showed no significant correlation to DLBCL subtypes (GCB or non‐GCB) but was associated with a worse clinical outcome. For cFLIP positive and negative patients, the five‐year event free survival was 20 and 31%, respectively (p = 0.049), and the five‐year overall survival was 20 and 57%, respectively (p = 0.041). Copyright © 2011 John Wiley & Sons, Ltd.     

Evaluation of clinical trial eligibility and prognostic indices in a population‐based cohort of systemic peripheral T‐cell lymphomas from the Danish Lymphoma Registry

Clinical trials (CTs) are needed to improve the outcome for peripheral T‐cell lymphomas (PTCL), and accrual into CTs is one of the main recommendations in international treatment guidelines. The use of risk‐adapted strategies has been suggested as a way to optimize treatment outcome in PTCL. The aim of the present study was to evaluate CT eligibility and selected prognostic indices in a population‐based PTCL cohort of 481 PTCL patients identified from the Danish Lymphoma Registry in the period 2000–2010. According to five predefined parameters (age, performance status, P‐creatinine, P‐ALAT and measurable tumour lesion), patients were subdivided into four groups: ‘younger fit’, ‘elderly fit’, ‘frail’ and ‘not CT eligible’. International prognostic index (IPI), prognostic index for T‐cell lymphoma (PIT) and anaplastic lymphoma kinase (ALK) protein expression were tested at subtype‐specific level. Overall, 41% of the patients were considered eligible for interventional CTs implicating curatively intended multiagent chemotherapy, including, if considered appropriate, consolidating stem cell transplantation (SCT), as part of the upfront management strategy. Moreover, 28% was elderly fit and eligible for interventional CT, including those with SCT as part of the trial design. Approximately 7% were defined as ‘too frail’ for aggressive treatment schedules, whereas 24% were deemed not to be eligible for any CT. Both overall and progression‐free survivals were effectively predicted by IPI and PIT (p < 0.001). ALK‐positive anaplastic large cell lymphoma patients were significantly younger (median age 40 vs. 62, p < 0.001) and had a better outcome than their ALK‐negative counterparts (p < 0.001). However, ALK expression lost its prognostic significance when adjusting for age. In a population‐based cohort of adult Caucasian PTCL patients, approximately half were eligible for multiagent chemotherapy with or without consolidating SCT. Both IPI and PIT are useful prognostic indices in all ‘primary nodal’ PTCL entities. The prognostic value of ALK protein expression in anaplastic large cell lymphoma is significantly downsized when adjusting for age. Copyright © 2014 John Wiley & Sons, Ltd.     

Malignant lymphomas involving the prostate. A study of 13 cases

The clinical and pathologic findings in 13 cases of malignant lymphoma involving the prostate gland were reviewed. The lymphomas tended to occur in elderly men with a mean age of 60 years (range, 30-86 years) and were clinically manifested by prostatic enlargement with urinary obstruction. In only one of the patients was there clinical suspicion of lymphoma before surgery. Seven patients had primary extranodal lymphoma of the prostate, with a variety of histologic subtypes, including small cell lymphocytic (one patient), diffuse small cleaved cell (two patients), diffuse mixed small and large cell (two patients), diffuse large non-cleaved cell (one patient), and high-grade diffuse small non-cleaved cell (undifferentiated non-Burkitt's) (one patient). At the time of presentation, none of these patients had hepatosplenomegaly, inguinal lymphadenopathy, abnormal complete blood counts, or elevated serum acid phosphatase levels. Six other patients with previously documented malignant lymphoma at other sites had prostatic involvement 2 to 60 months (mean, 14 months) after the primary diagnosis. Histologically, these secondary prostatic lymphomas included diffuse small cleaved cell (two patients), diffuse mixed small and large cell (one patient), diffuse large non-cleaved cell (two patients), and large cell immunoblastic, polymorphous type (T-cell by immunotyping) (one patient). The mean survival was 14 months for all patients (range, 2-44 months), with no apparent difference between primary and secondary involvement. One patient remains alive 44 months after secondary prostatic involvement with diffuse large non-cleaved cell lymphoma. Although malignant lymphomas involving the prostate are rare, they should be included in the differential diagnosis of lower urinary tract obstruction, particularly in patients with a previous history of lymphoma.     

IDO 在弥漫大 B 细胞淋巴瘤中的表达及其临床意义

目的：探讨弥漫大 B 细胞淋巴瘤组织中吲哚胺2,3双加氧酶（indoleamine 2,3- dioxygenase,IDO）的表达及意义。方法：收集2007年1月至2012年12月四川省肿瘤医院存档蜡块63例,其中弥漫大 B 细胞淋巴瘤组织41例,炎症反应性增生组22例,采用免疫组织化学技术检测 IDO 的表达,并分析与临床病理资料的关系及其临床意义。结果：弥漫大 B 细胞淋巴瘤组织中 IDO 阳性率为56.1%,明显高于反应性增生炎症组织22.7%,差异有统计学意义,P =0.011;IDO 表达水平与 Hans 分型、B 症状具有相关性,P =0.000、0.035;IDO的表达与患者的年龄、性别、分期、结外受侵数目、IPI、ECOG、LDH 无明显相关,P ﹥0.05;IDO 与弥漫大 B 细胞淋巴瘤的近期疗效具有相关性,P =0.001;Log - rank 单因素生存分析显示 IDO 的表达水平、Hans 分型、B 症状及 IPI 评分差异有统计学意义,P =0.009、0.003、0.000、0.030;Cox 多因素生存分析,仅 IDO 表达水平具有显著性差异,P =0.024。结论：IDO 的高表达,可能参与弥漫大 B 细胞淋巴瘤的免疫逃逸相关。IDO 高表达与弥漫大 B 细胞淋巴瘤疾病进展、疗效及预后不良相关,提示 IDO 可能成为弥漫大 B 细胞淋巴瘤患者的独立预后因子及新的治疗靶点。     

Peripheral blood lymphocytes of nonleukemic lymphoma patients exhibit aberrant expression of T-cell activation markers after polyclonal stimulation in vitro

The authors evaluated suppressed in vitro functions of peripheral blood lymphocytes (PBL) as a possible tool in the early diagnosis of human lymphoma. In 13 of 22 patients with recent onset of various types of nonleukemic lymphomas (Mb. Hodgkin and non-Hodgkin's lymphomas of B-cell and T-cell origin) the mitogen response of PBL against phytohemagglutinin (PHA) and concanavalin A (Con A), as measured by 3H-thymidine (3HTdR) uptake, was found to be significantly suppressed, whereas the response to pokeweed mitogen (PWM) was normal in 18 cases. In parallel, cytofluorimetric analysis was done with PBL after 72 hours in culture with and without PHA, using antibodies against the differentiation antigens: CD3, CD8, CD4, CD19, and CDw14 and the activation antigens: interleukin-2 (IL-2) receptor (IL-2R, CD25), human leukocyte antigen DR (HLA-DR), and transferrin receptor (TR). Compared with healthy controls and patients with other diseases, a significant reduction of the total T-cell blast response, i.e., the percentage of large T-cells bearing activation markers, was found in all lymphoma cases including those with a normal 3HTdR uptake. Furthermore, a pronounced inhibition in the expression of the activation markers Il-2R and TR, but not of HLA-DR, was detected on CD3+ cells in PHA-stimulated PBL of all lymphoma cases. Thus, polyclonal activation combined with activation antigens seems to give more accurate information about the functional defect(s) of PBL in an early state of lymphoma; these parameters may therefore be valuable diagnostically. The abnormal pattern in the expression of T-cell activation antigens after polyclonal stimulation may help in the understanding the cellular immune defects associated with lymphoma.     

Epstein–Barr virus presence in pediatric diffuse large B‐cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment

Non‐Hodgkin's lymphoma represents 6–10% of pediatric malignancies, and diffuse large B‐cell lymphoma (DLBCL) is one of the three major subtypes. The 2008 WHO classification included a new entity, Epstein–Barr virus (EBV)‐positive DLBCL of the elderly, affecting patients >50 years. It has been demonstrated that EBV may play a role in tumor microenvironment composition, disturbing antitumor immune response and disease progression. As most studies were performed in adults, our aim was to assess EBV presence and latency pattern, as well as T‐cell microenvironment in a pediatric DLBCL series of Argentina. The study was conducted on formalin‐fixed paraffin‐embedded biopsies from 25 DLBCL patients. EBV‐encoded small nuclear early regions (EBERs) expression was performed by in situ hybridization, whereas EBV gene expression was analyzed using real‐time PCR. Epstein–Barr virus latent membrane proteins (LMP)1, LMP2A, CD3, CD4, CD8 and Foxp3 expression were assessed by immunohistochemistry (IHC). Forty percent of cases showed EBV expression, with a significantly higher incidence among patients <10 years (p = 0.018), and with immunosuppressed (p = 0.023). T‐cell subsets were not altered by EBV presence. Full EBV latency antigen expression (latency type III) was the most frequently pattern observed, together with BZLF1 lytic gene expression. One patient showed II‐like pattern (LMP1 without LMP2A expression). Based exclusively on IHC, some patients showed latency II/III (EBERs and LMP1 expression) or I (EBERs only). These findings suggest that EBV association in our series was higher than the previously demonstrated for elderly DLBCL and that EBV latency pattern could be more complex from those previously observed. Therefore, EBV could be an important cofactor in pediatric DLBCL lymphomagenesis.     

Antiviral therapy improves overall survival in hepatitis C virus‐infected patients who develop diffuse large B‐cell lymphoma

Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non‐Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV‐infected patients with diffuse large B‐cell lymphoma (DLBCL) is unclear. We therefore analyzed AVT's impact on oncologic outcomes of HCV‐infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004–May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon‐based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% vs. 72%; p = 0.07) and upper gastrointestinal (GI; 42% vs. 24%; p = 0.004) involvement. Cases never given AVT had DLBCL more refractory to first‐line chemotherapy than that in the controls (33% vs. 17%; p = 0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% vs. 32%; p = 0.09) or cases given AVT (50% vs. 27%; p = 0.06). Cases never given AVT had worse 5‐year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01–5.3]; p = 0.04). Furthermore, AVT improved 5‐year OS rates among cases in both univariate (median [Interquartile range]: 39 [26–56] vs. 16 [6–41] months, p = 0.02) and multivariate analyses (HR = 0.21 [95% CI, 0.06–0.69]; p = 0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5‐year OS.