Primary lymphoma of the prostate: A report of two cases

The primary lymphoma of prostate is rare, representing 0.2–0.8% of extranodal lymphomas and 0.1% of all prostate neoplasias.     

原发性乳腺弥漫性大B细胞淋巴瘤5例并文献复习

目的探讨原发性乳腺弥漫性大B细胞淋巴瘤(primary breast diffuse large B-cell lymphoma,PB-DLBCL)的临床病理学特点、诊断及鉴别诊断、治疗及预后。方法采用HE染色和免疫组织化学SP法分析5例PB-DLBCL患者的临床表现、病理学及免疫表型特征,并复习相关文献。结果 5例均为女性患者,发病年龄48~70岁,中位年龄59.2岁,均为单侧乳腺肿块,其中左乳3例,右乳2例。镜下见乳腺正常结构被破坏,成片的中等偏大的肿瘤细胞弥漫浸润乳腺小叶、导管周围、间质及周围脂肪组织。根据免疫组织化学表型,4例为非生发中心型,1例为生发中心型;Ki67增殖指数为60%~90%;根据 Ann Arbor 分期标准,5例均为II E期。病例随访时间截止至2018年6月,随访期内,有2例复发,分别于7和19个月后死亡;2例健在,分别已存活12和72个月;另外一例失访。结论 PB-DLBCL是一种少见的恶性淋巴瘤,临床表现为单侧乳腺无痛性包块进行性增大,以右侧多见。确诊主要依靠病理活检及免疫表型,免疫表型以非生发中心为主,以化疗联合放疗等综合治疗方案为宜。     

Primary mediastinal B-cell lymphoma: detection of BCL2 gene rearrangements by PCR analysis and FISH

Primary mediastinal large B-cell lymphoma (PMBCL) has a characteristic clinical presentation, morphology, and immunophenotype, representing a clinically favorable subgroup of diffuse large B-cell lymphoma (DLBCL). By gene expression profiling (GEP), PMBCL shares features with classical Hodgkin lymphoma (cHL). Of further interest, BCL6 gene mutations and BCL6 and/or MUM1 expression in a number of PMBCLs have supported an activated B-cell (ABC) origin. Several studies, including GEP, have failed to detect BCL2 gene rearrangements (GRs) in PMBCL. An index case of t(14; 18)+ PMBCL prompted our study of the incidence of BCL2 GRs in PMBCL by polymerase chain reaction (PCR)/fluorescence in situ hybridization (FISH) analyses and its possible clinical impact. Twenty-five retrospectively identified, well-defined PMBCLs (five with cytogenetics) from three institutions were analyzed for a BCL2 GR by PCR/FISH analyses. The formalin-fixed, paraffin-embedded tissue blocks of 24 available cases were also analyzed by BCL2 immunohistochemistry (IHC). Of the five with cytogenetics, two had a t(14; 18) (q32; q21). Of the 25 analyzed by PCR, 2 had no amplifiable DNA (aDNA), including 1 t(14; 18)+ case. Of those with aDNA, two showed a BCL2 GR; by FISH analysis, three demonstrated a BCL2 GR. BCL2 protein expression by IHC analysis was variably detected in 21 out of 24 (strongly, uniformly expressed: 6, including all with a t(14; 18) or a BCL2 gene rearrangement; moderately weakly expressed in a subset of the malignant cells: 15). Available clinical follow-up of this BCL2+ subset showed a similar course to the other PMBCL cases. Our results imply that a subset of PMBCL [(4 out of 24 analyzed) in our series] may be of GC origin. A larger study is necessary to determine any clinical significance.     

Discordant lymphoma consisting of mediastinal large B-cell lymphoma and nodular sclerosis Hodgkin lymphoma in the right supraclavicular lymph nodes: a case report

PD-L1 is a glycoprotein from the family of T-cell co-stimulatory molecules that are constitutively expressed by macrophages. Aberrant expression of PD-L1 is observed in human cancers associated with inhibition of the tumor-directed T-cell immune response. There are few reports in the literature evaluating PD-L1 expression in association to prognosis specifically in renal cell cancer clear cell type (RCC-CC). Immunohistochemistry using a PD-L1 polyclonal antibody was performed on a tissue microarray (TMA) that contained 115 surgical specimens of RCC-CC. Cases were classified based on the absence or presence of staining intensity in the cytoplasm and membranes of the tumor cells. Statistical analysis was used to determine the association of PD-L1 expression with classic prognostic factors and tumor recurrence. PD-L1 expression was positive in 56.5 % of tumors. The univariate analysis showed a correlation between PD-L1 expression and nuclear Fuhrman grade (p = 0.021) and microvascular tumor embolization (p = 0.039). One hundred and four patients were monitored for a mean time of 115.7 months. Seventeen patients (16.3 %) suffered tumor recurrence. Negative outcomes were associated with higher nuclear grade tumors, PD-L1 expression, and the presence of microvascular invasion. Our findings confirm that PD-L1 expression is an important prognostic factor in RCC-CC.     

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.     

CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma

Biomarkers which can identify Diffuse Large B-Cell Lymphoma (DLBCL) likely to be refractory to first-line therapy are essential for selecting this population prior to therapy initiation to offer alternate therapeutic options that can improve prognosis. We tested the ability of a CT-based radiomics approach with machine learning to predict Primary Treatment Failure (PTF)-DLBCL from initial imaging evaluation. Twenty-six refractory patients were matched to 26 non-refractory patients, yielding 180 lymph nodes for analysis. Manual 3D delineation of the total node volume was performed by two independent readers to test the reproducibility. Then, 1218 hand-crafted radiomic features were extracted. The Random Forests machine learning approach was used as a classifier for constructing the prediction models. Seventy percent of the nodes were randomly assigned to a training set and the remaining 30% were assigned to an independent test set. The final model was tested on the dataset from the 2 readers, showing a mean accuracy, sensitivity and specificity of 73%, 62% and 82%, respectively, for distinguishing between refractory and non-refractory patients. The area under the receiver operating characteristic curve (AUC) was 0.83 and 0.79 for the two readers. We conclude that machine learning CT-based radiomics analysis is able to identify a priori PTF-DLBCL with a good accuracy.     

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.     

Bispecific Ab therapy of B-cell lymphoma: target cell specificity of antibody derivatives appears critical in determining therapeutic outcome

Despite the success of mAb and bispecific (bs)Ab in the treatment of certain malignancies, there is still considerable uncertainty about the most appropriate format in which they should be used. In the current work we have investigated a panel of bsAb [IgG and F(ab)₂] with dual specificity for T cells and neoplastic B cells. Throughout this work, anti-CD2 or anti-CD3 were used to bind the mouse T cells, and antibodies to surface IgM idiotype (Id), CD19, CD22, or MHC class II were used to target mouse B cell lymphomas BCL₁ or A31. In vitro, killing was measured in a conventional cytotoxicity assay using ⁵¹Cr-labelled A31 and BCL₁ cells as targets and activated mouse splenocytes as effectors. bsAb showed a wide range of cytotoxic activities, which could be ranked in the following order: [anti-CD3×anti-class-II]>[anti-CD3×anti-CD19] >[anti-CD3×anti-Id]>[anti-CD3×anti-CD22], with the [anti-CD2×anti-Id] derivative showing relatively little cytotoxic activity. This hierarchy of activity indicates some correlation with the binding activity of the bsAb on target cells, but showed a much stronger parallel with the tendency of the anti-(target cells) mAb to undergo antigenic modulation (less modulation, more killing). In vivo, the situation was completely different and only the anti-ld derivatives, [anti-CD3×anti-ld] and [anti-CD2×anti-ld], were effective in prolonging the survival of tumour-bearing animals. Under optimal conditions Id-positive tumour was eradicated with a single treatment of bsAb. We conclude from this work that the target cell specificity of a bsAb is critical in determining therapeutic outcome and that in vitro cytotoxicity assays do not predict in vivo activity. Accepted: 14 October 1997     

Immunotherapy in the treatment of lymphoma

Relapsed or refractory non-Hodgkin's lymphomas, especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat diseases. Patients who do not respond to initial therapy or experience relapse are treated with salvage regimens, and if eligible for aggressive therapy, treatment is continued with high-dose chemotherapy and autologous stem cell transplantation. Current therapy options can cure substantial numbers of patients, however for some it is still an uncurable disease. Numerous new drugs and cell therapies are being investigated for the treatment of relapsed or refractory lymphomas. Different types of immunotherapy options have shown promising results, and some have already become the standard of care. Here, we review immunotherapy options for the treatment of lymphoma and discuss the results, positions, practical aspects, and future directions of different drugs and cellular therapies for the treatment of this disease.     

Identification of a prognostic metabolic gene signature in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a clinically diverse disease. Given the numerous genetic mutations and variations associated with it, a prognostic gene signature that can be related to the overall survival (OS) is a clinical implication. We used the mRNA expression profiles and clinicopathological data of patients with DLBCL from the Gene Expression Omnibus (GEO) database to identify a metabolism-related gene signature. Using LASSO regression analysis, a novel 13-metabolic gene signature was identified to evaluate prognosis. The information gathered was used to construct the nomogram model to improve risk stratification and quantify risk factors for individual patients. We performed gene set enrichment analysis to identify the enriched signalling axes to further understand the underlying biological pathways. The receiver operating characteristic (ROC) curve revealed a satisfactory performance in the training cohorts. The model also showed clinical benefit when compared to the standard prognostic factors (P < .05) in validation cohorts. This study aimed to combine metabolic dysregulation with clinical features of patients with DLBCL to generate a prognostic model that might not only indicate the value of the metabolic microenvironment for prognostic stratification but also improve the decision-making during individual therapy.     

Case report: The effect of a Chinese herbal medicine,BG-104 in two HIV positive hemophiliacs

The BG-104, a Chinese herbal medicine, has been reported to restore decreased plasma superoxide scavenging activity.This report showedin vivo effect of BG-104 on two patients with hemophilia A infected with human immunodeficiency virus by infusions of the concentrated Factor VIII. Both patients, showed a peripheral CD4⁺ T-lymphocytopenia for more than half a year. BG-104 was administered daily and follow-up observations were continued for 3 years. The number of CD4⁺ T-lymphocytes remained relatively constant during BG-104 treatment without disease progression.Abbreviations CD cluster differentiation - HIV human immunodeficiency virus - IgG immunoglobulin G - CDC Center of disease control - MoAb monoclonal antibody     

Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment

Over half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured by standard R-CHOP treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the remaining patients are refractory and ultimately succumb to progressive or relapsed disease. During the past decade, there has been significant progress in the understanding of molecular mechanisms in DLBCL, largely owing to collaborative efforts in large-scale gene expression profiling and deep sequencing, which have identified genetic alterations critical in lymphomagenesis through activation of key signaling transduction pathways in DLBCL. These discoveries have not only led to the development of targeted therapies, including several currently in clinical trials, but also laid a solid foundation for the future identification of more effective therapies for patients not curable by R-CHOP. This review summarizes the recent advances in our understanding of the molecular characterization and pathogenesis of DLBCL and new treatment directions.     

One drug for two targets: Biological evaluation of antiretroviral agents endowed with antiproliferative activity

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt’s Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.     

Evaluation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus(EBV) in saliva and relationship with highly active antiretroviral therapy(HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use(H) and non-HAART use(NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS(NH) group had the highest seropositive rate(IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS(H)(73.69%) and the HIV/AIDS(NH)(100%) groups showed significantly higher values than the HIV-negative control group(35.79%,[ twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS(H) group and the HIV/AIDS(NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.     

Evaluation of ARG protein expression in mature B cell lymphomas compared to non-neoplastic reactive lymph node

The participation of Abl-Related Gene (ARG) is demonstrated in pathogenesis of different human malignancies. However there is no conclusive evidence on ARG expression level in mature B cell lymphomas. In this study we evaluated ARG protein expression in Follicular Lymphoma (FL), Burkitt’s Lymphoma (BL) and Diffused Large B Cell Lymphoma (DLBCL) in comparison with non-neoplastic lymph nodes. Semi-quantitative fluorescent ImmunoHistoChemistry was applied on 14, 7 and 4 patients with DLBCL, FL and BL respectively, adding to 4 normal and 4 reactive lymph nodes. The mean ratio of ARG/GAPDH expression was significantly different (p < 0.00) between lymphomas and control samples, with DLBCL having the highest ARG expression amongst all. Over expression of ARG was seen in FL and BL, with FL expressing statistically more ARG than BL. Moreover, the ARG/GAPDH expression ratio increased from DLBCL stage I towards stage VI, all showing significantly more ARG expression than FL and BL (in all cases p < 0.00).     

HIV抗体阳性合并马尔尼菲青霉菌感染的临床特点

目的 对HIV阳性合并马尔尼菲青霉菌的临床特点进行分析,揭示免疫能力递减的程度,易感马尔尼菲青霉菌之间的关系,给临床诊断提供帮助。方法 以我院收治的3例HIV阳性合并马尔尼菲青霉菌感染患者为例,总结分析其生物学特点。结果 三位患者都为中年男性,以间断发热、呼吸困难、干咳为主要临床表现,肺部影像学提示双肺弥漫性病变,外院治疗无效后转入我院,确诊为HIV阳性,经血培养诊断为马尔尼菲青霉菌感染。患者血CD4+ T细胞计数后,CD4+ T细胞均＜2%（正常值31%~60%）。结论 HIV阳性时,不明原因发热,肺部感染,免疫功能受损到一定程度时,易合并马尔尼菲青霉菌感染,临床症状较重并有很高的死亡率。