Non-Hodgkin's Lymphoma and Hepatitis C Virus Infection

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.     

Hepatitis C Virus Serum Markers and Liver Disease in Children with Leukemia

This review summarises serologic profiles and clinical features of HCV infection in children with leukemia. The diagnosis of HCV infection is currently based on the detection in serum of antiviral antibodies and HCV-RNA. Studies on leukemic children, however, have clearly shown that only HCV-RNA testing correctly identifies HCV infection, as specific antibodies become detectable in serum only after chemotherapy withdrawal in almost all cases. Viraemia instead appears early in the course of leukemia, and infected patients become carriers. The pattern of liver disease is rather homogeneous. Early onset, persisting ALT elevation during chemotherapy often with drastic reduction during high-dose chemotherapy, followed by sharp exacerbations of liver cell necrosis. ALT normalise after chemotherapy withdrawal in most cases, despite persisting viraemia. As regards to the ultimate prognosis of liver disease in these children, we have observed that, among a series of 119 patients followed for at least 10 years off-therapy, none has developed clinical decompensated liver disease and only 6% still has abnormal ALT levels. On the other hand, the need for prolonged follow-up of children surviving leukemia with chronic HCV infection is emphasized by the fact that the natural history of HCV infection has not been fully clarified and that additional late sequelae are likely to occur.     

Lactoferrin Inhibits Hepatitis C Virus Viremia in Patients with Chronic Hepatitis C: A Pilot Study

Hepatitis C virus (HCV) is associated with the development of cirrhosis and hepatocellular carcinoma. We recently found that bovine lactoferrin, a milk protein belonging to the iron transporter family, effectively prevented HCV infection in cultured human hepatocytes (PH5CH8). We tested the hypothesis that lactoferrin inhibits HCV viremia in patients with chronic hepatitis C. Eleven patients with chronic hepatitis C received an 8-week course of bovine lactoferrin (1.8 or 3.6 g/day). At the end of lactoferrin treatment, a decrease in serum alanine transaminase and HCV RNA concentrations was apparent in 3 (75%) of 4 patients with low pretreatment serum concentrations of HCV RNA. However, 7 patients with high pretreatment concentrations showed no significant changes in these indices. This pilot study suggests that lactoferrin is one potential candidate as an anti-HCV reagent that may be effective for the treatment of patients with chronic hepatitis.     

利妥昔单抗联合GDP方案治疗非霍奇金淋巴瘤的疗效及对患者免疫水平的影响

目的研究利妥昔单抗联合GDP方案治疗非霍奇金淋巴瘤的疗效及对患者免疫水平的影响。方法选择非霍奇金淋巴瘤患者121例,按照随机数表法将患者分为研究组(61例)和对照组(60例)。对照组患者仅采用GDP方案治疗,研究组在对照组的基础上联合应用利妥昔单抗。根据国际NHL疗效评价标准进行疗效判定。采用免疫比浊法测定体液补体(C3、C4)和免疫球蛋白水平(Ig G、Ig M、Ig A)。记录2组患者不良反应发生情况。结果研究组中完全缓解18例,部分缓解23例,治疗有效率为67.21%,显著高于对照组(P<0.05)。治疗前2组患者补体和免疫球蛋白水平比较,差异无统计学意义(P>0.05);治疗后,2组患者的免疫球蛋白无显著变化,但是补体水平显著降低,研究组补体水平降低程度较对照组高,差异有统计学意义(P<0.05)。2组患者均出现脱发、白细胞减少、恶心呕吐、血小板减少、骨髓抑制、贫血等不良反应,但2组差异无统计学意义(P>0.05)。结论利妥昔单抗联合GDP方案能够显著提高非霍奇金淋巴瘤的治疗效果,同时对血清免疫球蛋白没有显著影响,具有较好的安全性,值得临床推广。     

Two Translocations: a Follicular Variant 2; 18 and a Burkitt 8;14 in a Small Non Cleaved Non Hodgkin's Lymphoma

The t(2;18)(p11;q21) has recently been described in two lymphoma cases as a variant of the t(14;18)(q32;q21) typical chromosome translocation in follicular lymphomas. Molecular investigations of t(2;18) confirmed juxtaposition of the bcl-2 gene to the immunoglobulin kappa (Igk) locus and described a new break point region on 18q21 found also in the recently reported, second follicular variant translocation (18;22)(q21;q11). Thus, cytogenetic and molecular studies established the same mechanism of (onco)gene activation by the heavy or light Ig gene in follicular lymphomas and Burkitt lymphomas.

We describe a case of small non cleaved non Hodgkin's lymphoma in which translocation (2;18) coexisted with a typical (8;14) Burkitt translocation. Absent HLA-DR expression by the tumour cells was noted in this case. The possible implications of the cytogenetic and immunologic findings are discussed.     

Hepatitis B Virus Infection and B-Cell Non-Hodgkin's Lymphoma in a Hepatitis B Endemic Area: A Case-control Study

Several studies have reported a higher prevalence of chronic hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma and suggested a pathogenic role for HCV, but studies on hepatitis B virus (HBV) infection and non-Hodgkin's lymphoma are limited. To determine the association between HBV infection and non-Hodgkin's lymphoma, we performed a case-control study in Korea, a hepatitis B endemic area. We recruited 222 patients newly diagnosed with non-Hodgkin's lymphoma at Seoul National University Hospital between January 1997 and December 1998 as cases. Four age- and sex-matched controls were selected for each case, and the control groups comprised of 439 patients with non-hematological malignancy (control group 1) and 444 subjects with non-malignant conditions (control group 2). Relative risk of developing non-Hodgkin's lymphoma among individuals tested positive for hepatitis B surface antigen was calculated after controlling for other potential risk factors of lymphoma, such as smoking, alcohol drinking, transfusion history and HCV infection. Hepatitis B surface antigen was positive in 28 of 222 patients (12.6%) with non-Hodgkin's lymphoma compared with 32 of 439 (7.3%) in control group 1, and 21 of 444 (4.7%) in control group 2 (P=0.001). The crude odds ratio for B-cell non-Hodgkin's lymphoma among the HBV carriers was 2.54 (1.46–4.45) and the adjusted odds ratio was 3.30 (1.69–6.45) by multivariate analysis. The present study suggests that the risk of B-cell non-Hodgkin's lymphoma is increased in HBV carriers and warrants further investigation of the possible role of hepatitis B virus in the pathogenesis of B-cell non-Hodgkin's lymphoma.     

E1/E2 of Hepatitis C Virus Genotype4 and Apoptosis

Several studies have addressed the possible role of hepatitis C virus genotype4 (HCV GT4) in apoptosis. However, this still not fully understood. In the current study a reconstructed clone of E1/E2 polyprotein region of the HCV GT4 was transfected into the Huh7 cell line and a human apoptotic PCR array of 84 genes was used to investigate its possible significance for apoptosis. Out of the 84 genes, only 35 showed significant differential expression, 12 genes being upregulated and 23 downregulated. The highestup regulated genes were APAF1 (apoptotic peptidaseactivating factor 1), BID (BH3 interacting domain death agonist) and BCL 10 (Bcell CLL/ lymphoma protein 10) with fold regulation of 33.2, 30.1 and 18.9, respectively. The most downregulated were FAS (TNF receptor super family), TNFRSF10B (tumor necrosis factor receptor superfamily member 10b) and FADD (FASassociated death domain) with fold regulation of 30.2, 27.7 and 14.9, respectively. These results suggest that the E1/E2 proteins may be involved in HCVinduced pathogenesis by modulating apoptosis through the induction of the intrinsic apoptosis pathway and disruption of the BCL2 gene family.     

Hodgkin Lymphoma: An Update on its Biology with New Insights into Classification

In the past few years, there has been a greater understanding of the spectrum and biology of Hodgkin lymphoma (HL). In standard texts, HL is classified as 2 distinct entities, namely nodular lymphocyte-predominant HL and classical HL (CHL). However, recent evidence suggests that CHL is not a single disease. Although the mixed cellularity and lymphocyte-depleted subtypes might be part of a biologic continuum, the nodular sclerosis subtype has a distinct epidemiology, clinical presentation, and histology. Nodular sclerosis HL might also be related to primary mediastinal B-cell lymphoma and mediastinal gray-zone lymphomas. We present an update on the pathobiology of HL and discuss these biologic and clinical differences in this review.     

Cost Analysis of Autologous Peripheral Stem Cell Transplantation Versus Autologous Bone Marrow Transplantation for Patients with Non Hodgkin's Lymphoma and Acute Lymphoblastic Leukaemia

We evaluated the costs of unpurged autologous stem cell transplantation in a non-randomised study of 54 consecutive patients with lymphoproliferative malignancies who have been transplanted at the Nijmegen University Hospital between July 1992 and March 1998. Thirty-five patients were transplanted with autologous peripheral stem cells (APSCT): 30 had non Hodgkin's lymphoma (NHL) and 5 acute lymphoblastic leukaemia (ALL). Nineteen patients were transplanted with autologous bone marrow stem cells (ABMT): 17 had NHL and 2 ALL. The number of progenitor cells (CFU-GM, BFU-E) and nucleated cells was significantly higher in peripheral blood transplants. The duration of cytopenia was shorter after APSCT. The leucocyte recovery to 0.5 × 10⁹ /L was 13 days for recipients of peripheral stem cells compared to 20 days for bone marrow recipients (P 4.001). The platelet recoveries to 20 × 10⁹L were 13 and 29 days, respectively (P = 0.001). This resulted in significantly shorter admission duration 24 days after APSCT versus 30 days (P = 0.003) after ABMT.

Furthermore, a statistically significant difference between both groups was observed for antimicrobial costs (mean: fl 2,939 vs fl 4,888; P = 0.008), platelet transfusions (median: 3 vs 7 units; P = 0.01) and erythrocyte transfusions (median: 6 vs 10 units; P = 0.03). The mean overall costs were lower in patients transplanted with stem cells from' peripheral blood: fl 34, 178 versus fl 43, 469 (P = 0.007). This study suggests that the APSCT results in significant cost savings due to shorter hospital stay and less costs of supportive care, despite higher mobilisation costs. The costs of blood transfusions and antimicrobials for patients with ALL were significantly higher when compared to patients with NHL.     

乙肝病毒感染与淋巴瘤化疗后肝损害关系初探

 目的: 探讨乙肝病毒感染与淋巴瘤化疗后肝损害关系。方法: 分析182例中高度恶性淋巴瘤化疗后肝功能改变, 其中携带乙肝病毒53例, 未携带者129例, 化疗前肝功能均正常, 观察化疗后肝功能变化情况。结果: 经过二周期以上的正规化疗后, HBsAg(+)组肝损害发生率占45.3 %(24/53), HBsAg(-)组肝损害发生率占27.1 %(35/129), P <0.05。HBsAg(+)组中并用利分能(重组人a-2b干扰素)治疗10例, 肝损害发生率为10.0 %(1/10), 而未用利分能治疗43例, 肝损害发生率为53.5 %(23/43), P <0.05。 结论: 乙肝病毒感染的淋巴瘤患者化疗后易致肝损害, 并用利分能治疗可减轻其损害。     

Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection

BackgroundThe safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).Materials and MethodsThis was a single‐institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.ResultsWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1–2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).ConclusionAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.Implications for PracticeThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors’ institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.     

Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.     

Inflammation and/or necrosis of tumors cannot account for fever in most febrile patients with Hodgkin's disease

Inflammation and/or necrosis (I/N) of the tumor are generally believed to be a cause of fever in patients with Hodgkin's disease. However, there have been few studies in the literature which can corroborate this common belief. Inflammation and/or necrosis were studied in biopsy specimens of 140 untreated patients with Hodgkin's disease (57 febrile and 83 afebrile). In 37 of the 140 tumors I/N were readily observed; 18 were from febrile patients, and 19 from afebrile. Thus, it is evident that I/N cannot account for fever in the majority of febrile patients, necessitating an alternative explanation. Among the patients with I/N of their tumor, fever occurred most often in male patients and in virtually all patients who had histologic types other than nodular sclerosis. However, it was peculiarly absent in the great majority of patients whose tumors were of the nodular sclerosis type. This paradoxic inverse correlation of fever with I/N of tumors in patients with the nodular sclerosing histologic type has not been described previously.     

非霍奇金淋巴瘤中HCV感染、p53和bcl-6表达及其相关性研究

目的 :探讨非霍奇金淋巴瘤 (NHL)与丙型肝炎病毒 (HCV)感染的相关性及其可能发病机制。方法 :应用免疫组织化学S P法对 133例NHL和 2 5例良性淋巴组织病变 (BLPC)进行p5 3、bcl 6及HCVTORDJI 2 2蛋白的检测 ,对其中 5 8例NHL和全部BLPC进行HCVRNA的原位RT PCR检测。结果 :NHL中HCV感染阳性率 12 8% (17 133) ,BLPC中HCV感染阴性 ,两组比较差异有显著意义 ,P <0 0 5。NHL中p5 3阳性 71例 (5 3 4 % ) ,bcl 6阳性 5 2例 (39 1% ) ;BLPC中p5 3为阴性 ,bcl 6阳性 10例(40 0 % )。 17例HCV阳性NHL中p5 3阳性 13例 ,P <0 0 5 ,bcl 6阳性 8例。结论 :1)HCV感染与NHL之间有关 ;2 )HCV可能通过调控p5 3的表达而与NHL的发生有一定的关系 ;3)NHL中HCV的感染和bcl 6的表达可能是两个独立的事件     

Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease.

PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria. MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists. RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non-Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients. CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a "watch and wait" approach, remains unanswered.