Early-stage splenic diffuse large B-cell lymphoma is highly associated with hepatitis C virus infection

Splenic marginal zone lymphoma (SMZL) and splenic diffuse large B-cell lymphoma (DLBCL) are the most common types of lymphomas involving the spleen. Geographic variation in hepatitis C virus (HCV) seroprevalence is characteristic of splenic lymphomas. In Italy, HCV seroprevalence was higher in patients with SMZL and splenic DLBCL than in patients with all types of lymphoma. In Japan, HCV seroprevalence was higher in patients with splenic DLBCL than in patients with all types of lymphoma; however, HCV seroprevalence in patients with SMZL was similar to that in patients with all types of lymphoma. In this study, clinicopathological data of 74 splenic lymphoma cases between 1988 and 2011 collected from the Department of Pathology at National Taiwan University Hospital were analyzed. Serology for HCV infection was available for 41 cases. Splenic DLBCL and SMZL accounted for 36% (n = 27) and 42% (n = 31) of splenic lymphomas, respectively. Microscopically, most cases of DLBCL (26/27) presented with circumscribed tumor and most cases of SMZL (28/31) presented with white pulp expansion. HCV seroprevalence in patients with DLBCL and SMZL was 44% and 10%, respectively (7/16 vs. 2/20, p = 0.020). The pattern identified in this study is closer to that in Japan than in Italy. HCV seroprevalence in patients with early-stage (I/II) and late-stage (III/IV) DLBCL was 100% and 10%, respectively (6/6 vs. 1/10, p < 0.001). Early-stage DLBCL is clinically considered a form of primary splenic lymphoma rather than a systemic lymphoma with splenic involvement. High HCV seroprevalence in patients with early-stage DLBCL suggests a role of HCV in the pathogenesis of primary DLBCL.     

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%–56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%–77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.     

Lenalidomide plus cyclophosphamide,doxorubicin, vincristine,prednisone and rituximab is safe and effective in untreated,elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi

Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1–14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164–0.553). Grade 3–4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00907348","term_id":"NCT00907348"}}NCT00907348.     

Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL)

Survival rates for elderly Hodgkin Lymphoma (HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered ‘non‐frail’ according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced‐intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression‐free survival (PFS). Seventeen patients were in early stage (I‐IIA), while 37 were advanced stage. Median age was 72 years and median follow‐up was 76 months. Five‐year PFS rates were 48% vs. 70% [adjusted Hazard ratio (HR) = 2·19, 95% confidence interval (CI) = 0·94–5·10, P = 0·068] and 5‐year overall survival (OS) rates were 63% vs. 77% (adjusted HR = 1·67, 95% CI = 0·69–4·03, P = 0·254) for VEPEMB compared to ABVD. Overall treatment‐related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients.     

Outcome of transformed follicular lymphoma worsens according to the timing of transformation and to the number of previous therapies. A retrospective multicenter study on behalf of Fondazione Italiana Linfomi (FIL)

Optimal treatment for transformed follicular lymphoma (tFL) is not fully defined. Clinical characteristics and treatments that impact on post-transformation outcome of 176 biopsy-proven tFL were analysed. Transformation occurred at initial diagnosis in 52% (Group 1) and after a FL diagnosis in 48% (Group 2). Five-year overall survival was 84% for Group 1 and 51% for Group 2 (P < 0·001). In Group 1, 5-year progression-free survival was superior after rituximab maintenance compared to observation only (94% vs. 53%, P = 0·024). In Group 2, an inverse trend was found between survival and both a higher number of pre-transformation treatment lines and a short time-to-transformation.     

Rare primary extranodal lymphomas: diffuse large B-cell lymphomas of the genital tract

Primary non-Hodgkin’s lymphoma (NHL) of the genital tract is a rare entity. Etiology and pathogenesis of these NHLs are unknown, although there might be a possible association between chronic inflammation and lymphomas. The most common histological subtype is the diffuse large B-cell lymphoma. We report two cases of uterine lymphoma and one case of prostate lymphoma in this paper. The symptoms and the differential diagnosis are also discussed. Because of the low incidence, there is no widely accepted consensus on its treatment. We demonstrate that the rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) chemoimmunotherapy is a good and tolerable treatment option in all cases. The two young patients are disease-free nowadays; the older patient with poor prognostic histological-type lymphoma relapsed in a short time and died after second relapse. A multicenter analysis is necessary to evaluate the long-term results of chemoimmunotherapy in these rare extranodal lymphoma entities.     

丙型肝炎病毒相关的肾脏疾病

丙型肝炎病毒（hepatitis C virus,HCV）是一种常见的血源性传播的病毒,50％～80％的急性丙型肝炎可进展为慢性丙型肝炎、肝硬化甚至肝癌。许多研究发现,HCV感染除有肝脏表现外,还有许多肝外表现,如冷球蛋白血症、干燥综合征、淋巴细胞增生性疾病及肾小球肾炎等。膜增殖性肾小球肾炎是HCV相关的肾脏疾病中最常见的一种。笔者对HCV相关的肾脏疾病的发病机制、临床表现、治疗和预后的研究进展进行综述,以提示临床医师注意慢性丙型肝炎患者出现的肾功能异常,为HCV相关的。肾脏疾病的诊治提供依据。     

丙型肝炎相关性IgA肾病1例

丙型肝炎相关性肾小球肾炎较为罕见,其临床表现与病理类型有关.肾脏病理损害以膜增殖性肾炎最常见,其次为膜性肾炎,罕见IgA肾病[1].本研究报道1例HCV感染相关性IgA肾病.     

Relapsing polychondritis associated with hepatitis C virus infection

This article is aimed to review of relapsing polychondritis (RP) and its association to hepatitis C virus (HCV) infection. A case of RP associated with HCV infection in a 59-year-old male is reported. The English medical literature was reviewed for RP and its association with HCV infection. RP is a rare autoimmune and multisystem disorder of unknown etiology in which the cartilaginous and related tissues are the primary targets of inflammation. HCV infection is a more common systemic illness with known hepatic and extra-hepatic manifestations. Although RP is associated with other diseases in about 35% of cases, only one case of RP, HCV, and mixed cryoglobulinemia has been reported. We report a case of RP associated with HCV infection. Treatment with pegylated interferon and ribavirin resulted in sustained virologic response and remission of treatment-resistant RP with azathioprine. We report a case of RP and associated HCV infection. Although treatment of HCV infection resulted in remission of RP, it is unknown if there is a causal relationship between HCV infection and RP.     

Cutaneous disorders associated with hepatitis C virus infection

Since the discovery of hepatitis C virus (HCV) in 1989, many cutaneous disorders have been observed in patients suffering from chronic HCV infection. The relationship between HCV infection and cryoglobulinemia or porphyria cutanea tarda (PCT) is now clearly established, but the link between HCV and other dermatoses is still controversial. This review of the main dermatologic disorders, directly or indirectly related to HCV infection, lead to conclude that HCV markers have to be investigated systematically in case of cryoglobulinemia, PCT or pruritus. In other dermatologic disorders, HCV serology will be necessary only in case of risk factors for HCV infection, or presence of abnormal liver function tests.     

Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study

Hepatitis C virus (HCV) infection is associated with systemic inflammation and metabolic complications that might predispose patients to atherosclerosis. However, it remains unclear if HCV infection increases the risk of acute myocardial infarction (MI). To determine whether HCV infection is an independent risk factor for acute MI among adults followed in general practices in the United Kingdom (UK), a retrospective cohort study was conducted in The Health Improvement Network, from 1996 through 2008. Patients ≥18 years of age with at least 6 months of follow-up and without a prior history of MI were eligible for study inclusion. HCV-infected individuals, identified with previously validated HCV diagnostic codes (n = 4809), were matched on age, sex and practice with up to 15 randomly selected patients without HCV (n = 71 668). Rates of incident MI among patients with and without a diagnosis of HCV infection were calculated. Adjusted hazard ratios were estimated using Cox proportional hazards regression, controlling for established cardiovascular risk factors. During a median follow-up of 3.2 years, there was no difference in the incidence rates of MI between HCV-infected and -uninfected patients (1.02 vs 0.92 events per 1000 person-years; P = 0.7). HCV infection was not associated with an increased risk of incident MI (adjusted HR, 1.10; 95% confidence interval [CI], 0.67-1.83). Sensitivity analyses including the exploration of a composite outcome of acute MI and coronary interventions yielded similar results (adjusted HR, 1.16; 95% CI, 0.77-1.74). In conclusion, HCV infection was not associated with an increased risk of incident MI.     

Lower expression of CD81 B-cell receptor in lymphoproliferative diseases associated with hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is frequently associated with type II mixed cryoglobulinaemia (MC), a benign lymphoproliferative disease (LPD). More recently, HCV has been implicated as a possible aetiologic factor of B-cell non-Hodgkin lymphoma (B-NHL). CD81, a B-cell surface receptor, has been proposed as a receptor for HCV binding and entry in circulating B cells. The stimulation of CD81 complex enables B cells to respond to lower concentrations of antigen and finally induces B-cell proliferation. We studied the phenotypic expression of CD81, CD19 and CD5 on circulating B cells in HCV patients LPD-positive or LPD-negative. Sixty-two patients were anti-HCV antibody positive. Among HCV positive patients, 44 were HCV RNA positive with an histologically proven chronic active hepatitis of whom 10 had a B-NHL, 14 an MC and 24 no extrahepatic manifestation. Eighteen patients were HCV RNA negative with evidence of resolved infection. A control group included 40 healthy subjects. Peripheral blood mononuclear cells (PBMC) were stained for surface expression of CD81, CD19 and CD5 using monoclonal antibodies, and were analyzed by flow cytometry. The percentage of PBMC expressing CD81, CD19 and CD5 receptors were compared between the groups by univariate analysis. Logistic regression model variables were then evaluated to correlate the presence of an LPD with HCV infection characteristics (i.e. age, gender, genotype, duration of infection, HCV RNA positivity, liver histological lesions), or phenotypic expression of CD81, CD19 and CD5 receptors on PBMC. HCV antibody-positive compared with HCV-negative subjects had a higher expression of CD19 receptor (23 +/- 13 vs 13 +/- 1%, P = 0.003). Among HCV RNA positive-patients, LPD+ compared with LPD- patients had a lower expression of CD81 (58 +/- 28 vs 82 +/- 18%, P = 0.001) and CD5 receptor (66 +/- 16 vs 74 +/- 13%, P = 0.04). In multivariate analysis, the expression of CD81 receptor was a negative (OR = 0.15, 95% CI = 0.04-0.64, P = 0.01) and CD19 receptor a positive (OR = 4.81, 95% CI =1.29-17.88, P = 0.02) predictive factor for an LPD. We found two negative predictive factors for HCV RNA positivity, i.e. age (OR = 0.23, 95% CI. = 0.08-0.62, P = 0.003) and the expression of CD81 receptor (OR = 0.34, 95% CI = 0.13-0.89, P = 0.02). In patients with a chronic active HCV infection, the presence of a lymphoproliferative disease, either MC or B-NHL, is associated with lower expression of CD81 and higher expression of CD19 receptor on peripheral B cells.     

Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas

To identify, in high-resolution regions of DNA, the copy number changes associated with outcome in patients with diffuse large B-cell lymphoma (DLBCL), a disease with an approximately 50% mortality rate, we performed array comparative genomic hybridization (array-CGH) on specimens from 64 patients with newly diagnosed DLBCL treated with anthracycline-based chemotherapy. For the entire cohort, 55 commonly gained/lost regions, ranging in size from less than 1 Mbp to entire chromosomes, were identified using 1- to 2-Mbp and 2- to 4-Mbp resolution BAC arrays. Copy number changes of 9 minimal regions significantly correlated with overall survival, of which 6 were 10 Mbp or smaller. On multivariate analysis, loss of chromosomes 2 (2.4-4.1 Mbp) and 16 (33.8-35.6 Mbp) were found to be prognostic indicators of poor survival, independent of clinical features routinely used to predict outcome. Loss of chromosome 1 (78.2-79.1 Mbp) was predictive of good outcome. For a subset of 55 specimens classified according to cell-of-origin expression signature subtype, gain of chromosome 12 (45.4-53.8 Mbp) was found to be significantly associated with the germinal center B-cell-like DLBCL subtype. Overall, array-CGH identified relatively small genomic regions associated with outcome, which, along with follow-up expression studies, may reveal target genes important in DLBCL clinical behavior.     

Chronic hepatitis C virus infection associated with autonomic dysfunction

Background: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. Aims: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. Methods: Autonomic function was assessed in 45 treatment‐naïve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R–R interval was determined by electrocardiogram recording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. Results: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1±3.4 vs. 11.5±6.5 ms/mmHg for BRS, 168.5±160.9 vs. 370.7±349.4 ms² for low‐frequency HRV (mean±SD); P<0.01]. Multivariate analysis showed that autonomic dysfunction in HCV‐infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. Conclusion: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms.