Prevalence of hepatitis C virus and hepatitis G virus in patients with non‐Hodgkin's lymphoma

Hepatitis C virus (HCV) and hepatitis G virus (HGV) belong to the same family of flaviviridea. A causative role of HCV infection in the pathogenesis of non‐Hodgkin's lymphoma (NHL) has been discussed widely. Little is known about the possible association between NHL and HGV discovered recently. In this study, anti‐HCV and HGV‐RNA prevalence were investigated in a group of 70 patients with NHL. The results were compared to a control group of 70 age‐ and sex‐matched healthy subjects. One patient in each group (1.4%) was found to be anti‐HCV‐positive; the difference was not statistically significant (P > 0.05). Five subjects in the patient group (7.1%) were positive for HGV‐RNA, while a single subject was positive in the control group (1.4%); the difference was not statistically significant (P > 0.05). Odds ratios for anti‐HCV and HGV‐RNA were 1 and 5.30, respectively. Our findings suggest that neither HCV nor HGV are causative or contributing factors in the aetiopathogenesis of NHL.     

Enteroviral meningoencephalitis in a patient with non‐Hodgkin's lymphoma treated previously with rituximab

A 75‐year‐old man, with a long history of recurrent lymphoplasmacytoid lymphoma, presented with diffuse large‐cell lymphoma affecting adrenal glands and causing severe hypoadrenalism. The lymphoma responded to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP) chemotherapy. Seven months postcompletion of chemotherapy, he developed signs of gastroenteritis and septicaemia. He deteriorated 24 h postadmission with a significant fall in Glasgow Coma Scale Score. Polymerase chain reaction testing of cerebrospinal fluid suggested enteroviral encephalitis. He responded symptomatically to intravenous immunogobulins. His immunoglobulin levels were monitored weekly and supplemented to maintain immunoglobulin G level at 10 g/l, but in spite of this, his neurological condition deteriorated and he died after 14 weeks. Rituximab can cause prolonged B‐cell deficiency. We speculate that profound immunosuppression induced by rituximab, together with previous chemotherapy, predisposed this patient to fatal enteroviral meningoencephalitis.     

Hepatitis B reactivation in HBsAg‐negative/HBcAb‐positive patients receiving rituximab for lymphoma: a meta‐analysis

Patients with chronic hepatitis B (HBsAg‐positive) are at risk of viral reactivation if rituximab is administered without antiviral treatment, a potentially fatal complication of treatment. Patients with so‐called ‘resolved hepatitis B virus infection’ (HBsAg‐negative/cAb‐positive) may also be at risk. We performed a systematic review of the English and Chinese language literature to estimate the risk of hepatitis B virus (HBV) reactivation in HBsAg‐negative/cAb‐positive patients receiving rituximab for lymphoma. A pooled risk estimate was calculated for HBV reactivation. The impact of HBsAb status and study design on reactivation rates was explored. Data from 578 patients in 15 studies were included. ‘Clinical HBV reactivation’, (ALT >3 × normal and either an increase in HBV DNA from baseline or HBsAg seroreversion), was estimated at 6.3% (I² = 63%, P = 0.006). Significant heterogeneity was detected. Reactivation rates were higher in prospective vs retrospective studies (14.2% vs 3.8%; OR = 4.39, 95% CI 0.83–23.28). Exploratory analyses found no effect of HBsAb status on reactivation risk (OR = 0.083; P = 0.151). Our meta‐analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients exposed to rituximab. However, heterogeneity in the existing literature limits the generalizability of our findings. Large, prospective studies, with uniform definitions of HBV reactivation, are needed to clarify the risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients.     

Combination of 177Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Objectives

To investigate the therapeutic potential of the next‐generation anti‐CD37 radioimmunoconjugate ¹⁷⁷Lu‐lilotomab satetraxetan (¹⁷⁷Lu‐lilotomab) in combination with the anti‐CD20 antibody rituximab for treatment of mice with non‐Hodgkin's lymphoma (NHL) xenografts.

Methods

Nude mice with subcutaneous (s.c.) Burkitt's lymphoma Daudi xenografts and SCID mice intravenously (i.v.) injected with Mantle cell lymphoma Rec‐1 cells were treated with either ¹⁷⁷Lu‐lilotomab or rituximab alone or with the combination of both treatments. Tumour volume, body weight, blood counts and clinical status were monitored. CD20 expression was measured using flow cytometry with fluorescence‐labelled rituximab.

Results

The combination of ¹⁷⁷Lu‐lilotomab and rituximab was synergistic for treatment of nude mice with s.c. Daudi xenografts while it was additive for treatment of SCID mice with i.v. injected Rec‐1 cells. Binding of rituximab to NHL cells in‐vitro was increased by pretreatment with ¹⁷⁷Lu‐lilotomab.

Conclusions

Treatment of mice with NHL xenografts with ¹⁷⁷Lu‐lilotomab synergistically increased tumour suppression of subsequent anti‐CD20 immunotherapy and improved survival. If the same effect is confirmed in a recently started clinical study, it could change the way radioimmunotherapy and CD20 immunotherapy would be used in the future.

     

Primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma and hereditary hemochromatosis: a fortuitous association?1

Summary We report here a case of primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma in a 60 year old patient followed for hereditary hemochromatosis.     

Secondary amyloidosis causing nephrotic syndrome in a patient with non‐Hodgkin's lymphoma: quite a rare diagnosis

Secondary amyloidosis is usually a complication of chronic inflammation. Amyloidosis cases during the course of non‐Hodgkin's lymphoma (NHL) are usually of AL‐type, only one NHL patient with secondary amyloidosis has been reported. Our 79‐year‐old male patient visited us with multiple lymphadenopathies, and he was diagnosed with nodal marginal zone B‐cell lymphoma. After four cycles of combined chemotherapy; his urea, creatinine levels started to increase and he developed nephrotic‐range proteinuria. His rectal biopsy demonstrated amyloid deposition in submucosal vessel walls. The patient has been under hemodialysis for 10 months and his lymphoma is still in partial remission. We presented this case because it is the second NHL patient who developed secondary amyloidosis during his disease course.     

Detection of hepatitis C virus RNA in paraffin-embedded tissues from patients with non-Hodgkin's lymphoma

The aim of this study is to detect the possible role of hepatitis C Virus (HCV) in lymphomagenesis. HCV-RNA and anti-HCV antibodies were studied in tissue and serum samples taken from patients with non-Hodgkin's Lymphoma (NHL). The prevalence of HCV, the clinical presentation of these cases, and association with histologic subtypes were determined. RT-PCR was used to detect the HCV-RNA in serum and tissue samples. The anti-HCV antibodies were tested with microparticle enzyme immunoassay. Immunohistochemistry with the ABC method was used to detect the HCV core protein in HCV-RNA(+) cases. RNA could be detected in 30 of 35 cases, and other tests were performed in these 30 samples. HCV-RNA was detected in 11 tissue samples (11/30, 37%). HCV core protein was studied in 10 of 11 HCV-RNA(+) cases, and 1-3% nuclear staining was found in only 2 samples. Serologically, HCV-RNA was detected in 7 of 30 samples (23.3%) and anti-HCV antibody was detected in 3 of 30 samples (10%). Detection of HCV-RNA in 37% of the lymphoma tissue samples suggests that HCV may have a role or is a contributing factor in the pathogenesis of lymphoma. The very low HCV core protein in lymphoma tissues may be due to the low viral load in lymphoid tissues and/or higher sensitivity of the PCR method. Detection of anti-HCV antibody in only three cases may be associated with undetectable levels of antibodies due to the immune deficiency in cases with NHL.     

Successful treatment with recombinant factor VIIa of therapy-resistant severe bleeding in a patient with acquired von Willebrand disease

We describe an elderly man who presented with life-threatening hematuria and gastrointestinal bleeding caused by acquired von Willebrand disease associated with monoclonal gammopathy of undetermined significance (MGUS). Standard therapy with desmopressin, von Willebrand factor-containing factor VIII concentrate, tranexamic acid, and immunoglobulin failed to achieve adequate hemostasis. However, treatment with recombinant activated factor VII (rFVIIa) arrested the bleeding completely. Since acquired von Willebrand disease can lead to life-threatening hemorrhage, clinicians should consider rFVIIa as an effective treatment option if standard therapy fails.     

Accelerated hepatitis C virus replication with rituximab treatment in a non-Hodgkin's lymphoma patient

The treatment of patients with non-Hodgkin's lymphoma (NHL) may be complicated by concomitant chronic hepatitis C virus (HCV) infection. Recent data suggest that HCV may also be a contributing factor to the development of this disease. Although antiviral treatment has occasionally been reported to result in the regression of lymphoma in patients with HCV infection, the importance of the control of this infection on the prognosis of lymphoma needs to be defined. Here we report a patient with diffuse large B-cell lymphoma who presented with a mass in her left breast. She had had HCV-related liver cirrhosis for 6 years. She was given rituximab monotherapy for three consecutive weeks, but treatment had to be discontinued as a result of hematological toxicity. HCV viral load also increased, but then decreased gradually after rituximab was stopped. She could be given no further therapy. Six months later she presented with spinal involvement with infiltration of the cauda equina. Though cranial-spinal radiotherapy and steroids were started, she died shortly thereafter. Though rituximab is an invaluable drug in the treatment of B-cell lymphomas, we believe that the use of such agents with potentially long-lasting effects on B lymphocytes requires extended vigilance for accelerated replication of hepatitis B and C viruses.     

Telomeric 1p36.3 deletion and Ki‐67 expression in B‐Non‐Hodgkin's Lymphoma patients associated with chronic hepatitis C virus infection

The hepatitis C virus (HCV) core protein is able to accumulate genetic p53 mutations and may be considered co‐oncogenic. This study investigates 1p36.3 telomere deletion in B‐non‐Hodgkin's lymphoma (NHL) patients with chronic HCV infection using fluorescence in situ hybridization (FISH) in relation to survival to assess Ki‐67 antigen expression. A study group and a control group of 100 patients with B‐NHL (50 HCV positive and 50 HCV negative) and 60 control bone marrow biopsies were subjected to FISH for the detection of 1P36.3 deletion and to immunohistochemical staining with Ki‐67 antigens. 1p36.3 deletion by FISH was detected in 40% of the study group, and Ki‐67 was expressed in approximately 74% of patients. A significant difference was found between positive and negative HCV patients in their overall survival, the qualitative expression of Ki‐67 and the quantitative detection of 1p36.3 deletion by FISH. The overall survival was shorter with the presence of an 1p36 deletion by FISH and HCV positive. We concluded that the coexistence of Ki‐67 positivity, HCV positivity and 1p36.3 deletion may contribute to infection‐related cancers at the 1p36.3 locus.     

Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B‐cell‐like phenotype (GCB) and an activated B‐cell‐like phenotype (ABC). Particularly ABC‐DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo‐immune therapy. Through the availability of novel experimental technologies, such as next‐generation sequencing and cutting‐edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC‐DLBCL. Currently, a picture is emerging which suggests that ABC‐DLBCL critically depends on sustained activity of the NFκB pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B‐, CARD11‐, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC‐DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non‐physiological NFκB activity and repressing anti‐apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials.     

Intralobar pulmonary sequestration in a patient with non-Hodgkin's lymphoma: a cause of confusion

Pulmonary sequestration, a rare congenital pulmonary disorder, is characterized by nonfunctioning lung tissue that is separated from normal tracheobronchial tree. We present a 60-year-old woman with diffuse large cell non-Hodgkin's lymphoma. After 6 cycles of chemotherapy, paratracheal and aorticopulmonary lymphadenopathies had disappeared. However, the size of the pulmonary mass in the left lower lobe had persisted. Percutaneous fine-needle aspiration biopsy of the pulmonary mass was not diagnostic, so thoracotomy was applied. The lesion was defined as pulmonary sequestration, and basal segmentectomy was performed. After proper and sufficient chemotherapy, histopathological diagnosis of any persisting masses should be confirmed prior to overtreatment decision.     

Derangement of the T‐cell repertoire in patients with B‐cell non‐Hodgkin's lymphoma

Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non‐Hodgkin's lymphomas (NHL), the shape of the T‐cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T‐cell receptor (TCR) repertoire and the distribution of different T‐cell subsets – including regulatory T cells (Treg) – in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T‐cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T‐cell branch of the immune system of patients with B‐cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg.     

Evans' syndrome following autologous peripheral blood stem cell transplantation for non‐Hodgkin's lymphoma

A 34‐year‐old woman with non‐Hodgkin's lymphoma received high‐dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). She developed Evans’ syndrome, the association of immune thrombocytopenia and autoimmune hemolytic anemia, 49 days after transplantation. Multiple autoimmune disorders may occur concurrently after autologous PBSCT.     

Brentuximab vedotin desensitization in a patient with refractory Hodgkin's lymphoma

Brentuximab vedotin has emerged as a useful treatment option for relapsed or refractory Hodgkin's lymphoma; however, uncommon cases of anaphylactic reactions may require its permanent discontinuation. We report a 29‐yr‐old woman with refractory Hodgkin's lymphoma, who developed an anaphylactic reaction during the second dose of brentuximab vedotin. A 12‐step desensitization protocol was followed; after premedicating with antihistaminic agents, methylprednisolone and montelukast, a total dose of 156 mg of brentuximab vedotin (1.8 mg/kg) was given as three infusions with increasing rate and concentration. Such desensitization protocol can allow safe administration of brentuximab vedotin and may have a broader applicability in managing hypersensitivity reactions with other monoclonal antibodies.     

Prevalence of hepatitis B virus infection in non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Background and aim: A recent meta‐analysis has demonstrated an association between hepatitis C virus and non‐Hodgkin lymphoma (NHL). There is also evidence on the association between hepatitis B virus (HBV) and NHL. The aim of this study was to evaluate this evidence using a meta‐analytic approach. Methods: We searched the MEDLINE database from 1962 to 2008 for case–control studies that have reported the association of HBV with NHL. We calculated the odds ratio (OR) and 95% confidence intervals (CI) to assess the prevalence of HBV infection and pooled the results using three different statistical models. Results: Our search yielded 12 studies with 11 studies (3262 NHL patients, 1 523 205 controls) evaluating HBV infection in NHL and one study (3888 HBV‐infected individuals, 205 203 controls) that had investigated for NHL in HBV infection. The OR of detecting HBV infection in NHL when compared with the control population was 2.56 (95% CI, 2.24–2.92) by the fixed effects model; 2.61 (95% CI, 2.29–2.98) by the exact method and 2.67 (95% CI, 2.04–3.49) by the random effects model suggesting a high prevalence of HBV carrier state in lymphoma. There was evidence of statistical heterogeneity which disappeared after exclusion of retrospective studies on sensitivity analysis. Conclusions: The results of this study suggest a possible causal relation between HBV infection and NHL which needs to be confirmed by experimental and epidemiological studies. In countries where prevalence of HBV infection is 1% or more, it may be prudent to screen patients with NHL for occult HBV infection.     

Anti-HCV and HCV-RNA prevalence and clinical correlations in cases with non-Hodgkin's lymphoma

Hepatitis C virus (HCV) is an RNA virus in the Flaviviridae family. It displays lymphotropism in addition to hepatotropism and extrahepatic manifestations are very well known. There are many studies showing an association between HCV infection and non-Hodgkin's lymphomas (NHL). In this study the evidence for HCV infection was studied in cases with NHL. To this end, anti-HCV antibody and HCV-RNA were screened in serum samples of cases with NHL using third-generation ELISA and RT-PCR. Anti-HCV antibody was studied in 223 patients and was found to be positive in 18 cases (8.1%). Anti-HCV antibody positivity was compared with our blood bank/blood donor population. There was an important increased risk of HCV infection--the common odds ratio was 34.56 and corrected odds ratio was 19.07. HCV-RNA was studied in 67 of 223 serum samples. HCV-RNA was found to be positive in 21 of 67 samples (31.3%). When compared with clinico-demographic parameters for anti-HCV and HCV-RNA, including age, nodal status, and grade (in evaluable cases), except age in cases with or without HCV-RNA, we did not find an important correlation with HCV status and clinical findings (P=0.155; 0.442; 0.288 for anti-HCV and 0.027; 0,558; 0.126, respectively). These results suggest that HCV infection may be an important risk factor for lymphomagenesis and HCV-RNA is more useful for the detection of HCV infection in these immunosuppressed cases. Simultaneous detection of anti-HCV and HCV-RNA will be more informative in this population.     

Acquired haemophilia complicating the remission of a patient with high grade non‐Hodgkin's lymphoma treated by fludarabine

We report the development of a high titre antibody to factor VIII in a patient with previous high grade B cell non‐Hodgkin's lymphoma treated with fludarabine. Unlike previous reports of factor VIII inhibitors and lymphoproliferative disease this patient's lymphoma was in remission. We speculate that the occurrence of the inhibitor is another manifestation of the increasingly recognized autoimmune side‐effects of fludarabine.