Prognostic factors influencing survival in patients with B-cell small lymphocytic lymphoma

The term "B-cell small lymphocytic lymphoma" (B-SLL) is generally reserved for patients with lymph node masses that show the histology and immunophenotype of B-cell chronic lymphocytic leukemia (B-CLL) but who are not leukemic. The aim of our study was to define clinical factors that predict for survival in B-SLL. Thirty-nine patients with B-SLL and with less than 5,000 mature-appearing lymphocytes/microL in the peripheral blood were studied. The median follow-up of survivors was 6.6 years (range, 1.6-12.3 years). The estimated 5-year overall survival (OS) and failure-free survival (FFS) were 66% and 23%, respectively. In the univariate analysis, significant adverse predictors for OS were age > or =60 years, B symptoms, elevated serum LDH, low hemoglobin (<11 g/dL), and high International Prognostic Index (IPI) score (3-5). In multivariate analysis, the IPI score was the only significant predictor of OS. Anemia and B symptoms were additionally predictive of poor OS in patients with low IPI scores.     

Understanding the reconstitution of the B‐cell compartment in bone marrow and blood after treatment for B‐cell precursor acute lymphoblastic leukaemia

A better understanding of the reconstitution of the B‐cell compartment during and after treatment in B‐cell precursor acute lymphoblastic leukaemia (BCP ‐ALL ) will help to assess the immunological status and needs of post‐treatment BCP ‐ALL patients. Using 8‐colour flow cytometry and proliferation‐assays, we studied the composition and proliferation of both the B‐cell precursor (BCP ) population in the bone marrow (BM ) and mature B‐cell population in peripheral blood (PB ) during and after BCP ‐ALL therapy. We found a normal BCP differentiation pattern and a delayed formation of classical CD 38^dim‐naive mature B‐cells, natural effector B‐cells and memory B‐cells in patients after chemotherapy. This B‐cell differentiation/maturation pattern was strikingly similar to that during initial B‐cell development in healthy infants. Tissue‐resident plasma cells appeared to be partly protected from chemotherapy. Also, we found that the fast recovery of naive mature B‐cell numbers after chemotherapy was the result of increased de novo BCP generation, rather than enhanced B‐cell proliferation in BM or PB . These results indicate that post‐treatment BCP ‐ALL patients will eventually re‐establish a B‐cell compartment with a composition and B‐cell receptor repertoire similar to that in healthy children. Additionally, the formation of a new memory B‐cell compartment suggests that revaccination might be beneficial after BCP ‐ALL therapy.     

Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies

Type 2 diabetes mellitus is a disease characterized by persistent and progressive deterioration of glucose tolerance. Both insulin resistance and impaired insulin secretion contribute to development of Type 2 diabetes. However, whilst insulin resistance is fully apparent in the pre‐diabetic condition, impairment of insulin secretion worsens over the time, being paralleled by a progressive decline in both pancreatic B‐cell function and B‐cell mass. Intense research has identified a number of genetic variants that may predispose to impaired B‐cell function, but such predisposition can be precipitated and worsened by toxic effects of hyperglycaemia (glucotoxicity) and elevated levels of free fatty acids (lipotoxicity). All these aspects of the pathogenesis of Type 2 diabetes are discussed in this review. Moreover, treatments that target reduction in glucotoxicity or lipotoxicity are outlined, including emerging strategies that target the role of glucagon‐like peptide 1 and sodium glucose co‐transporter 2.     

A clinician's guide to double hit lymphomas

Double hit lymphomas (DHL) represent a subset of highly aggressive B‐cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting MYC and either BCL2 and/or BCL6. Recent studies have expanded the concept to include MYC/BCL2 protein co‐expressing lymphomas. Around 5–10% of diffuse large B‐cell lymphomas are ‘double hit’ using the cytogenetic definition, whilst around 30–40% are MYC/BCL2 protein co‐expressing. In this review, we provide a comprehensive overview of this condition written with the practicing clinician in mind, covering the definition and classification, when DHL should be suspected and how to make the diagnosis, the prognostic factors and a detailed discussion of recent evidence regarding optimal therapy. In particular, we discuss choice of induction regimen, the role of central nervous system‐directed prophylaxis, stem cell transplantation and relapsing or refractory disease and provide our opinions based on the currently available evidence. Finally, we highlight some of the more exciting therapies currently in development for this highly aggressive disease.     

B‐type Natriuretic Peptide and Amino‐terminal Pro‐B‐type Natriuretic Peptide in Pediatric Patients with Pulmonary Arterial Hypertension

Objectives. B‐type natriuretic peptide (BNP) and the amino‐terminal fragment (NTproBNP) correlate with clinical variables, but have not been simultaneously studied in a large number of pediatric patients with pulmonary arterial hypertension (PAH). The purpose of our investigation was to compare BNP and NTproBNP with clinical indicators of disease in a pediatric PAH population for which biomarkers are much needed. Design. We retrospectively compared BNP and NTproBNP levels with exercise capacity, echocardiographic data, and hemodynamics in PAH patients under 21 years old. Two hundred sixty‐three blood samples from 88 pediatric PAH patients were obtained, with BNP and NTproBNP drawn at the same time. Results. There was a correlation between BNP and NTproBNP with mean pulmonary arterial pressure/mean systemic arterial pressure ratio (r= 0.40, P < .01; r= 0.45, P < .01; respectively), mean right atrial pressure (r= 0.48, P < .01; r= 0.48, P < .01), and tricuspid regurgitant velocity (r= 0.36, P < .01; r= 0.41, P < .01). BNP and NTproBNP are associated with 6‐minute walk distance, mean pulmonary arterial pressure, mean pulmonary arterial pressure/mean systemic arterial pressure ratio, mean right atrial pressure, pulmonary vascular resistance index, and tricuspid regurgitant velocity when investigated longitudinally. On the average, a 1‐unit increase in log BNP or NTproBNP was associated with 4.5 units × m² or 3.4 units × m² increase in pulmonary vascular resistance index, respectively. There was a strong correlation between log BNP and log NTproBNP measurements (r= 0.87, P < .01). Conclusion. In pediatric PAH, BNP and NTProBNP are strongly correlated and predict changes in clinical variables and hemodynamics. In a cross‐sectional analysis, NTproBNP correlated with echocardiographic and exercise data better than BNP; NTproBNP showed less within patient variability over time; therefore, NTproBNP can add additional information toward predicting these clinical measurements.     

Human leucocyte antigen‐B27 subtypes in Korean patients with ankylosing spondylitis: higher B*2705 in the patient group

Aim: To investigate the distribution of human leucocyte antigen (HLA) class I antigens and B27 subtypings in a group of B27(+) ankylosing spondylitis (AS) patients and a group of B27(+) control individuals, and to compare differences in their clinical features using subtyping. Methods: At otal of 143 B27(+) AS samples and 32 B27(+) control samples were collected consecutively from two rheumatology centres in South Korea. All patients were diagnosed according to the modified New York criteria for AS. Medical records of the patients were retrospectively reviewed for demographic information, Bath disease activity index (BASDAI) scores, laboratory parameters at diagnosis and extra‐articular manifestations. Polymerase chain reaction‐sequence‐specific primer typing for the B27 subtypes was performed using the Dynal HLA‐B27 high resolution kit. Results: Whereas subtypes in Korean AS patients include B*2704 (n = 11, 7.7%) B*2705 (n = 130, 90.9%), and B*2710 (n = 2, 1.4%), those of the control groups include B*2704 (n = 11, 34.4%), B*2705 (n = 19, 59.4%), B*2710 (n = 1, 3.1%), and B*2715 (n = 1, 3.1%). The proportion of B*2705 subtypes were significantly higher in the AS group than the control group (P < 0.01). There were no differences in clinical features (peripheral arthritis, uveitis, BASDAI scores) or laboratory parameters between the two groups. Conclusion: In Korean AS patients, not in the control group, the HLA‐B*2705 subtype was higher than other subtypes, in contrast to AS patients from Japan and China. B27 subtypes in AS patients were not associated with clinical features or laboratory parameters.     

Does HLA‐B*2706 protect against ankylosing spondylitis? A meta‐analysis

The human leukocyte antigen (HLA)-B*2706 is a relatively rare subtype of HLA-B27. In contrast to most HLA-B27 subtypes, some studies have reported HLA-B*2706 to be protective against ankylosing spondylitis (AS). A systematic review and a meta-analysis of available studies was performed to investigate the association of HLA-B*2706 with AS. After literature review a random effect meta-analysis was performed. No studies were found comparing the frequency of HLA-B*2706 in AS patients and controls. Meta-analysis of seven studies using HLA-B27-positive AS patients and controls showed a protective effect of HLA-B*2706 on development of AS in HLA-B27 individuals (odds ratio = 0.128, 95% CI = 0.043-0.378, P < 0.001). The results of the meta-analysis of HLA-B*2706 in HLA-B27-positive patients and controls is preliminary evidence of a protective effect of HLA-B*2706 against AS in the population. There is a clear need for additional studies on HLA-B*2706 in AS. Due to the fact that HLA-B*2706 is more or less restricted to Southeast Asia, researchers in this part of the world may have an essential role in performing these studies.     

Prediction of long‐term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE‐B score

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment‐naïve CHB patients at one tertiary care centre were scored by a single hepato‐pathologist. Laboratory values at liver biopsy were used to calculate the PAGE‐B, REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow‐up of 10.1 (IQR 5.7‐15.9) years. The PAGE‐B score predicted any clinical event (C‐statistic.86, 95% CI: 0.80‐0.92), HCC development (C‐statistic .91) and reduced transplant‐free survival (C‐statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C‐statistics (95% CI) of the REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores for any event were .70 (0.59‐0.81), .82 (0.75‐0.89), .73 (0.63‐0.84) and.79 (0.69‐0.89), respectively. The PAGE‐B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C‐statistic .87, 95% CI: 0.82‐0.93). The PAGE‐B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow‐up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.     

Factors associated with isolated anti‐hepatitis B core antibody in HIV‐positive patients: impact of compromised immunity

Summary. In regions that are hyperendemic for chronic hepatitis B virus (HBV) infection, prevalence of and risk factors associated with isolated anti‐hepatitis B core antibody (anti‐HBc) in HIV‐positive patients are less well described. HIV‐positive patients who were tested for hepatitis B surface antigen (HBsAg), anti‐hepatitis B surface antibody (anti‐HBs) and anti‐HBc at designated hospitals for HIV care in Taiwan were included for analysis. HBV DNA was detected by real‐time polymerase chain reaction in patients with and without isolated anti‐HBc. Of 2351 HIV‐positive patients, 450 (19.1%) were HBsAg positive, 411 (17.5%) were anti‐HBc positive alone and 963 (41.0%) for both anti‐HBs and anti‐HBc. Compared with patients who were positive for both anti‐HBs and anti‐HBc, patients with isolated anti‐HBc were older, less likely to have anti‐hepatitis C virus antibody (anti‐HCV), had lower CD4 lymphocyte counts and higher plasma HIV RNA loads. Older age (adjusted odds ratio, 1.029; 95% confidence interval, 1.015–1.043) and CD4 <100 cells/μL (adjusted odds ratio, 1.524; 95% confidence interval, 1.025–2.265) were independently associated with isolated anti‐HBc by logistic regression, while presence of anti‐HCV and injecting drug use were not. HBV DNA was detectable in 8.3% of 277 patients with isolated anti‐HBc and 14.3% of 56 patients with both anti‐HBs and anti‐HBc (P = 0.160). In a country hyperendemic for HBV infection, HIV‐positive patients at older age and with CD4 <100 cells/μL were more likely to have isolated anti‐HBc, suggesting that compromised immunity plays a role in the presence of this marker.     

Glucagon‐like peptide‐1 secretion by direct stimulation of L cells with luminal sugar vs non‐nutritive sweetener

Aims/Introduction: Oral ingestion of carbohydrate triggers secretion of glucagon‐like peptide (GLP)‐1, which inhibits the postprandial rise in blood glucose levels. However, the mechanism of carbohydrate‐induced GLP‐1 secretion from enteroendocrine L cells remains unclear. In the present study, GLP‐1 secretion was examined by meal tolerance tests of healthy Japanese volunteers. Materials and Methods: Twenty‐one healthy Japanese men participated in the study. The meal tolerance test was performed with modified nutrient compositions, with or without pretreatment with the α‐glucosidase inhibitor acarbose, or with substitution of sucrose with an equivalent dose of sweeteners in the meal. Blood concentrations of glucose, insulin, GLP‐1, and apolipoprotein (Apo) B‐48 were measured. Results: GLP‐1 secretion started concomitant with the increase in blood glucose levels 10 min after meal ingestion. Insulin secretion started at 5 min, before the increase in blood glucose levels, reflecting the contribution of direct nutrient stimulation on the former parameter and neural regulation in the latter. Carbohydrate retention in the gut lumen induced by acarbose pretreatment extended postprandial GLP‐1 secretion and negated the increase in serum ApoB‐48 levels. GLP‐1 secretion was markedly decreased by a reduction in the amount of sucrose in the meal and was not restored by an equivalent dose of sweeteners used to compensate for the sweet taste. Conclusions: The results indicate that direct stimulation of L cells with sugar, but not sweetener, is required for carbohydrate‐induced GLP‐1 secretion. In addition, inhibition of digestion of dietary carbohydrate by α‐glucosidase inhibitors may prevent postprandial hyperglycemia by increasing GLP‐1 secretion and by inhibiting glucose absorption. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00163.x, 2011)     

Flow cytometry in the diagnosis of mature B‐cell lymphoproliferative disorders

B‐lineage lymphoproliferative disorders (LPD) are rather frequent diseases, associated with specific clinical or biological features but also sometimes of fortuitous discovery. Multiparameter flow cytometry plays a major role for a rapid diagnostic indication, on peripheral blood or bone marrow samples in most instances, guiding complementary analyses and allowing for the proper therapeutic management of patients. After describing the important pre‐analytical precautions required for an adequate assessment, the immunophenotypic features of small‐cell and large‐cell lymphomas are described in this review. The ubiquitous expression of CD19 is a first mandatory gating step. A possible clonal proliferation is then suspected by the demonstration of surface immunoglobulin light chain restriction. The aberrant presence of CD5 allows to segregate chronic lymphocytic leukemia and mantle cell lymphoma in most cases. Other LPD exhibit specific immunophenotypic features. A table of useful markers and a decision tree are provided. Of note, immunophenotypic data should as much as possible be interpreted in an integrated manner, involving the patient's clinical and other biological features, and be completed by further chromosomal and/or molecular investigations.     

Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother‐to‐child transmission of hepatitis B virus

The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg‐positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log₁₀ copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive‐active immunoprophylaxis. The HBsAg‐positive rate of all infants at 7‐12 months of age was 5.1% (37/728). Specifically, the HBsAg‐positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti‐HBs levels between the infants aged 7‐12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV‐infected group were higher than those in the uninfected group (5.2 vs 3.4log₁₀ copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive‐active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti‐HBs levels of infants born to HBsAg‐positive mothers with HBV DNA higher than 6log₁₀ copies/mL.     

The impact of hepatitis B virus infection and vaccination on the development of non‐Hodgkin lymphoma

Hepatitis B virus (HBV) infection has been documented as a risk factor for non‐Hodgkin lymphoma (NHL). However, there are few large cohort studies, and there is no report about the impact of HBV vaccination. We conducted this study to evaluate these issues. We used the nationwide cohort of the Taiwan National Health Insurance Research Database for 1997–2013. We compared the incidence and the risk of developing NHL and CD20⁺ aggressive lymphoma between HBV and non‐HBV cohorts. The hazard ratios (HRs) were computed using Cox proportional hazards models. We matched these two large cohorts to reconfirm the data. We also compared the incidence of NHL between cohorts born before and after the inception of universal HBV vaccination. We found that HBV infection increased the risk for developing NHL and CD20⁺ aggressive lymphoma, with HRs of 4.14 and 5.52, with a higher incidence of 17.07 and 13.9 per 100 000 person‐years, respectively, compared to the non‐HBV cohort. The incidence of NHL in the cohort born in the era before universal HBV vaccination was higher with 1.85 per 100 000 person‐years compared to 0.74 in the cohort born later aged younger than 20. Our study confirms that HBV confers a greater risk for developing NHL, especially CD20⁺ aggressive lymphoma. The impact of HBV vaccination is protective against lymphoma development in the teenagers in an endemic area, but longer follow‐up is needed for older age.