Polymorphisms of drug‐metabolizing genes and risk of non‐Hodgkin lymphoma

Drug metabolizing genes are involved in the detoxification of chemical carcinogens. Polymorphisms in drug‐metabolizing genes affect the risk of some forms of cancer. We analyzed six polymorphisms to evaluate their association with risk for non‐Hodgkin lymphoma (NHL), and to examine whether smoking modifies these associations in population‐based study in Korea (713 cases and 1,700 controls). The GSTP1 rs1695 AG and the combined AG/GG genotypes were associated with decreased risk of NHL (odds ratio (OR)_AG = 0.67, 95% confidence interval (CI) = 0.55–0.82; OR_AG/GG = 0.66, 95% CI = 0.54–0.80) and DLBCL (OR_AG = 0.63, 95% CI = 0.49–0.82; OR_AG/GG = 0.64, 95% CI = 0.50–0.82). For T‐cell lymphoma, only the combined AG/GG genotype was associated with decreased risk (OR_AG/GG = 0.65, 95% CI = 0.44–0.96). The CYP1A1 rs1048943 AG genotype and the combined AG/GG genotypes were associated with increased risk of NHL (OR_AG = 1.28, 95% CI = 1.07–1.54; OR_AG/GG = 1.26, 95% CI = 1.06–1.51) and DLBCL (OR_AG = 1.32, 95% CI = 1.04–1.66; OR_AG/GG = 1.30, 95% CI = 1.03–1.63), but not T‐cell lymphoma. Smoking does not modify the association between these polymorphisms and NHL risk. Our data provide evidence that the GSTP1 rs1695 and the CYP1A1 rs1048943 genotypes affect the risk of NHL in Korea. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

The impact of E‐cadherin expression on the prognosis of esophageal cancer: a meta‐analysis

E‐cadherin is a 120‐KD transmembrane calcium‐dependent cell adhesion protein that has been demonstrated drownregulated in a large amount of invasive tumors. However, its effect on the prognosis of esophageal cancer (EC) remains controversial. All the relevant English articles that reported survival data or clinicopathological parameters were enrolled in this meta‐analysis. A total of 24 studies, including 2691 cases, were included in this study. Twelve studies containing 1669 cases were enrolled to synthesize with hazard ratio (HR) and its 95% confidence interval (CI). The pooled HR for all 12 studies enrolled in this meta‐analysis was 1.33 (95% CI 1.16–1.52; z = 3.99, P = 0.00). When the study measured by enzyme‐linked immunosorbent assay is excluded, the pooled HR‐evaluated E‐cadherin to reduce the expression in EC, and in esophageal squamous cell carcinoma was 1.39 (95% CI 1.22–1.58; z = 5.08, P = 0.00) and 1.38 (95% CI 1.21–1.56; z = 4.87, P = 0.00), respectively. The risk of reduced E‐cadherin expression on poor differentiation degree was 1.636 (95% CI 1.33–2.02). The pooled odds ratio of reduced E‐cadherin expression on deeper tumor invasion, lymph node metastasis, and higher clinical stage were 2.63 (95% CI 1.75–3.94), 1.77 (95% CI 1.06 ?2.97), and 3.39 (95% CI 1.85–6.23). Reduced E‐cadherin expression detected by immunohistochemistry could be a valid prognostic marker in patients with EC, especially in patients with esophageal squamous cell carcinoma. Reduced E‐cadherin expression is significantly associated with poorer differentiation degree.     

The anti‐lymphoma activity of antiviral therapy in HCV‐associated B‐cell non‐Hodgkin lymphomas: a meta‐analysis

Many epidemiological studies provide solid evidence for an association of chronic hepatitis C virus (HCV) infection with B‐cell non‐Hodgkin's lymphoma (B‐NHL). However, the most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B‐NHL regression after HCV eradication by antiviral therapy (AVT). We conducted a literature search to identify studies that included patients with HCV‐associated B‐NHL (HCV‐NHL) who received AVT, with the intention to treat lymphoma and viral disease at the same time. The primary end point was the correlation of sustained virological response (SVR) under AVT with lymphoma response. Secondary end points were overall lymphoma response rates and HCV‐NHL response in correlation with lymphoma subtypes. We included 20 studies that evaluated the efficacy of AVT in HCV‐NHL (n = 254 patients). Overall lymphoma response rate through AVT was 73% [95%>confidence interval, (CI) 67–78%]. Throughout studies there was a strong association between SVR and lymphoma response (83% response rate, 95%>CI, 76–88%) compared to a failure in achieving SVR (53% response rate, 95%>CI, 39–67%, P = 0.0002). There was a trend towards favourable response for AVT in HCV‐associated marginal zone lymphomas (response rate 81%, 95%>CI, 74–87%) compared to nonmarginal zone origin (response rate 71%, 95%>CI, 61–79%, P = 0.07). In conclusion, in the current meta‐analysis, the overall response rate of HCV‐NHL under AVT justifies the recommendation for AVT as first‐line treatment in patients who do not need immediate conventional treatment. The strong correlation of SVR and lymphoma regression supports the hypothesis of a causal relationship of HCV and lymphomagenesis.     

Incidence and Risk of Sorafenib‐Induced Hypertension: A Systematic Review and Meta‐Analysis

Hypertension is one of the major side effects of sorafenib, and reported incidences vary substantially among clinical trials. A systematic review was conducted using Medline, PubMed, Embase, and the Cochrane Library for all longitudinal studies to investigate the incidence and risk of hypertension events in cancer patients treated with sorafenib. A total of 14 randomized controlled trials and 39 prospective single‐arm trials involving 13,555 patients were selected for the meta‐analysis. The relative risk of all‐grade and high‐grade hypertension associated with sorafenib were 3.07 (95% confidence interval [CI], 2.05–4.60; P<.01) and 3.31 (95% CI, 2.21–4.95; P<.01), respectively. The overall incidence of sorafenib‐induced all‐grade and high‐grade hypertension were 19.1% (95% CI, 15.8%–22.4%) and 4.3% (95% CI, 3.0%–5.5%), respectively. A significantly higher incidence of hypertension was noted in patients with renal cell carcinoma (RCC) compared with those with non‐RCC malignancies (all‐grade: 24.9% [95% CI, 19.7%–30.1%] vs 15.7% [95% CI, 12.1%–19.3%]; P<.05; high‐grade:8.6% [95% CI, 6.0%–11.2%] vs 1.8% [95% CI, 0.9%–2.6%]; P<.05). The trials with median progression‐free survival (PFS) longer than 5.3 months (mean PFS) demonstrated a significantly higher incidence of high‐grade hypertension than trials with shorter PFS (6.3% [95% CI, 4.1%–8.5%] vs 2.6% [95% CI, 1.4%–3.8%]; P<.05). Findings of the meta‐analysis indicated a significantly high risk of sorafenib‐induced hypertension. Patients with RCC have a significantly higher incidence of hypertension and the occurrence of hypertension may be associated with improved prognosis.     

Impact of intravascular ultrasound‐guided percutaneous coronary intervention on long‐term clinical outcomes in a real world population

Objectives : To compare long‐term clinical outcomes between intravascular ultrasound (IVUS)‐guided and angiography‐guided percutaneous coronary intervention (PCI) in a large “real world” registry. Background : The impact of IVUS‐guided PCI on clinical outcomes remains unclear. Methods : Between January 1998 and February 2006, 8,371 patients who underwent IVUS‐ (n = 4,627) or angiography‐ (n = 3,744) guided PCI were consecutively enrolled. Three‐year clinical outcomes were compared after adjustment for inverse‐probability‐of‐treatment weighting (IPTW) in the overall population and in separate populations according to stent type. Results : A crude analysis of the overall population showed that the 3‐year mortality rate was significantly lower in the IVUS‐guided group than in the angiography‐guided group (96.4% ± 0.3% vs. 93.6% ± 0.4%, log‐rank P < 0.001). When adjusted by IPTW, patients undergoing IVUS‐guided PCI remained at lower risk of mortality (hazard ratio [HR] 0.627; 95% CI 0.50–0.79, P < 0.001). Similarly, in the drug‐eluting stent (DES) population, the 3‐year risk of mortality was significantly lower in patients undergoing IVUS‐guided PCI (HR 0.46; 95% CI 0.33–0.66, P < 0.001). In contrast, IVUS‐guided PCI did not reduce the risk of mortality in the bare metal stent population (HR 0.82; 95% CI 0.60–1.10, P = 0.185). However, the risks of myocardial infarction (HR 0.95; 95% CI 0.63–1.44, P = 0.810), target vessel revascularization (HR 1.00; 95% CI 0.86–1.15, P = 0.944), and stent thrombosis (HR 0.82; 95% CI 0.53–1.07, P = 0.109) were not associated with IVUS guidance. Conclusions : IVUS‐guided PCI may reduce long‐term mortality when compared with conventional angiography‐guided PCI. This may encourage the routine use of IVUS for PCI in patients undergoing DES implantation. © 2012 Wiley Periodicals, Inc.     

Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic‐onset juvenile idiopathic arthritis

Objective

To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA).

Methods

Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls.

Results

Significant associations between multiple single‐nucleotide polymorphisms (SNPs) across SLC26A2 and systemic‐onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4–3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7–4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2–5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4–3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3–5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9–5.6, P = 0.04).

Conclusion

These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup‐specific association between SNPs within the SLC26A2 gene and systemic‐onset JIA. Our findings also highlight systemic‐onset JIA as being a distinctly different disease from that in the other JIA subgroups.

     

Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft‐versus‐host disease: analysis of BMT CTN‐0201 and ‐0901 samples

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft‐versus‐host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α‐defensin‐5 (HD5) and regenerating islet‐derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre‐transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced‐intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN‐0201 and a SNP × conditioning intensity term in CTN‐0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II–IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37–0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01–2·32, P = 0·05] in CTN‐0201, but not CTN‐0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function.     

Polymorphisms in DNA repair genes and risk of non‐Hodgkin lymphoma in a pooled analysis of three studies

Genetic variations in DNA repair genes are thought to play an important role in the pathogenesis and development of non‐Hodgkin lymphoma (NHL). To further explore this hypothesis, we genotyped 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions in 1946 cases and 1808 controls pooled from three population‐based case‐control studies of NHL in the US and Australia. Relative risks of NHL and NHL subtypes in relation to SNP genotypes were assessed using logistic regression. Associations of gene regions and pathways with NHL or NHL subtypes were explored using the minP and tail‐strength statistics, respectively. Overall, genetic polymorphisms within the DNA repair pathway were associated with NHL (P = 0·005). Similar associations were seen with the double‐strand break repair (P = 0·02) and nucleotide excision repair (P = 0·04) pathways. Five SNPs (BLM rs441399, RAD50 rs2237060, FAM82A2 rs2304583, ERCC3 rs4150506, and XRCC4 rs13178127) were particularly noteworthy because their gene regions were significantly associated with NHL or NHL subtypes (minP ≤ 0·05), or because of high level of statistical significance (P ≤ 0·005) and consistent findings across the three studies. These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL.     

Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis

Objective

IL2RA/CD25, the gene for interleukin‐2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single‐nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA).

Methods

Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66–0.88], P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63–1.0], P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65–0.99], P for trend = 0.05). Meta‐analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62–0.88], P = 4.9 × 10⁻⁵).

Conclusion

These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.

     

Association of sarcopenic obesity with the risk of all‐cause mortality: A meta‐analysis of prospective cohort studies

Many prospective studies have investigated the relationship between sarcopenic obesity (SO) and risk of mortality. However, the results have been controversial. The aim of the present study was to evaluate the association between SO and all‐cause mortality in adults by a meta‐analysis of prospective cohort studies. A systematic literature search was carried out through electronic databases up to September 2014. A total of nine articles with 12 prospective cohort studies, including 35 287 participants and 14 306 deaths, were included in the meta‐analysis. Overall, compared with healthy subjects, subjects with SO had a significant increased risk of all‐cause mortality (pooled HR 1.24, 95% CI 1.12–1.37, P < 0.001), with significant heterogeneity among studies (I² = 53.18%, P = 0.0188), but no indication for publication bias (P = 0.7373). Heterogeneity became low and no longer significant in the subgroup analyses by three SO definitions. More importantly, SO, defined by mid‐arm muscle circumference and muscle strength criteria, significantly increased the risk of mortality (HR 1.46, 95% CI 1.23–1.73 and 1.23, 1.09–1.38, respectively). The risk of all‐cause mortality did not appreciably change considering the geography (USA cohorts and non‐USA cohorts) or the duration of follow up (≥10 years and <10 years). However, the risk estimate was only significant in men (HR 1.23, 95% CI 1.08–1.41, P = 0.0017), not in women (HR 1.16, P = 0.1332). The results of the present study show that subjects with SO are associated with a 24% increase risk of all‐cause mortality, compared with those without SO, in particular in men; the significant association was found independent of geographical location and duration of follow up. Geriatr Gerontol Int 2016; 16: 155–166.     

Bendamustine in chronic lymphocytic leukemia: Outcome according to different clinical and biological prognostic factors in the everyday clinical practice

Bendamustine proved to be effective for the treatment of chronic lymphocytic leukemia (CLL). However, the relationship between its activity with clinico‐biological prognosticators has been addressed only in few studies. We retrospectively evaluated the efficacy of bendamustine, in a real‐life contest, on 142 patients, median age 70 years, median number of previous regimens 2 (0–8, 13% previously untreated). Bendamustine was administered for a median number of 4 cycles, in 84% of cases with rituximab. Overall (ORR) and complete response (CRR) rates were 68 and 16.5%, respectively. Multivariate analysis demonstrated a relationship between ORR and number of prior treatments (OR 0.25, 95% CI 0.08–0.71; P = 0.009), del(17p) (OR 0.10, 95% CI 0.03–0.32; P < 0.001) and concomitant rituximab (OR 4.37, 95% CI 1.12–17.04; P = 0.033). The estimated 1‐ and 2‐years overall survival (OS) and progression free survival (PFS) rates were 76, 61, 51, and 26%, respectively. Previous sensitivity to fludarabine (HR 0.36, 95% CI 0.16–0.82), response to bendamustine (HR 0.21, 95% CI 0.10–0.45), and del(17p) (HR 2.18, 95% CI 1.002–4.74) had a prognostic significance in multivariate analysis for PFS, while the number of previous therapies (HR 3.48, 95% CI 1.29–9.38; P = 0.014), concomitant use of rituximab (HR 0.32, 95% CI 0.11–0.93) and response to bendamustine (HR 0.22, 95% CI 0.07–0.66) were significant for OS. Side effects included grade 3–4 neutropenia, infections, thrombocytopenia and anemia which occurred in 40, 14, 14, and 10% of patients, respectively. These results confirm the activity and safety of bendamustine and rituximab combination even in patients with unfavorable clinical and biological features excluding del(17p). Am. J. Heamtol. 88:955–960, 2013. © 2013 Wiley Periodicals, Inc.     

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.     

Stromal‐derived factor‐1 gene variations in pediatric patients with primary immune thrombocytopenia

Primary immune thrombocytopenia (ITP) of childhood is an autoimmune disease characterized by abnormally increased destruction of platelets and decreased megakaryopoiesis. Stromal‐derived factor‐1 (SDF‐1) plays a role in megakaryopoiesis and may be involved in the pathogenesis of ITP. Five single nucleotide polymorphisms (SNPs) of the SDF‐1 gene, including rs1801157, rs2839693, rs2297630, rs1065297, and rs266085, were assessed in 100 children with ITP and 126 healthy controls. The genotypes were analyzed by tetra ARMS polymerase chain reaction and confirmed by direct sequencing. Compared with controls, the rs2839693 A/A and rs266085 C/T genotypes were decreased in ITP patients (P = 0.004 and 0.007, respectively). The odds ratios of the latter genotypes were 0.48, 95% CI 0.28–0.82. Further analysis of the relationship between SDF‐1 polymorphisms and clinical features showed that rs2297630 A/G was associated with protection from chronicity (P = 0.002; OR, 0.07; 95% CI, 0.01–0.61) and steroid dependence (P = 0.007; OR, 0.10; 95% CI, 0.01–0.84) in ITP patients. However, rs266085 genotype C/C was associated with risk of steroid dependence (P = 0.012, OR 3.87, 95% CI 1.27–11.77). The findings of this study suggest that SDF‐1 gene variations may be associated with the occurrence and prognosis of childhood ITP.     

HbA1c‐based diabetes diagnosis among patients with glucokinase mutation (GCK‐MODY) is affected by a genetic variant of glucose‐6‐phosphatase (G6PC2)

Aims Genetic variation at the rs560887 locus of the glucose‐6‐phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK‐MODY) and correlated the genotypes with HbA_1c levels. Methods Patients from families with GCK‐MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real‐time quantitative polymerase chain reaction. The effect of rs560887 genotype on age at diagnosis of GCK‐MODY and initial HbA_1c levels were evaluated separately within both cohorts. Following that, a meta‐analysis of rs560887 genotype–HbA_1c associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort‐specific results. Results GG homozygosity at rs560887 was associated with marginally elevated HbA_1c levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68). Meta‐analysis showed that GG homozygosity at rs560887 was associated with mean HbA_1c levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.5–4.4 mmol/mol (0.05–0.44%) than in individuals with other genotypes. Additionally, meta‐analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol/mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.07–3.36; P = 0.03). No such effects were observed for age at diagnosis of diabetes. Conclusions Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA_1c level.     

High doses of β‐blockers and alcohol abstinence improve long‐term rebleeding and mortality in cirrhotic patients after an acute variceal bleeding

Background & aim: We analysed prognostic indicators of long‐term outcome in cirrhotic patients surviving the critical 6‐week period after an episode of acute variceal bleeding. Methods: All patients with oesophageal variceal bleeding from 2001–2007 were prospectively registered. Follow‐up extended from day 42 after index bleeding to last visit, death or liver transplantation (LT). Multivariate Cox regression analysis was performed. Results: Two hundred and fifty variceal bleeding episodes were registered. Fifty‐four patients (26%) died before day 42, and 123 patients were finally included. Median follow‐up was 23.5 months. Nadolol±nitrates alone or combined with variceal ligation were used as prophylaxis in 93% of patients. During follow‐up, 43 patients (35%) experienced rebleeding, 34 (27.5%) died and 10 (8%) were transplanted. Follow‐up β‐blocker dose (HR 0.993, 95% CI 0.987–0.998, P=0.027) and alcohol abstinence (HR 0.324, 95% CI 0.152–0.691, P=0.004) were independent rebleeding predictors. The Cox analysis disclosed the Child–Pugh score (HR 1.24, 95% CI 1.08–1.43, P=0.002), creatinine (HR 1.82, 95% CI 1.17–2.82, P=0.008), β‐blocker dose (HR 0.992, 95% CI 0.987–0.997, P=0.003), viral cirrhosis (HR 2.72, 95% CI 1.31–5.67, P=0.008), hepatocellular carcinoma (HR 9.44, 95% CI 3.54–25.20, P<0.001) and alcohol abstinence (HR 0.29, 95% CI 0.13–0.62, P=0.002) to be independent prognostic markers for mortality/LT. Conclusion: High doses of β‐blockers and alcohol abstinence decrease rebleeding and mortality in cirrhotic patients surviving the 6‐week period after acute variceal bleeding.     

Single nucleotide polymorphisms of CD244 gene predispose to renal and neuropsychiatric manifestations with systemic lupus erythematosus

Abstract

The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) of the CD244 gene with several clinical features of systemic lupus erythematosus (SLE). Two hundred and forty-three patients with SLE and 369 healthy controls were enrolled. Two SNPs (rs6682654 and rs3766379) in the CD244 gene were determined by allelic discrimination using a specific TaqMan probe. Only SNP rs3766379 was significantly associated with susceptibility to SLE [P = 0.009; odds ratio (OR) 1.28; 95% confidence interval (CI) 1.04–1.57]. The association was preferentially observed in subsets of SLE patients with nephritis and neuropsychiatric lupus. The frequency of the rs6682654 C allele was strongly associated with nephritis and neuropsychiatric lupus (P = 0.00065; OR 1.99; 95% CI 1.34–2.95, and P = 1.6 × 10^?7; OR 3.47; 95% CI 2.12–5.70, respectively), as was the frequency of the rs3766379 T allele (P = 0.0014; OR 1.86; 95% CI 1.27–2.71, and P = 2.6 × 10^?7; OR 3.15; 95% CI 2.00–4.96, respectively). In this study, an SNP of the CD244 gene was associated with susceptibility to SLE. There was a strikingly strong association in SLE patients with nephritis and neuropsychiatric lupus, suggesting that this genetic marker could predict involvement of those severe complications.     

Association between the tumour necrosis factor-α-308G/A polymorphism and chronic obstructive pulmonary disease: an update

Background and objective: Previous studies have suggested that the ?308A allele in the tumour necrosis factor‐α (TNF‐α) gene promoter (rs1800629) may be a potential risk factor for COPD. However, more recent findings have been inconsistent. In the present study, a meta‐analysis was performed to assess the association between the TNF‐α?308G/A single nucleotide polymorphism (SNP) and the risk of COPD. Methods: Published studies were retrieved from PubMed, EMBASE and other databases. All studies assessing the association between the TNF‐α?308G/A SNP and the risk of COPD were assessed. Pooled ORs with 95% CIs were calculated. Results: In the 36 studies that met the inclusion criteria, 4975 patients and 6518 control subjects had been genotyped. The overall results showed that the association between the TNF‐α?308G/A SNP and the risk of COPD was statistically significant for Asians (OR = 2.36, 95% CI: 1.84–3.02, P < 0.0001) but not for Caucasians (OR = 1.07, 95% CI: 0.91–1.25, P = 0.438). As smoking is one of the most important risk factors for COPD, a second meta‐analysis that included only smokers (3018 patients and 2749 control subjects) was performed. This analysis confirmed that the association between the TNF‐α?308G/A SNP and COPD was statistically significant for Asians (OR = 1.72, 95% CI: 1.14–2.61, P = 0.011) but not for Caucasians (OR = 1.16, 95% CI: 0.86–1.56, P = 0.33). Conclusions: This meta‐analysis suggests that the TNF‐α?308A genotype is associated with an increased risk of COPD in Asian but not Caucasian populations. Further studies are necessary to evaluate the relationship between TNF‐α polymorphisms and the risk of COPD.     

Hepatitis B virus and risk of non‐Hodgkin lymphoma: An updated meta‐analysis of 58 studies

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non‐Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta‐analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV‐infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20‐2.83) regardless of the study design (case–control studies: sOR: 2.47; 95% CI: 2.16‐2.82; cohort studies: sOR: 2.64; 95% CI: 1.78‐3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta‐regression: P < .05). Overall, B‐cell NHL (sOR: 2.46; 95% CI: 1.97‐3.07) presented a stronger association with HBV infection than T‐cell NHL (sOR: 1.67; 95% CI: 1.34‐2.10). Within the B‐cell NHL subtypes, HBV infection was significantly associated with diffuse large B‐cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48‐2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11‐2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta‐analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV‐induced NHL are warranted.     

Long‐term macrolides for non‐cystic fibrosis bronchiectasis: A systematic review and meta‐analysis

Long‐term macrolides are increasingly being prescribed for stable bronchiectasis. This meta‐analysis assessed the clinical effect of this treatment in bronchiectasis. A systematic review and meta‐analysis were carried out. All randomized, controlled trials (RCT) comparing long‐term macrolides with placebo and/or usual medical care, with outcome measures relating to efficacy and safety were selected. Nine RCT recruiting 530 patients were included. Compared with placebo and/or usual medical care, long‐term macrolides significantly reduced the risk of the exacerbations (number of participants with exacerbations (relative risk = 0.70, 95% confidence interval (CI) 0.60–0.82, P < 0.00001); average exacerbations per participant (weighted mean difference = ?1.01, 95% CI ?1.35 to ?0.67, P < 0.00001)), the St George's Respiratory Questionnaire total scores (weighted mean difference = ?5.39 95% CI ?9.89 to ?0.88, P = 0.02), dyspnoea scale (weighted mean difference = ?0.31 95% CI ?0.42 to ?0.20, P < 0.00001), 24‐h sputum volume (P < 0.00001), and attenuated the decline of forced expiratory volume in 1 s (weighted mean difference 0.02 L, 95% CI 0.00–0.04, P = 0.01). Eradication of pathogens (P = 0.06), overall rate of adverse events (P = 0.61), and emergence of new pathogens (P = 0.61) were not elevated, while gastrointestinal events increased significantly with macrolides (P = 0.0001). Macrolide resistance increased, but a meta‐analysis was not possible due to the diversity of parameters. Long‐term use of macrolides appears to be a treatment option for stable bronchiectasis. The results of this review justify further investigation about adding this intervention to the treatment regimens of bronchiectasis.     

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non‐Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3‐weekly standard (s) or intensive (i) chemotherapy: s‐CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5; i‐CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5‐year overall survival (OS). Relative to s‐CEOP patients, i‐CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5‐year OS (56.7% i‐CEOP; 55.1% s‐CEOP; P = 0.80), 5‐year progression free survival (PFS; 41% i‐CEOP; 43% s‐CEOP; P = 0.73), 5‐year time to progression (TTP; 44% i‐CEOP; 47% s‐CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i‐CEOP; 59% s‐CEOP; P = 0.64). Long‐term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i‐CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6‐month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.