A case–control study of HIV infection and cancer in the era of antiretroviral therapy in Rwanda

The aim of this study was to assess the association between HIV infection and cancer risk in Rwanda approximately a decade after the introduction of antiretroviral therapy (cART). All persons seeking cancer care at Butaro Cancer Center of Excellence (BCCOE) in Rwanda from 2012 to 2016 were routinely screened for HIV, prior to being confirmed with or without cancer (cases and controls, respectively). Cases were coded according to ICD‐O‐3 and converted to ICD10. Associations between individual cancer types and HIV were estimated using adjusted unconditional logistic regression. 2,656 cases and 1,196 controls differed by gender (80.3% vs. 70.8% female), age (mean 45.5 vs. 37.7 years), place of residence and proportion of diagnoses made by histopathology (87.5% vs. 67.4%). After adjustment for these variables, HIV was significantly associated with Kaposi Sarcoma (n = 60; OR = 110.3, 95%CI 46.8–259.6), non‐Hodgkin lymphoma (NHL) (n = 265; OR = 2.5, 1.4–4.6), Hodgkin lymphoma (HL) (n = 76; OR = 5.2, 2.3–11.6) and cancers of the cervix (n = 560; OR = 5.9, 3.8–9.2), vulva (n = 23; OR = 17.8, 6.3–50.1), penis (n = 29; OR = 8.3, 2.5–27.4) and eye (n = 17; OR = 4.7, 1.0–25.0). Associations varied by NHL/HL subtype, with that for NHL being limited to DLBCL (n = 56; OR = 6.6, 3.1–14.1), particularly plasmablastic lymphoma (n = 6, OR = 106, 12.1–921). No significant associations were seen with other commonly diagnosed cancers, including female breast cancer (n = 559), head and neck (n = 116) and colorectal cancer (n = 106). In conclusion, in the era of cART in Rwanda, HIV is associated with increased risk of a range of infection‐related cancers, and accounts for an important fraction of cancers presenting to a referral hospital.     

A prospective investigation of serum 25‐hydroxyvitamin D and risk of lymphoid cancers

Studies indicate that higher sun exposure, especially in the recent past, is associated with reduced risk of non‐Hodgkin lymphoma (NHL). Ultraviolet radiation‐derived vitamin D may be protective against lymphomagenesis. We examined the relationship between prediagnostic serum 25‐hydroxyvitamin D (25(OH)D) and lymphoid cancer risk in a case–control study nested within the Alpha‐Tocopherol Beta‐Carotene Cancer Prevention Study cohort (1985–2002) of 29,133 Finnish male smokers (ages 50–69). We identified 270 incident lymphoid cancer cases and matched them individually with 538 controls by birth‐year and month of fasting blood draw at baseline. In conditional logistic regression models for 10 nmol/L increments or tertile comparisons, serum 25(OH)D was not associated with the risk of overall lymphoid cancers, NHL (n = 208) or multiple myeloma (n = 41). Odds ratios (OR) for NHL for higher tertiles were 0.75 (95% confidence interval (CI), 0.50, 1.14) and 0.82 (95% CI, 0.53, 1.26). The 25(OH)D‐NHL association, however, differed by follow‐up duration at diagnosis. Cases diagnosed less than 7 years from the baseline showed an inverse association (OR for highest vs. lowest tertile = 0.43; 95% CI: 0.23, 0.83; p for trend = 0.01), but not later diagnoses (OR = 1.52; 95% CI: 0.82, 2.80; p for trend = 0.17). The inverse association found for close exposure to diagnosis was not confounded by other risk factors for lymphoma or correlates of 25(OH)D. Although our findings suggest that circulating 25(OH)D is not likely associated with overall lymphoid cancer, they indicate a potentially protective effect on short‐term risk of NHL. © 2008 Wiley‐Liss, Inc.     

Hepatitis C virus and GBV-C virus prevalence among patients with B-cell lymphoma in different European regions: a case-control study of the International Extranodal Lymphoma Study Group

Hepatitis C virus (HCV) infection is associated with some B‐cell non‐Hodgkin lymphoma (B cell‐NHLs). Patients with HCV infection frequently show co‐infections with GB virus C (GBV‐C, formerly known as hepatitis G virus), and some studies have suggested a higher incidence of GBV‐C infection in patients with B cell‐NHLs. The aim of this study was to prospectively evaluate the association between HCV and/or GBV‐C infection and B cell‐NHLs in different geographic areas. One hundred thirty‐seven lymphoma cases and 125 non‐lymphoma matched controls were enrolled in an international case‐control study conducted in Switzerland (Bellinzona), Spain (Barcelona) and England (Southampton) on samples collected from 2001 to 2002. In Bellinzona (41 cases and 81 controls), the overall prevalence of HCV was 3.3% (4.9% in NHLs), and the overall prevalence of GBV‐C was 24% (22% in NHLs). In Barcelona (46 cases and 44 controls), the prevalence of HCV was 10% (8.7% in NHLs) and the prevalence of GBV‐C 20% (13% in NHLs). There was no statistically significant difference in the frequency of both infections between patients with NHL and controls. In Southampton, 50 NHL cases were analysed, none of them was found to be HCV‐positive; therefore, no control group was analysed and GBV‐C analysis was not performed, too. Both in Bellinzona and in Barcelona, the seropositivity rate was significantly lower for HCV than for GBV‐C, suggesting that their transmission can be independent. The incidence of HCV was significantly higher in Barcelona than that in Bellinzona. This study confirmed the existence of marked geographic differences in the prevalence of HCV in NHL but cannot provide any significant evidence for an association between HCV and/or GBV‐C and B‐cell NHLs. Copyright © 2011 John Wiley & Sons, Ltd.     

Lifestyle factors,autoimmune disease and family history in prognosis of non‐hodgkin lymphoma overall and subtypes

Lifestyle factors and medical history are known to influence risk of non‐Hodgkin lymphoma (NHL). Whether these factors affect the prognosis of NHL, especially its subtypes, is unclear. To investigate this, the association between these factors and all‐cause and lymphoma‐related mortality was assessed in a population‐based cohort of 1,523 Swedish NHL patients included in the Scandinavian Lymphoma Etiology study in 1999–2002. Participants contributed time from NHL diagnosis until death or October 1, 2010, with virtually complete follow‐up through linkage to the Swedish Cause of Death Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using stratified and multivariable‐adjusted Cox regression models. During a median follow‐up of 8.8 years, 670 patients (44%) died, with the majority of deaths attributed to lymphoma (86%). Current versus never smoking at diagnosis was associated with increased rate of all‐cause death for all NHL (HR = 1.5, 1.2–1.8) and diffuse large B‐cell lymphoma (HR = 1.8, 1.2–2.7). Low educational level (HR = 1.3, 1.1–1.7, <9 vs. >12 years) and NHL risk‐associated autoimmune disease (HR = 1.4, 1.0–1.8) were associated with death for all NHL combined. However, evidence of an association with lymphoma‐related death was limited. Body mass index, recent sunbathing and family history of hematopoietic malignancy were not consistently associated with death after NHL or its specific subtypes. These results add to the evidence that cigarette smoking, socioeconomic status and certain autoimmune diseases affect survival after NHL. Further investigations are needed to determine how these factors should be incorporated into clinical prognostic assessment.     

A functional TNFRSF5 polymorphism and risk of non‐Hodgkin lymphoma,a pooled analysis

Interaction between CD40 and its ligand, CD154, has a key function in immune regulation. Recent experimental data support a role of deregulated CD40 signalling in lymphomagenesis. Data from earlier studies that are part of this pooling study implicate a functional polymorphism (?1C>T, rs1883832) in the TNFRSF5 gene encoding CD40 in the etiology of follicular lymphoma. Here, the association of this variant with non‐Hodgkin lymphoma (NHL) risk was replicated in a European multicenter study of 855 NHL cases and 1,206 controls. In the combined analysis of 2,617 cases and 3,605 controls, carrying the TT genotype was associated with an increased risk for all NHL (OR = 1.4; p for linear trend = 0.00009), diffuse large B‐cell lymphoma (OR = 1.6; p for linear trend = 0.002) and follicular lymphoma (OR = 1.6; p for linear trend = 0.001). These data suggest a possible role of this functional polymorphism in lymphomas originating within the germinal center.     

Epstein‐Barr virus and risk of non‐Hodgkin lymphoma in the cancer prevention study‐II and a meta‐analysis of serologic studies

Epstein‐Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non‐Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively‐collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study‐II (CPS‐II) Nutrition Cohort and conducted a meta‐analysis of our and published results. The CPS‐II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA‐D) diffuse and BZLF1‐encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen‐1 and viral capsid antigen (VCA)‐p18 were elevated but not statistically significant. In the meta‐analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16–2.00) and VCA (summary OR = 1.20, 95% CI: 1.00–1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.     

Viral and non-viral risk factors for non-Hodgkin’s lymphoma in Egypt: heterogeneity by histological and immunological subtypes

Objective  Non-Hodgkin’s lymphomas (NHL) are etiologically heterogeneous malignancies. In Egypt, we previously reported an association of increased NHL risk with chronic hepatitis C virus (HCV) infection. Our present aim is to assess the association between HCV infection and histological subtypes of NHL. Methods  We conducted a case–control study at the National Cancer Institute of Cairo University. Cases with NHL (n = 486) were matched to controls (n = 786) who were orthopedic patients from the same referral regions. Participants provided a blood sample for HCV markers (anti-HCV, HCV RNA) and answered a questionnaire on possible risk factors. Case–control differences were assessed by odds ratios and 95% confidence intervals from logistic regression analysis. Results  Cases with diffuse large B cell lymphoma (n = 146), chronic lymphocytic leukemia (n = 58), marginal zone lymphoma (n = 24), follicular lymphoma (n = 23), and mantle cell lymphoma (n = 16) were recruited. HCV RNA prevalence was 27% in controls and 26%–48% in the NHL subgroups: it was associated (p < 0.001) with diffuse large B cell, marginal zone, and follicular lymphomas with odds ratios of 3.2, 4.4, and 3.3, respectively. Conclusion  HCV is a risk factor for diffuse large B cell, marginal zone, and follicular lymphomas in Egypt.     

Antiviral therapy improves overall survival in hepatitis C virus‐infected patients who develop diffuse large B‐cell lymphoma

Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non‐Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV‐infected patients with diffuse large B‐cell lymphoma (DLBCL) is unclear. We therefore analyzed AVT's impact on oncologic outcomes of HCV‐infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004–May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon‐based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% vs. 72%; p = 0.07) and upper gastrointestinal (GI; 42% vs. 24%; p = 0.004) involvement. Cases never given AVT had DLBCL more refractory to first‐line chemotherapy than that in the controls (33% vs. 17%; p = 0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% vs. 32%; p = 0.09) or cases given AVT (50% vs. 27%; p = 0.06). Cases never given AVT had worse 5‐year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01–5.3]; p = 0.04). Furthermore, AVT improved 5‐year OS rates among cases in both univariate (median [Interquartile range]: 39 [26–56] vs. 16 [6–41] months, p = 0.02) and multivariate analyses (HR = 0.21 [95% CI, 0.06–0.69]; p = 0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5‐year OS.     

Allergies,atopy, immune‐related factors and childhood rhabdomyosarcoma: A report from the children's oncology group

Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case‐control study of 322 childhood RMS cases and 322 pair‐matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex and age. The following atopic conditions were assessed: allergies, asthma, eczema and hives; in addition, we examined other immune‐related factors: birth order, day‐care attendance and breastfeeding. Conditional logistic‐regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income and parental education. As the two most common histologic types of RMS are embryonal (n = 215) and alveolar (n = 66), we evaluated effect heterogeneity of these exposures. Allergies (OR = 0.60, 95% CI: 0.41–0.87), hives (OR = 0.61, 95% CI: 0.38–0.97), day‐care attendance (OR = 0.48, 95% CI: 0.32–0.71) and breastfeeding for ≥ 12 months (OR = 0.36, 95% CI: 0.18–0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p > 0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system's role in the development of this tumor.     

Serologic markers of viral infection and risk of non‐Hodgkin lymphoma: A pooled study of three prospective cohorts in China and Singapore

Incidence rates of non‐Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre‐diagnostic blood and NHL risk in East Asians. We conducted a nested case‐control study of 214 NHL cases and 214 matched controls from three population‐based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead‐based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA‐D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10‐3.81; p_trend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96‐4.89; p_trend = 0.008) Epstein‐Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus‐6 (HHV‐6) antigen (OR = 1.85, 95% CI = 1.04‐3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV‐HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV‐6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication.     

A polymorphism in miR‐1262 regulatory region confers the risk of lung cancer in Chinese population

It has been proposed that the majority of disease‐associated loci identified by genome‐wide association studies (GWAS) are enriched in non‐coding regions, such as the promoter, enhancer or non‐coding RNA genes. Thus, we performed a two‐stage case‐control study to systematically evaluate the association of genetic variants in miRNA regulatory regions (promoter and enhancer) with lung cancer risk in 7,763 subjects (discovery stage: 2,331 cases and 3,077 controls; validation stage: 1,065 cases and 1,290 controls). As a result, we identified that rs12740674 (C > T) in miR‐1262 enhancer was significantly associated with the increased risk of lung cancer (additive model in discovery stage: adjusted OR = 1.31, 95%CI = 1.13–1.53, p = 3.846 × 10^?4 in Nanjing GWAS; adjusted OR = 1.20, 95%CI = 1.00–1.44, p = 0.041 in Beijing GWAS; validation stage: adjusted OR = 1.20, 95%CI = 1.03–1.41, p = 0.024). In meta‐analysis, the p value for the association between rs12740674 and lung cancer risk reached 6.204 × 10^?6 (adjusted OR = 1.24, 95%CI = 1.13–1.36). Using 3DSNP database, The Cancer Genome Atlas (TCGA) data and functional assays, we observed that the risk T allele of rs12740674 reduced the expression level of miR‐1262 in lung tissue through chromosomal looping, and overexpression of miR‐1262 inhibited lung cancer cell proliferation probably through targeting the expression levels of ULK1 and RAB3D . Our findings confirmed the important role that genetic variants of noncoding sequence play in lung cancer susceptibility and indicated that rs12740674 in miR‐1262 may be biologically relevant to lung carcinogenesis.     

Menopausal estrogen therapy and non‐Hodgkin's lymphoma: A post‐hoc analysis of women's health initiative randomized clinical trial

Estrogens are important immunomodulators, exerting significant effects on cell proliferation, apoptosis, cytokine production and differentiation of hematopoietic cells. Estrogen receptors are expressed on normal B and T lymphocytes, bone marrow and in leukemia and lymphoma cell lines. Epidemiologic evidence for the association of menopausal hormone use with risk of non‐Hodgkin's lymphoma (NHL) has been mixed; however, all of the investigations have been observational. We analyzed the data from Women's Health Initiative hormone therapy trials where conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 16,654) or CEE alone (women with prior hysterectomy) (n = 10,685) were tested against placebos and the intervention lasted a median of 5.6 years in the CEE + MPA trial and 7.2 years in the CEE alone trial. During 13 years of follow‐up through September 20, 2013 383 incident NHL cases were identified. We used the intent‐to‐treat approach to calculate incidence rates of NHL, hazards ratios (HR) and 95% confidence intervals (CI) by treatment group. Incidence of NHL was virtually the same in the treatment and placebo groups. The HR was 1.02 (95%CI 0.74–1.39) for CEE alone, 0.98 (95% CI 0.76–1.28) for CEE+MPA, and 1.00 (95% CI 0.82–1.22) for both combined. There were no specific NHL subtypes associated with either type of the treatment, except a marginally decreased risk of plasma cell neoplasms (HR= 0.53 95% CI 0.27–1.03) in the CEE‐alone group. These results do not support a role of estrogen alone or combined with progestin in the development of NHL among postmenopausal women.     

Case–control study of genus‐beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma

Cutaneous human papillomaviruses (HPV) have been reported in cutaneous squamous cell carcinoma (SCC). We conducted a clinic‐based case–control study to investigate the association between genus‐beta HPV DNA in eyebrow hairs (EBH) and SCC. EBH from 168 SCC cases and 290 controls were genotyped for genus‐beta HPV DNA. SCC tumors from a subset of cases (n = 142) were also genotyped. Viral load was determined in a subset of specimens positive for a single HPV type. Associations with SCC were estimated by odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and sex using logistic regression. Statistical tests were two‐sided. EBH DNA prevalence was greater in cases (87%) than controls (73%) (p < 0.05), and the association with SCC increased with the number of HPV types present, (≥4 types vs. HPV‐negative: OR = 2.02, 95% CI = 1.07–3.80; p_trend = 0.02). Type‐specific associations were observed between SCC and DNA in EBH for HPV23 (OR = 1.90, 95% CI = 1.10–3.30) and HPV38 (OR = 1.84, 95% CI = 1.04–3.24). Additionally, when compared with the controls, the DNA prevalence in EBH was significantly higher among cases for 11 of the 25 genus‐beta types tested, when accounting for DNA for the same HPV type in the tumor (ORs = 3.44–76.50). Compared to controls, the mean viral DNA load in EBH among the selected cases was greater for HPV5, HPV8 and HPV24, but lower for HPV38. SCC cases were more likely than controls to have HPV DNA+ EBH for single and multiple HPV types, providing additional support for the potential role of genus‐beta HPV infections in SCC development.     

The p73 G4C14‐to‐A4T14 polymorphism is associated with risk of lung cancer in the Han nationality of North China

p73, a structural and functional homolog of p53, plays an important role in tumor carcinogenesis. Previous studies have suggested that the association between the p73 G4C14‐to‐A4T14 polymorphism and the risk of lung cancer, but the results have not been entirely consistent. We examined whether the p73 G4C14‐to‐A4T14 polymorphism was related to the risk of developing lung cancer in a Chinese population. The p73 G4C14‐to‐A4T14 polymorphism was genotyped in 293 lung cancer patients and 380 cancer‐free controls of Han nationality in North China using PCR‐RFLP. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly increased susceptibility to lung cancer (OR, 1.48; 95% CI, 1.08–2.02; P = 0.014). In addition, compared with the GC/GC genotype, the GC/AT genotype was also significantly associated with increased susceptibility to lung cancer (OR, 1.46; 95% CI, 1.06–2.02; P = 0.046). Our findings suggest that the p73 G4C14‐to‐A4T14 polymorphism contributes to the risk of developing lung cancer in Chinese population. © 2012 Wiley Periodicals, Inc.     

Common genetic variants and risk for non‐Hodgkin lymphoma and adult T‐cell lymphoma/leukemia in Jamaica

We evaluated whether risk of non‐Hodgkin lymphoma (NHL), particularly adult T‐cell leukemia/lymphoma (ATL) related to human T‐lymphotropic virus (HTLV) infection was associated with 63 single nucleotide polymorphisms (SNPs) from 38 candidate genes. The 395 NHL cases registered in Jamaica were matched by age, sex, calendar‐year and HTLV serostatus to 309 controls from the same population. Interleukin 13 (IL13) Ex4+98A>G SNP (rs20541) was associated with decreased NHL risk (OR_AG/AA = 0.62,95% CI = 0.44–0.87, p = 0.006), as was vascular cell adhesion molecule‐1, VCAM1 Ex9+149G>A SNP (rs1041163) (OR_CT = 0.77, 95% CI = 0.54–1.10, OR_CC=0.35, 95% CI = 0.16–0.76, p‐trend = 0.007). Both results were stronger in analyses restricted to ATL cases and HTLV‐positive controls, suggesting a role for these genes in ATL etiology (IL13 OR_AG/AA = 0.54, 95% CI = 0.36–0.84, p = 0.005; VCAM1 OR_CT = 0.65, 95% CI = 0.42–1.01, OR_CC = 0.20, 95% CI = 0.08–0.54, p‐trend = 0.001). Confirmation of these results in Caribbean and other populations is needed. © 2009 UICC     

IL12 polymorphisms,HBV infection and risk of hepatocellular carcinoma in a high‐risk Chinese population

To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3′UTR G>A), rs2243115 (5′UTR T>G) in IL12A and rs3212227 (3′UTR A>C) in IL12B in a case–control study of 869 hepatocellular carcinoma (HCC) cases and 891 cancer‐free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.17–2.00), compared with the wild‐type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR = 1.71, 95% CI = 1.23–2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.     

Tumor necrosis factor‐alpha inhibitors and risk of non‐Hodgkin lymphoma in a cohort of adults with rheumatologic conditions

Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor‐alpha inhibitors (TNFIs) and risk of non‐Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti‐TNF agent. We performed a nested case‐control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional‐synthetic disease‐modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever‐use was associated with nearly two‐fold increased risk of NHL (OR = 1.93; 95% CI: 1.16–3.20) with suggestion of increasing risk with duration (P‐trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40–5.33), whereas risk with anti‐TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87–3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.     

Prediagnostic circulating concentrations of plasma insulin‐like growth factor‐I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition

Insulin‐like growth factor (IGF)‐I has cancer promoting activities. However, the hypothesis that circulating IGF‐I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF‐I concentration was measured in pre‐diagnostic plasma samples from a nested case–control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF‐I concentration was not associated with overall lymphoma risk (multivariable‐adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57–1.03], p _trend = 0.06). There was no statistical evidence of heterogeneity in this association with IGF‐I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (p _{heterogeneity for all} ≥ 0.05). There were no associations between IGF‐I concentration and risk for specific BCL subtypes, T‐cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF‐I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF‐I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF‐I concentrations with lymphoma subtypes.     

Genetic variation of PSCA gene is associated with the risk of both diffuse‐ and intestinal‐type gastric cancer in a Chinese population

Prostate stem cell antigen (PSCA), a member of the LY‐6/Thy‐1 family of glycosylphosphatidylinositol‐anchored cell surface proteins, is considered to be involved in the cell‐proliferation inhibition and/or cell‐death induction activity. Two single nucleotide polymorphisms (SNPs) (rs2976392 and rs2294008) in the PSCA gene were recently identified as the susceptibility loci of gastric cancer, especially in diffuse type. Therefore, this study was to investigate whether these 2 SNPs were associated with the risk of gastric cancer in Chinese population. We genotyped rs2976392 and rs2294008 in PSCA in a case–control study including 1,053 incident gastric cancer patients and 1,100 cancer‐free controls in a high‐risk Chinese population. We found that variant genotypes of rs2976392 (GA/AA) were associated with a significantly 37% increased risk of gastric cancer (adjusted OR =1.37, 95% CI = 1.15–1.62), compared with variant homozygote GG, and the associations were all consistently significant in both intestinal and diffuse subtypes, and among different subgroups stratified by age, sex, drinking or smoking status. Interestingly, a significant multiplicative interaction between rs2976392 (GA/AA) and alcohol drinking was detected on the development of intestinal‐type gastric cancer (p = 0.009). However, rs2294008 variant genotypes (CT/TT) were associated with a nonsignificant increased risk of gastric cancer (adjusted OR = 1.14, 95% CI = 0.96–1.36). A small meta‐analysis including 5 case–control studies showed undoubtedly associations between PSCA rs2294008 and rs2976392 and gastric cancer risk (OR = 1.83, 95% CI: 1.29–2.60 and OR = 1.84, 95% CI: 1.33–2.56, respectively). These findings provide further evidence supporting that the genetic variants of PSCA gene may contribute to the gastric carcinogenesis.     

Use of non‐steroidal anti‐inflammatory drugs and risk of non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Epidemiological study findings regarding the association between use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and risk of non‐Hodgkin lymphoma (NHL) have been inconsistent. We aimed to systematically review epidemiological studies of the association and calculate pooled relative risks using meta‐analytic methods. We searched eight electronic literature databases and three clinical trial registers to identify all studies (including observational studies and randomized clinical trials) of the association published prior to October 2013. Identified studies were independently reviewed by two researchers. We used a random effects model to calculate pooled odds ratio (PORs). Heterogeneity amongst studies was examined using Cochran's Q and I‐squared (I²) tests; and sources of heterogeneity were explored using subgroup and meta‐regression analyses. A total of 17 studies (12 case‐control studies and five cohort studies), all adult studies, were included. Use of NSAIDs was not associated with overall risk of NHL [POR = 1.05, and 95% confidence interval (95% CI) 0.90–1.22] or NHL subtypes including B‐cell lymphoma, T‐cell lymphoma, follicular lymphoma, diffuse large B‐cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aspirin use was associated with reduced risk of CLL/SLL (POR = 0.70, 95% CI 0.54–0.91) but not with the risk of all NHLs (POR = 1.02, 95% CI 0.89–1.17). Use of non‐aspirin NSAIDs was associated with increased risk of NHL (POR = 1.41, 95% CI 1.01–1.97) amongst females only. The epidemiologic evidence remains inconclusive. Effects of NSAIDs may differ by drug type, NHL subtype, and sex and more studies taking into consideration these differences are needed. Copyright © 2014 John Wiley & Sons, Ltd.