Risk Factor For non-Hodgkin Lymphoma Research Articles

C677T and A1298C polymorphisms of methylene tetrahydrofolate reductase in non-Hodgkin lymphoma: southeast Iran.

Polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene have been reported as risk factors for non-Hodgkin lymphoma (NHL) in some populations. Our goal was to evaluate the potential role of A1298C and C677T polymorphisms of MTHFR in risk of NHL in southeast Iran. In the present case-control study, 127 patients with newly diagnosed NHL along with 150 ethnicity- and age-matched controls were examined. The A1298C and C677T polymorphisms were genotyped using the Tetra Amplification Refractory Mutation System polymerase chain reaction method. There were no significant differences in genotype frequencies between cases and controls regarding either A1298C polymorphism. For this polymorphism, 53.8% of the controls and 54.3% of the patients with NHL showed homozygous wild-type (AA) genotype. Variant 1298C allele was recognized with overall frequency of 34.6% in both groups. Frequencies of CC, CT, and TT genotypes of C677T polymorphism were observed in 73.1%, 25.8%, and 1.3% of the controls, and 64.5%, 33.1%, and 2.4% of the patients with NHL (p>0.05). In combination, CT + TT conferred a significantly higher risk of NHL (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.9-2.4, p = 0.03). Overall, variant 677T allele presented with higher frequency in the patients with NHL than the controls (26.7% versus 21.3%, respectively; OR 1.3, 95% CI 0.8-2.1, p>0.05). Although statistically insignificant, the highest risk of NHL was identified in patients with C677T; A1298C: CT; CC haplotype (OR 4.7, 95% CI 0.4-46.4, p = 0.1). Combination of CT and TT genotypes of C677T polymorphism conferred a significantly higher risk for NHL. It is recommended to investigate further the potential role of this polymorphism in NHL development.

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; ptrend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96-4.89; ptrend = 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.

HLA-G Gene Polymorphism in Egyptian Patients with Non-Hodgkin Lymphoma and its Clinical Outcome

ABSTRACT Background: Non-Hodgkin lymphoma (NHL) is a major cancer in Egypt and worldwide and has many risk factors including genes involved in the immune response. Aim: we investigated the HLA-G 14bp gene polymorphism as a risk factor for NHL and its clinic pathologic features. The study involved 150 patients with NHL and 100 healthy control. Full histories, clinical examination, C.T scan and laboratory investigations such as CBC, LDH, ?2microglobulin and HCV RNA by qualitative real time PCR were performed for all subjects. HLA-G 14bp ins/del gene polymorphism was determined by PCR. Results: in our study, del/del, ins/del and dominant genotypes increased the risk of NHL by 11.01, 10.55 and 10.88 fold respectively (p<0.001) but the recessive genotype did not increase the risk of NHL (p=0.112). Cases with the del allele had a greater risk of NHL than those with the ins allele (p<0.001). del/del and ins/del genotypes were significantly associated with higher LDH and ?2microglobulin levels (p<0.001), lower Hb and platelet values (p<0.001), extra nodal sites (p=0.001), poor performance status (p=0.04) and relapse (p=0.001). Conclusions: the results suggest that HLA-G 14bp ins/del gene polymorphism is a risk factor for NHL in our Egyptian population and is associated with poor clinical pathological features. Abbreviations Non-Hodgkin lymphoma (NHL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Epstein-Barr virus (EBV), human T-cell lymphotropic/leukemia virus-1 (HTLV-1)

Occupational ultraviolet exposure and risk of non-Hodgkin’s lymphomas: a meta-analysis

Non-Hodgkin lymphoma is a heterogeneous group of lympho-proliferative disorders. We performed a meta-analysis to summarize the available evidence from case-control studies and cohort study on the inconsistent association between occupational sun exposure and the risk of non-Hodgkin lymphoma. We searched PubMed, ISI web of science, the Cochrane Library, EMBASE and reference lists for relevant articles. Study specific odds ratios or relative risk and 95% confidence intervals were pooled by using fixed-effects or random-effects models. Ten case-control studies and one cohort study were included in the meta-analysis. Overall, the pooled odds ratios for occupational ultraviolet exposure and non-Hodgkin lymphoma risk was 1.15(95% confidence intervals: 0.99, 1.32; I2 = 44.4%). Occupational sun exposure was positively associated with the risk of NHL 1.14 (95% confidence intervals: 1.05, 1.23; I2=25.4% p for heterogeneity =0.202) in Caucasian population. Common subtypes of non-Hodgkin lymphoma and ultraviolet exposure had the negative results. The pooled odds ratios was 1.16, (95%confidence intervals: 0.90, 1.50) for T-cell non-Hodgkin lymphoma; 0.79, (95%confidence intervals: 0.61, 1.02) for B-cell non-Hodgkin lymphoma; 1.13, (95%confidence intervals: 0.96, 1.34) for chronic lymphocytic leukemia; 1.25, (95%confidence intervals: 0.95, 1.64) for males; 1.49, (95%confidence intervals: 0.99, 2.25) for females. Data suggested that occupational ultraviolet exposure was a risk factor for non-Hodgkin lymphoma in Caucasian population. While, there had no relationship between occupational ultraviolet exposure and risk of non-Hodgkin lymphoma in general population as well as non-Hodgkin lymphoma common subtypes. Besides, gender specific occupational sun exposure also indicated no association on risk of non-Hodgkin lymphoma.

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 100000 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 100000 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.

Multivariate meta-analysis with an increasing number of parameters.

Meta-analysis can average estimates of multiple parameters, such as a treatment's effect on multiple outcomes, across studies. Univariate meta-analysis (UVMA) considers each parameter individually, while multivariate meta-analysis (MVMA) considers the parameters jointly and accounts for the correlation between their estimates. The performance of MVMA and UVMA has been extensively compared in scenarios with two parameters. Our objective is to compare the performance of MVMA and UVMA as the number of parameters, p, increases. Specifically, we show that (i) for fixed-effect (FE) meta-analysis, the benefit from using MVMA can substantially increase as p increases; (ii) for random effects (RE) meta-analysis, the benefit from MVMA can increase as p increases, but the potential improvement is modest in the presence of high between-study variability and the actual improvement is further reduced by the need to estimate an increasingly large between study covariance matrix; and (iii) when there is little to no between-study variability, the loss of efficiency due to choosing RE MVMA over FE MVMA increases as p increases. We demonstrate these three features through theory, simulation, and a meta-analysis of risk factors for non-Hodgkin lymphoma.

Characterizing Autoimmune Disease-Associated Diffuse Large B Cell Lymphoma in a SEER-Medicare Cohort

Introduction: Severe immune dysregulation as seen in human immunodeficiency virus infection, immunosuppression after solid organ transplant, and autoimmune (AI) disease is known to act as a major risk factor for non-Hodgkin lymphoma (NHL). Recently, the InterLymph Subtypes Project pooled cases and controls to provide well-powered comparisons of risk factors for specific NHL subtypes, such as diffuse large B cell lymphoma (DLBCL), and showed that B cell-activating AI diseases in general (odds ratio 2.4; 95% confidence interval 1.8-3.1) and systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) in particular were strongly associated with increased DLBCL risk after controlling for all other risk factors (Cerhan J Natl Cancer Inst Monogr. 2014). However, little is known about the demographics or clinical outcomes of DLBCL that arises in the setting of AI disease. We examined the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to determine the frequency of common B cell AI diseases among older patients with DLBCL and characterize the patterns of presentation, treatment, and survival for DLBCL patients with concomitant AI disease.Methods: We used the SEER database for patients diagnosed 2002-2009 linked to their Medicare claims data through 2011 to characterize presentation, treatment, and survival patterns in patients with DLBCL, including those with rheumatoid arthritis (RA), SLE, SS, and other B cell-mediated autoimmune diseases as defined by InterLymph criteria (autoimmune hemolytic anemia, Hashimoto's thyroiditis/hypothyroidism, myasthenia gravis; pernicious anemia; Wang Am J Epidemiol. 2015). Patient age, sex, race/ethnicity, region of residence, marital status, year of diagnosis, cause of death, census tract-level characteristics (education, poverty, and metropolitan/urban/rural status), stage, B symptoms, and nodal or extranodal primary site of involvement were identified from the SEER data. Assessments of poor performance status, anemia, the Charlson comorbidity index, survival, and treatment strategies were identified using Medicare inpatient, outpatient and physician claims. Treatments were categorized as: rituximab (R), cyclophosphamide and vincristine (CVP), R-CVP; cyclophosphamide, hydroxydaunorubicin, and vincristine (CHOP), and R-CHOP. Patients who did not receive any DLBCL-directed treatment within 6 months of diagnosis were categorized separately. We examined the baseline clinical characteristics for patients with DLBCL and RA, SLE, SS, or any B cell-mediated autoimmune disease, plotted overall survival and lymphoma-related survival for these groups and compared median survival times.Results: Patient characteristics are summarized in the Table. With the exception that patients with DLBCL and AI disease were more commonly female[KJL1] [CF2] , patients with DLBCL and RA, SLE, SS, or other B cell AI diseases have similar baseline presenting features as other DLBCL patients and received similar first line treatments. There was a trend towards decreased lymphoma-related survival in patients with SLE and DLBCL compared to all other groups, but this difference was not statistically significant in this cohort (Figure) [KJL3] [KJL4] .Conclusions: In this retrospective claims-based cohort of older patients with DLBCL, concomitant AI disease was uncommon and was more likely to occur in female DLBCL patients, which likely reflects the higher incidence of AI disease in women. The possibility of lower lymphoma-related survival for these patients should be explored in future studies. [Display omitted] [Display omitted] DisclosuresFlowers:Millenium/Takeda: Research Funding; NIH: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Mayo Clinic: Research Funding; Infinity: Research Funding; ECOG: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.

Periodontal disease and risk of non-Hodgkin lymphoma in the Health Professionals Follow-Up Study.

Periodontal disease is a chronic inflammatory condition that has been associated with chronic diseases, including cancer. In an earlier prospective cohort analysis within the Health Professionals Follow-Up Study (HPFS), we observed a 31% higher risk of non-Hodgkin lymphoma (NHL) among participants with severe periodontal disease at baseline. Here, we extend the study with an additional 8 years of follow-up, and conduct analyses with updated periodontal disease status and NHL subtypes. The HPFS is an ongoing prospective cohort study of 51,529 men in the USA Between baseline in 1986 and 2012, 875 cases of NHL were diagnosed, including 290 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 85 diffuse large B-cell lymphomas and 91 follicular lymphomas. We performed multivariable Cox proportional hazards regression to evaluate associations of interest. History of periodontal disease at baseline was positively associated with risk of NHL overall (hazard ratio (HR) = 1.26, 95% confidence interval (CI): 1.06-1.49) and CLL/SLL (HR = 1.41, 95% CI: 1.04-1.90). With updated periodontal status, HRs were 1.30 (95% CI: 1.11-1.51) for NHL overall and 1.41 (95% CI: 1.08-1.84) for CLL/SLL. In contrast, after adjusting for periodontal disease, tooth loss was inversely associated with NHL, suggesting that other causes or consequences of tooth loss may have different implications for NHL etiology. Our findings suggest that periodontal disease is a risk factor for NHL. Whether periodontal disease is a direct or indirect cause of NHL, or is a marker of underlying systemic inflammation and/or immune dysregulation, warrants further investigation.

Non-Hodgkin lymphoma in adults: a guide for practice nurses

Practice nurses have a valuable role to play in instigating earlier diagnosis in patients with possible symptoms of non-Hodgkin lymphoma, and supporting those undergoing treatment, writes Margaret Perry Non-Hodgkin lymphoma is an uncommon cancer that develops in the lymphatic system and accounts for approximately 85% of cancers of this type. This article—part one in a two-part series, the second part of which will consider Hodgkin lymphoma—outlines the causes and possible risk factors for non-Hodgkin lymphoma, diagnosis, treatment and management and prognosis. It aims to provide nurses with insight into the disease, to enhance their knowledge of a complex condition and increase their confidence in treating patients in primary care. Practice nurses can play a vital role in instigating earlier diagnosis and treatment when they encounter patients with suspicious symptoms, and can offer support to those undergoing treatment.

Organochlorine insecticide use and risk of non-Hodgkin lymphoma: findings from the North American Pooled Project

INTRODUCTION: Organochlorine insecticides are persistent, bio-accumulative compounds that are frequently used worldwide. Recently, the International Agency for Research on Cancer (IARC) classified several organochlorines as Group 1 and 2A carcinogens for non-Hodgkin lymphoma (NHL). However, some previous studies had limited statistical power and did not assess exposure-response relationships. We investigated self-reported organochlorine exposure and NHL risk in a large population-based study: the North American Pooled Project (NAPP). METHODS: Four case-control studies conducted in Canada (1991-1994) and Midwestern U.S. (1981-1986) were pooled to form the NAPP, which includes 1690 NHL cases and 5131 controls. Odds ratios (OR) and 95% confidence intervals (CI) for ever/never use and duration of use (years), were estimated using logistic regression with adjustment for demographic characteristics and NHL risk factors. RESULTS: Compared to unexposed subjects, statistically significant associations with NHL risk were observed among those reporting use of chlordane (OR=1.44, 95% CI=1.13-1.84), DDT (OR=1.32, 1.10-1.58), dieldrin (OR=1.52, 1.04-2.22), heptachlor (OR=1.47, 1.02-2.11) and lindane (OR=1.69, 1.31-2.17). A consistent exposure-response trend was observed for years of lindane use: OR &gt;0-5=1.36, OR 5-&gt;10=1.87, OR 10-&gt;15=1.93, OR &gt;15=2.01 (p-trend=&lt;.0001). Increased risk of NHL was observed for &gt;15 years of DDT use (OR=1.52, 1.06-2.17, p-trend=0.001). Non-monotonic positive trends in risk were also observed for years of chlordane (p-trend=0.03) and heptachlor (p-trend=0.04) use. Conclusions: This analysis uncovered statistically significant associations for several organochlorines and NHL risk. The sample size of the NAPP allowed us to estimate risk across more refined exposure levels and identify significant exposure-response trends for lindane. Overall, these findings contribute to the epidemiologic literature supporting the recent IARC classifications.

Comprehensive Evaluation of Medical Conditions Associated with Risk of Non-Hodgkin Lymphoma using Medicare Claims ("MedWAS").

Certain medical conditions affect risk of non-Hodgkin lymphoma (NHL), but the full range of associations is unknown. We implemented a novel method ("medical condition-wide association study," MedWAS) to comprehensively evaluate medical risk factors for NHL documented in administrative health claims. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we conducted a case-control study comparing NHL cases [N = 52,691, age 66+ years, with five subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma (TCL)] to controls (N = 200,000). We systematically screened for associations with 5,926 medical conditions documented in Medicare claims more than 1 year before selection. Fifty-five conditions were variously associated with NHL. Examples include well-established associations of human immunodeficiency virus, solid organ transplantation, and hepatitis C virus with increased DLBCL risk (ORs 3.83, 4.27, and 1.74, respectively), and autoimmune conditions with DLBCL and MZL (e.g., ORs of 2.10 and 4.74, respectively, for Sjögren syndrome). Risks for all NHL subtypes were increased after diagnoses of nonmelanoma skin cancer (ORs 1.19-1.55), actinic keratosis (1.12-1.25), or hemolytic anemia (1.64-4.07). Nine additional skin conditions increased only TCL risk (ORs 2.20-4.12). Diabetes mellitus was associated with increased DLBCL risk (OR 1.09). Associations varied significantly across NHL subtypes for 49 conditions (89%). Using an exploratory method, we found numerous medical conditions associated with NHL risk, and many associations varied across NHL subtypes. These results point to etiologic heterogeneity among NHL subtypes. MedWAS is a new method for assessing the etiology of cancer and other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1105-13. ©2016 AACR.

Iatrogenic immunosuppression and risk of non-Hodgkin lymphoma in solid organ transplantation: A population-based cohort study in Australia.

Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (<1year after transplantation; n=29) and late (≥1year; n=61) NHL using the Fine and Gray proportional subdistribution hazards model that accounted for death as a competing risk. After adjustment for immunosuppression, the risk of both early and late NHL did not significantly differ by organ type. In final models, higher mean daily doses of azathioprine were associated with increased risk of both early [HR 2·20, 95% confidence interval (CI): 1·21-4·01] and late NHL (HR 1·78, 95% CI: 1·12-2·84). There was no association between any other maintenance immunosuppressive agent and NHL risk. This study provides evidence that differences in immunosuppression may explain variation in NHL incidence by organ type, and high doses of azathioprine may independently predict NHL risk.

Genetic characteristics of non-Hodgkin lymphoma in ethnic Uighur people, and their clinical significance.

The incidence of non-Hodgkin lymphoma (NHL) in China is increasing and is attracting attention as a topic of research. The percentage of NHL cases in ethnic Uighur people is also gradually increasing. We therefore recruited Uighur people with NHL to investigate the correlation between genetic alternations and clinical/pathological features in an attempt to determine their clinical significance. A total of 60 NHL patients were recruited from our hospital for a microscopic examination of their tumor cell morphology. Further analysis of chromosome karyotypes revealed the relationship between genetic alternations and clinical/pathological features. Microscopic examination revealed increased numbers of tumor cells with altered morphology. The recruited patients all exhibited abnormal karyotypes. Chromosomal breakages were detected at 14q32, 18q21, 6q21-25, +3, +, +18, and short tandem repeat 17 (str17) in 18.3, 25, 25, 18.3, 15, and 21.7% of patients, respectively. Karyotype change was not related to age, gender, performance status score, or pathological type (P > 0.05), but was correlated with clinical stage, average lactate dehydrogenase (LDH) level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Independent risk factors for genetic change in Uighur NHL patients included clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Uighur NHL patients exhibited genetic changes including t(14:18), 6q21-25, +3, +7, +18, and str17. Clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy were all independent risk factors for NHL.

Lifetime physical activity and the risk of non-Hodgkin lymphoma.

Research regarding the association between physical activity and the risk of non-Hodgkin lymphoma (NHL) is limited and inconsistent, and few studies have investigated whether the intensity and timing of physical activity influence the association. A case-control study of NHL was conducted in British Columbia, Canada, in 2000 to 2004. Data were collected on various NHL risk factors, including moderate-intensity and vigorous-intensity physical activity performed over the lifetime. Logistic regression was used to estimate the association between physical activity and the risk of NHL. This analysis included 818 controls and 749 cases. Lifetime vigorous-intensity physical activity was inversely associated with NHL risk. Participants in the second, third, and fourth quartiles of lifetime vigorous-intensity physical activity had an approximately 25% to 30% lower risk of NHL than those in the lowest quartile [adjusted odds ratios, 0.69 (95% confidence interval [CI], 0.52-0.93); 0.68 (95% CI, 0.50-0.92); and 0.75 (95% CI, 0.55-1.01), respectively]. No consistent associations were observed for total or moderate-intensity physical activity. There were no apparent age periods in which physical activity appeared to confer a greater risk reduction. In this study, we found that lifetime vigorous-intensity physical activity was associated with a significantly reduced risk of NHL. Given this finding, more research on physical activity intensity and timing in relation to NHL risk is warranted.

Analysis of Environmental Chemical Mixtures and Non-Hodgkin Lymphoma Risk in the NCI-SEER NHL Study.

BackgroundThere are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one).ObjectivesWe determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk.MethodsWe conducted a population-based case–control study of NHL in four National Cancer Institute–Surveillance, Epidemiology, and End Results centers—Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington—from 1998 to 2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL.ResultsThe WQS index was statistically significantly associated with NHL overall [odds ratio (OR) = 1.30; 95% CI: 1.08, 1.56; p = 0.006; for one quartile increase] and in the study sites of Detroit (OR = 1.71; 95% CI: 1.02, 2.92; p = 0.045), Los Angeles (OR = 1.44; 95% CI: 1.00, 2.08; p = 0.049), and Iowa (OR = 1.76; 95% CI: 1.23, 2.53; p = 0.002). The index was marginally statistically significant in Seattle (OR = 1.39; 95% CI: 0.97, 1.99; p = 0.071). The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa.ConclusionsAn index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk.CitationCzarnota J, Gennings C, Colt JS, De Roos AJ, Cerhan JR, Severson RK, Hartge P, Ward MH, Wheeler DC. 2015. Analysis of environmental chemical mixtures and non-Hodgkin lymphoma risk in the NCI-SEER NHL Study. Environ Health Perspect 123:965–970; http://dx.doi.org/10.1289/ehp.1408630

Regular Aspirin Use and Risk of Non-Hodgkin Lymphoma: A Prospective Analysis in the Nurses’ Health Study

Background: There is increasing evidence that aspirin reduces the incidence and mortality of several cancers. The results of epidemiologic studies of aspirin in relation to non-Hodgkin lymphoma (NHL) however, are inconsistent, and the association appears to vary by NHL histologic subtype. We aimed to prospectively assess the association between aspirin and major subtypes of NHL in a cohort with detailed data on aspirin use.Methods: The Nurses’ Health Study (NHS) comprises 121,701 female United States licensed registered nurses who were ages 30-55 years at enrollment in 1976 and have been followed thereafter with biennial questionnaires to update medical history and personal and lifestyle information. Aspirin use was first queried in 1980. We incorporated a two-year exposure lag to minimize influence of reverse causation. Thus, “baseline” was 1982 for this analysis. We followed participants from baseline through June 2010, including all who had no baseline history of cancer or rheumatoid arthritis (RA)—a risk factor for NHL that may also affect aspirin use habits—and who completed the first questions on aspirin use. Participants were censored at the date of a cancer or RA diagnosis, or at date of death. We identified incident primary diagnoses of NHL via the follow-up questionnaires or by National Death Index follow-up. We confirmed the diagnoses and determined the histologic subtype by medical record review. Aspirin use was quantified both as cumulative average quantity (adult-strength tablets/week), and as duration of continuous regular use (years). To estimate the relative risk of NHL associated with a given quantity or duration of regular aspirin use, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) in Cox models that were stratified on calendar period and age (months) and adjusted for geographic region of residence and height. Trend tests were based on comparable multivariable models in which the medians of aspirin use variable categories were modeled as ordinal variables.Results: In 1,749,512 person-years of follow-up we identified 738 cases of NHL with available information about regular aspirin use. In the 2-year lagged analyses of regular aspirin quantity, regular aspirin use showed a suggestive positive association with risk of follicular lymphoma. In particular, women who used a cumulative average of 1 to <2, 2 to <5, or ≥5 tablets/week had a modest non-significant increased risk of follicular lymphoma compared to non-users (HR [95% CI] were 1.56 [0.84-2.91], 1.28 [0.69-2.35] and 1.64 [0.91-2.94], respectively; p-trend=0.03, based on 135 cases). No association was suggested for regular aspirin quantity with diffuse large B-cell lymphoma (DLBCL; p-trend=0.72, 114 cases), chronic lymphocytic leukemia (CLL; p-trend=0.13, 219 cases) or with NHL overall (p-trend=0.14). Duration of regular aspirin use was not associated significantly with follicular lymphoma (p-trend=0.70) or with DLBCL (p-trend=0.52), CLL (p-trend=0.32) or NHL overall (p-trend=0.45).Conclusions: Our findings of no association between regular aspirin use and NHL, other than a suggestive positive association between cumulative average quantity of use and follicular lymphoma risk, were contrary to expectation but consistent with an earlier published cohort study. The present analysis was limited in part by sparse data, especially in subtype-specific analyses. Further evaluation in a comparable cohort of men and in the two cohorts combined (where statistically appropriate) may lend further insights. If confirmed in other large populations, the findings in the NHS suggest that aspirin use may be only associated with risk of follicular lymphoma, consistent with the view that there is some etiologic heterogeneity across major subtypes of NHL. DisclosuresZhang:Takeda Pharmaceuticals Inc: Employment.

Pre-Diagnosis Plasma Immune Markers and Risk of Non-Hodgkin Lymphoma and Its Major Histologic Subtypes: A Prospective Analysis in Two Large Cohorts

Introduction: Severe immune compromise is a strong risk factor for non-Hodgkin lymphoma (NHL), and serum B-cell activation and inflammation markers predicted AIDS-NHL risk in HIV+ persons. We performed a nested case-control analysis in the prospective Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts to characterize pre-diagnosis plasma immune marker profiles associated with risk of HIV-unrelated NHL and major histologic subtypes.Methods: The NHS formed in 1976 with 121,701 female US registered nurses. The HPFS enrolled 51,529 male health professionals in 1986. Both cohorts are followed via biennial questionnaires and confirm cancer diagnoses by medical record review and National Death Index follow-up. Among participants who contributed peripheral blood samples in 1989-90 (NHS) or 1993-4 (HPFS), we confirmed incident primary NHL diagnoses in 345 women and 255 men with no other cancer history. We matched one control per case on cohort (gender), age, race and time of blood draw among persons with no cancer history as of the index date. We determined plasma concentrations of 13 cytokines, soluble receptors and immune activation markers using multiplexed Luminex assays (R & D Systems). In preliminary cohort-specific analyses we calculated matching factor-adjusted odds ratios (OR) and 95% confidence intervals (CI) using logistic regression to estimate the relative risk of NHL per standard deviation (SD) increase in assay batch-adjusted natural log-transformed biomarker concentration. We examined associations for NHL overall and for more common World Health Organization-defined histologic subtypes, including chronic lymphocytic leukemia (CLL; 78 female/70 male cases), follicular lymphoma (FL; 61/24), diffuse large B-cell lymphoma (DLBCL; 69/37) and T-cell NHL (all histologic types, 18/10).Results: The mean (range) years from blood draw to NHL diagnosis was 11 (0.2-22) in women and 7 (0.1-17) in men. In both cohorts, pre-diagnosis levels of the immune activation markers soluble interleukin-2 receptor-α (sIL-2Rα) and sCD30, the B cell chemokine CXCL13, and the inflammatory marker soluble tumor necrosis factor receptor-2 (sTNF-R2) were significantly positively associated with risk of NHL overall (Table 1). Table 1Association of pre-diagnosis plasma immune marker level with risk of NHL overallBiomarkerWomen, OR [95% CI] per SD, p-valueMen, OR [95% CI] per SD, p-valuesIL-2Rα1.41 [1.23, 1.61], p<0.00011.46 [1.22, 1.75], p<0.0001sCD301.36 [1.18, 1.56], p<0.00011.55 [1.29, 1.86], p<0.0001CXCL131.37 [1.20, 1.56], p<0.00011.28 [1.02, 1.59], p=0.03sTNF-R21.23 [1.06, 1.42], p=0.0071.50 [1.23, 1.82], p<0.0001In subtype analyses, risk of CLL was significantly increased in association with increased levels of sIL-2Rα (OR [95% CI] per SD, women: 1.57 [1.26, 1.96], p<0.0001; men: 1.62 [1.24, 2.11], p=0.003) and sTNF-R2 (men only: 1.79 [1.34, 2.39], p<0.0001). To our surprise, the B-cell stimulatory cytokine BAFF was inversely associated with CLL risk in both cohorts (women: 0.59 [0.47, 0.76], p<0.0001; men: 0.56 [0.43, 0.73], p<0.0001); BAFF levels were not associated with any other NHL endpoint. Risk of FL was significantly positively associated with sIL-2Rα (women only: 1.78 [1.36, 2.35], p<0.0001), CXCL13 (women only: 1.64 [1.28, 2.11], p=0.0001), and sTNF-R2 concentrations (women only: 1.57 [1.21, 2.04], p=0.0007). Risk of DLBCL was positively associated with sIL-2Rα (men only: 1.67 [1.21, 2.31], p=0.002) and sTNF-R2 levels (men only: 1.48 [1.04, 2.11], p=0.03). T-cell NHL risk was positively associated with levels of sIL-2Rα, significantly in women (1.83 [1.13, 2.96], p=0.01) and marginally in men (1.65 [0.98, 2.78], p=0.06). No other markers were associated with NHL overall or any subtype. Preliminary analyses by follow-up interval suggested that some of the aforementioned associations may be evident 10+ years after blood draw.Discussion: These findings support an etiologic role for immune activation and inflammation in HIV-unrelated NHL. Apparent gender differences in associations may be due to chance (sparse data); statistical heterogeneity by gender will be evaluated and, if appropriate, data will be pooled to improve stability of estimates. Further evaluation by follow-up interval may lend additional insights on the immune milieu that promotes lymphomagenesis and on potential markers of longer- or shorter-term NHL risk. DisclosuresNo relevant conflicts of interest to declare.

A Prospective Analysis of Blood Donation History and Incidence of Non-Hodgkin Lymphoma

Background: The incidence rate of non-Hodgkin lymphoma (NHL) has more than doubled over the last few decades, but the reason for this increase has been largely unexplained. The long-term effect of blood donation on cancer incidence is not well investigated despite its potentially large impact on the population. Immune deficiency is associated with increased risk of NHL. Blood donation may influence subsequent NHL development via temporary immune system alterations following blood donation, which have been demonstrated in several human studies. A large nested case-control study within a cohort of blood donors in Sweden and Denmark showed an increased odds ratio (OR) of NHL among frequent plasma donors comparing to non-donors (OR 2.14, 95% confidence interval (CI) 1.22-3.74) [Edgren G et al., 2008]. Results of this and other studies have been difficult to interpret because of the possible influence of healthy donor effects or different baseline characteristics among blood donors compared to general population. To test the hypothesis that frequent blood donation is associated with an increased risk of NHL and its most common histologic subtypes in a general, non-immune compromised population, we conducted a prospective study in the Health Professional Follow-up Study (HPFS) cohort.Methods: We followed 36,580 men in the HPFS cohort, who in 1992 had no prior diagnosis of cancer and provided information on frequency of blood donation in the past 30 years. Throughout follow-up of the HPFS cohort, participants completed questionnaires about lifestyle and medical history every two years. Non-respondents were followed through the National Death Index. Identified diagnoses of cancer were confirmed by medical record review. The present analysis included all confirmed incident diagnoses of NHL through January 2008. Person-time accrued for each participant from January 1992 to the earliest among dates of NHL diagnosis, death, or January 2008. Cox proportional hazards regression was used to calculate hazards ratios (HR) and 95% CIs for the risk of all NHL and major NHL histologic subtypes associated with number of blood donations (1-5, 6-9, 10-19, or >20, vs. none), stratifying by age in months and follow-up cycle. Potential confounding by putative NHL risk factors (i.e. smoking, alcohol, BMI, height, physical activity, race) was evaluated by including these factors in multivariable models.Results: During 482,008 person-years of follow-up, 484 incident cases of NHL were confirmed. Participant characteristics were similar at baseline among blood donors and non-donors with respect to age, race, and selected lifestyle factors. In the age-adjusted model, there was no significant association between blood donation frequency and incidence of NHL (HR 1.12, 95% CI 0.82-1.55, comparing >20 donations vs. 0 donations over 30 years, p for trend = 0.44) or of any major NHL subtypes. Adjustment for potential confounders did not notably change the effect estimates for all NHL or any NHL subtypes.Conclusion: In this prospective study, there was no evidence that frequent blood donation is associated with incidence of all NHL or any major subtypes. DisclosuresNo relevant conflicts of interest to declare.

Chemical Mixtures in Carpet Dust and Risk of Non- Hodgkin Lymphoma Risk in the NCI-SEER NHL Study

Background Several environmental exposures including polychlorinated biphenyls (PCBs) and specific pesticides are suspected risk factors for non-Hodgkin lymphoma (NHL). Associations between chemical exposures and risk of NHL have typically been evaluated for individual chemicals or chemical groups, one-by-one. Objectives The goal was to determine the association between 27 correlated chemicals measured in house dust and NHL risk. Methods We conducted a population-based case-control study of NHL in four National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) sites: Detroit, Iowa, Los Angeles, and Seattle. House dust was sampled during in-home interviews (1998- 2000). We used weighted quantile sum (WQS) regression to model the association of 27 environmental chemicals and risk of NHL adjusting for age, gender, race, and education. We computed a WQS index that was a sum of weighted quartiles for 5 PCBs, 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical weights and risk estimates for all study sites combined and each site separately. For comparison, we computed risk estimates for individual chemicals using logistic regression. Results The effect of the chemical mixture was significant overall (OR=1.30, p=0.006), and in Detroit (OR=1.71, p=0.045), Los Angeles (OR=1.44, p=0.049), and Iowa (OR=1.76, p=0.002). The index was associated with a marginally significant increased risk in Seattle (OR=1.39, p=0.071). Over all sites, chemicals with the largest weights were PCB 180 and propoxur. Highly weighted chemicals varied by site; PCBs had higher weights in Detroit and specific pesticides (propoxur, chlordane) had higher weights in Iowa. Logistic regression analysis of individual chemicals and NHL risk overall revealed significant results for only PCB 180 only. Conclusions Our weighted index of chemicals was significantly associated with NHL risk, indicating the importance of evaluating chemical mixtures and disease risk.

Abstract 2918: Menopausal hormone therapy and B-cell non-Hodgkin lymphoma (NHL) risk in the Los Angeles County NHL Case-Control Study

Abstract Introduction: Immune modulation has long been established as a risk factor for non-Hodgkin lymphoma (NHL). Menopausal hormone therapy (MHT) has been shown to affect immune function in both animal and human studies. However, the evidence for an association between MHT and NHL remains unclear. Cohort studies have suggested either no association or increased risk between MHT use and NHL, particularly for the follicular lymphoma subtype. A recent pooled analysis of case-control studies from the United States, Europe, and Australia reported a decreased risk for NHL among women who used MHT, but this analysis was limited by the lack of information on MHT formulation, dose, and duration. Methods: The Los Angeles County NHL Case-Control Study comprises 1010 B-cell NHL patients diagnosed 2004-2008 from the Los Angeles Cancer Surveillance Program, matched 1:1 by age and race to female neighborhood controls. Extensive information on MHT use was ascertained, along with information on demographic and known NHL risk factors. Among 685 post-menopausal women diagnosed with NHL and 685 matched controls, we conducted conditional logistic regression, adjusting for age, race and socioeconomic status, to evaluate the association between MHT use, formulation, dose and duration, and risk for B-cell NHL. Results: B-cell NHL risk was reduced among women who reported having ever used MHT (HR = 0.66, 95% CI = 0.52-0.85) compared to never users. This risk reduction was similar for women who reported using unopposed estrogen only (HR = 0.75, 95% CI =0.56-1.01), estrogen plus progestin only (HR=0.62, 95% CI =0.45-0.85), sequential use of unopposed estrogen followed by estrogen plus progestin (HR=0.36, 95% CI=0.18-0.70), and sequential use of unopposed estrogen plus progestin followed by unopposed estrogen (HR=0.57, 95% CI=0.32-1.00). Among women who reported using unopposed estrogen or estrogen plus progestin by pill or patch (prescription only), reduced B-cell NHL risk was most pronounced among those who started MHT use early, at age 45 years or younger (HR=0.60, 95% CI=0.42-0.85) and generally among women with longer duration of use. The protective associations associated with MHT use were consistent among major B-cell NHL subtypes, including diffuse large B-cell lymphoma and follicular lymphoma. Conclusions: These data provide evidence for an association between MHT use - either unopposed estrogen or estrogen plus progestin use - and decreased risk of B-cell NHL, supporting a role for postmenopausal hormones in B-cell NHL etiology. Citation Format: Sophia S. Wang, Jianning Luo, Jane Sullivan-Halley, Yani Lu, James V. Lacey, Jr., Wendy Cozen, Leslie Bernstein. Menopausal hormone therapy and B-cell non-Hodgkin lymphoma (NHL) risk in the Los Angeles County NHL Case-Control Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2918. doi:10.1158/1538-7445.AM2014-2918