Blood transfusions and risk of non-Hodgkin's lymphoma subtypes and chronic lymphocytic leukemia.

Allogeneic blood transfusion has been suggested as a risk factor for non-Hodgkin's lymphoma (NHL), possibly specific to certain NHL subtypes, or chronic lymphocytic leukemia (CLL). Self-reported transfusion history and risk of NHL subtypes and CLL were examined in a cohort of 37,934 older Iowa women, using data from a questionnaire mailed in 1986. Through 1997, 229 cases of NHL and 57 cases of CLL in the cohort were identified through linkage to the Iowa Surveillance, Epidemiology and End Results Cancer REGISTRY: Women who reported ever receiving a blood transfusion were at increased risk for all NHLs [age adjusted relative risk (RR), 1.6; 95% confidence interval (CI), 1.2-2.1). On the basis of the Working Formulation classification, blood transfusion was positively associated with low-grade NHL (RR, 2.7; 95% CI, 1.7-4.5) but not with intermediate-grade NHL (RR, 1.1; 95% CI, 0.7-1.6); there were only 8 cases of high-grade NHL. Blood transfusion was positively associated with follicular (RR, 2.8; 95% CI, 1.6-5.1) and small lymphocytic (RR, 3.4; 95% CI, 1.5-7.9) NHL subtypes but not with diffuse NHL (RR, 1.0; 95% CI, 0.7-1.5). There was also a positive association with CLL (RR, 1.7; 95% CI, 1.0-3.0). Finally, transfusion was associated with nodal (RR, 1.8; 95% CI, 1.3-2.5) but not extranodal (RR, 1.2; 95% CI, 0.7-2.1) NHL. Further adjustment for marital status, farm residence, diabetes, alcohol use, smoking, and red meat and fruit consumption did not alter these associations. In conclusion, prior blood transfusion was associated with NHL and CLL, and the strongest associations were seen for low-grade NHL, particularly follicular and small lymphocytic NHL.     

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.     

Hormone replacement therapy and risk of non-hodgkin lymphoma and chronic lymphocytic leukemia.

Our objective in this study was to evaluate whether the use of hormone replacement therapy (HRT) is associated with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). A cohort of 37,220 Iowa women ages 55 to 69 years in 1986 with no history of prior cancer was linked annually to a population-based cancer registry. Through 1998 (13 years of follow-up), 258 incident cases of NHL were identified, including 135 cases of diffuse NHL, 58 cases of follicular NHL, and 31 cases of small lymphocytic NHL. In addition, 63 cases of CLL were identified. Current and former use of HRT (primarily estrogen) and other cancer risk factors were self-reported on the baseline (1986) questionnaire. Compared with never users of HRT at study baseline, current [multivariate relative risk (RR), 1.4; 95% confidence intervals (CIs), 0.9-2.0) but not former (RR, 1.1; 95% CI, 0.8-1.4) users were at increased risk of NHL after adjustment for age and other confounding factors. This association was seen only in nodal NHL [RR(current), 1.5 (95% CI, 1.0-2.4); RR(former), 1.1 (95% CI, 0.8-1.6)] and was not apparent for extra-nodal sites. Of the common subtypes, there was a strong positive association with follicular NHL [RR(current), 3.3 (95% CI, 1.6-6.9); RR(former), 2.6 (95% CI, 1.4-4.7)], and women who were current users for more than 5 years had the highest risk (RR, 3.9; 95% CI, 1.8-8.6). There was no association with diffuse or small lymphocytic NHL, or with CLL. Most of the follicular NHLs were nodal (88%), and exclusion of extra-nodal sites slightly strengthened the association with HRT. For diffuse NHL, 64% of the cases were nodal, and there was no association of HRT with either nodal or extra-nodal sites. These data suggest that HRT is a risk factor for follicular NHL but not for diffuse or small lymphocyte NHL or CLL.     

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.     

A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non‐Hodgkin lymphoma

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non‐Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre‐diagnosis red blood cell (RBC) specimens in the Nurses’ Health Study (NHS) and Health Professionals Follow‐Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T‐NHL), B cell NHL (B‐NHL) and three individual B‐NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B‐NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T‐NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B‐NHLs other than CLL/SLL and for VLCSFA and MUFA with T‐NHL suggest an influence of fatty acid metabolism on lymphomagenesis.     

Relationship between ambient ultraviolet radiation and non‐Hodgkin lymphoma subtypes: A U.S. population‐based study of racial and ethnic groups

Associations between ultraviolet radiation (UVR) exposure and non‐Hodgkin lymphoma (NHL) have been inconsistent, but few studies have examined these associations for specific subtypes or across race/ethnicities. We evaluated the relationship between ambient UVR exposure and subtype‐specific NHL incidence for whites, Hispanics and blacks in the United States for years 2001–2010 (n = 187,778 cases). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression. Incidence was lower for the highest UVR quintile for chronic/small lymphocytic/leukemia (CLL/SLL) (IRR = 0.87, 95% CI: 0.77–0.97), mantle cell (IRR = 0.82, 95% CI: 0.69–0.97), lymphoplasmacytic (IRR = 0.58, 95% CI: 0.42–0.80), mucosa‐associated lymphoid tissue (MZLMALT) (IRR = 0.74, 95% CI: 0.60–0.90), follicular (FL) (IRR = 0.76, 95% CI: 0.68–0.86), diffuse large B‐cell (IRR = 0.84, 95% CI: 0.76–0.94;), peripheral T‐cell other (PTCL) (IRR = 0.76, 95% CI: 0.61–0.95) and PTCL not otherwise specified (PNOS) (IRR = 0.77, 95% CI: 0.61–0.98). Trends were significant for MZLMALT, FL, DLBCL, BNOS and PTCL, with FL and DLBCL still significant after Bonferroni correction. We found interaction by race/ethnicity for CLL/SLL, FL, Burkitt, PNOS and MF/SS, with CLL/SLL and FL still significant after Bonferroni correction. Some B‐cell lymphomas (CLL/SLL, FL and Burkitt) suggested significant inverse relationships in whites and Hispanics, but not in blacks. Some T‐cell lymphomas suggested the most reduced risk for the highest quintile of UVR among blacks (PNOS and MF/SS), though trends were not significant. These findings strengthen the case for an inverse association of UVR exposure, support modest heterogeneity between NHL subtypes and suggest some differences by race/ethnicity.     

Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.

PURPOSE: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/microL (500/microL if documented bone marrow involvement); and platelet count more than 50,000/microL. RESULTS: Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). CONCLUSION: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.     

Risk of second malignant neoplasms among lymphoma patients with a family history of cancer

Radiotherapy and chemotherapy are known risk factors for second cancers after lymphoma. The role of genetic influences, however, remains largely unknown. We assessed risk of second cancers associated with family history of any cancer in 41,181 patients with Hodgkin lymphoma (HL) (n = 7,476), non-Hodgkin lymphoma (NHL) (n = 25,941), or chronic lymphocytic leukemia (CLL) (n = 7,764), using a large population-based database. Family history of cancer was based on a diagnosis of any cancer in 110,862 first-degree relatives. We found increased relative risk (RR) (1.81, 95% confidence interval (CI): 1.04-3.16) of breast cancer among HL patient with positive (vs. negative) family history of cancer. Among CLL patients with positive (vs. negative) family history of cancer, we observed elevated risks of bladder (RR = 3.53, 95% CI: 1.31-9.55) and prostate cancer (RR = 2.15, 95% CI: 1.17-3.94). For NHL patients with positive (vs. negative) family history of cancer, we observed non-significantly increased risk of non-melanoma skin cancer (RR = 1.94, 95% CI: 0.86-4.38) and lung cancer (RR = 1.99, 95% CI: 0.73-5.39). Our observations suggest that genetic factors, as measured by positive family history of cancer, may be influential risk-factors for selected second tumors following lymphoproliferative disorders.     

Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples.

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.     

Fruits and vegetables consumption and risk of non‐Hodgkin's lymphoma: A meta‐analysis of observational studies

Epidemiologic evidence suggests that intakes of fruits and/or vegetables may play a role in the etiology of non‐Hodgkin's lymphoma (NHL), but the findings are inconsistent. We aimed to assess fruits and/or vegetables intakes in relation to risk of NHL by a meta‐analytic approach. We searched on PubMed database from January 1966 to September 2012 to indentify case‐control and cohort studies. We used a random‐effects model to compute summary risk estimates. For vegetables, the summary relative risks (RRs) of NHL for high versus low intake for case‐control, cohort and all studies were 0.75 (95% CI, 0.60–0.94; N = 8), 0.90 (95% CI, 0.81–1.00; N = 5) and 0.81 (95%CI, 0.71–0.92; N = 13) ; and the corresponding RRs for intake of 1 serving per day were 0.88 (95% CI, 0.80–0.96; N = 8), 0.96 (95% CI, 0.92–1.00; N = 5) and 0.92 (95%CI, 0.87–0.96; N = 13). For fruits and vegetables combined, the summary RR for high versus low intake was 0.78 (95%CI, 0.66–0.92; N = 4), and for intake of 1 serving per day was 0.95 (95%CI, 0.91–1.00; N = 4). Regarding histological subtypes, vegetables intake was significantly inversely associated with diffuse large B‐cell lymphoma and follicular lymphoma, but not small lymphocytic lymphoma/chronic lymphocytic leukemia (high vs. low intake, RR = 0.70, 0.70 and 1.01, respectively; N = 7, 7 and 10, respectively). Fruits intake was generally not associated with total NHL, or any histological subtypes. Our findings suggest that intakes of vegetables, and fruits and vegetables combined, but not fruits alone, significantly reduce risk of NHL.     

Diabetes,metformin use and risk of non-Hodgkin's lymphoma in postmenopausal women: A prospective cohort analysis in the Women's Health Initiative

Epidemiologic evidence is limited about associations between T2DM, metformin, and the risk of non-Hodgkin's lymphoma (NHL). We aimed to examine associations between T2DM, metformin, and the risk of NHL in the Women's Health Initiative (WHI) Study. Information on T2DM status (diabetes status/types of antidiabetic drug use/diabetes duration) from study enrollment and during follow-up were assessed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate associations of T2DM status with risks of overall NHL and its three major subtypes [diffuse large B-cell lymphoma (DLBCL, n = 476), follicular lymphoma (FL, n = 301) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, n = 136)] based on multivariable-adjusted Cox proportional hazards models. During a median follow-up of 18.86 years (range, 0.01-25.13; SD ± 6.55), a total of 1637 women developed NHL among 147 885 postmenopausal women. Women with T2DM and with self-reported oral medication use had 38% and 55% higher risk of DLBCL, respectively [multivariable-adjusted model HR = 1.38, 95% CI (1.06-1.81) and HR = 1.55, 95% CI (1.16-2.06)] compared to the reference group (nondiabetics/untreated diabetes). Risks of NHL and DLBCL [multivariable-adjusted model: HR = 1.28, 95% CI (1.06-1.54) and HR = 1.56, 95% CI (1.13-2.14), respectively] were significantly higher in associations with relatively short duration (≤7 years) of diabetes, compared to reference group. Additionally, an increased risk of DLBCL [HR = 1.76, 95% CI (1.13-2.75)] was found in metformin users compared to the reference group. Postmenopausal women who had T2DM, who were oral antidiabetic drug users, especially metformin, and who had a shorter diabetes duration may have higher risks of DLBCL. Further well-designed research is needed to confirm our findings.     

Cardiovascular mortality among patients with non‐Hodgkin lymphoma: Differences according to lymphoma subtype

Survival rates of patients with non‐Hodgkin lymphoma (NHL) have improved over the last decade. However, cardiotoxicities remain important adverse consequences of treatment with chemotherapy and radiation, although the burden of cardiovascular mortality (CVM) in such patients remains unknown. We conducted a retrospective cohort study of patients greater than or equal to 20 years of age diagnosed with diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) between 2000 and 2013 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. Our primary endpoint was CVM. The association between NHL and CVM was evaluated using multivariable Cox regression analysis after adjusting for other patient characteristics. We calculated standardized mortality ratios (SMRs) for CVM, comparing NHL patients with the general population. We identified 153 983 patients who met the inclusion criteria (69 329 with DLBCL, 48 650 with CLL/SLL, and 36 004 with FL). The median follow‐up was 37 months (interquartile range, 10‐78 months); the mean patient age was 66.24 (±14.69) years; 84 924 (55.2%) were men; 134 720 (87.5%) were White, and 131 912 (85.7%) did not receive radiation therapy. Overall, 9017 patients (5.8%) died from cardiovascular disease, and we found that NHL patients had a higher risk of CVM than the general population, after adjusting for age (SMR 15.2, 95% confidence interval: 14.89‐15.52). The rates of CVM were 5.1%, 8%, and 4.4% in patients with DLBCL, CLL/SLL, and FL, respectively. Furthermore, across all NHL subtypes, older age, higher stage at the time of diagnosis (particularly stage 4), male sex, and living in the south were associated with higher risks of CVM. Our data suggest that risk assessment and careful cardiac monitoring are recommended for NHL patients, particularly those with the CLL/SLL subtypes.     

Anthropometric characteristics,physical activity and risk of hematological malignancies: A systematic review and meta-analysis of cohort studies

Overweight/obesity, adult attained height and physical activity are possible risk factors for hematological malignancies. This meta-analysis aims to evaluate the associations between these factors and hematological cancer risk in adults. Eligible cohort studies were sought in PubMed up to May 31, 2016; overall, 44 studies were included in the present analyses. Pooled relative risk estimates were calculated using random-effects models; separate analyses were conducted for non-Hodgkin lymphoma (NHL) and subtypes (diffuse large B-cell lymphoma, DLBCL; follicular cell lymphoma; small lymphocytic lymphoma/chronic lymphocytic leukemia, SLL/CLL), Hodgkin lymphoma (HL), multiple myeloma (MM), leukemia and subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, AML). Obesity was associated with increased risk of NHL, HL, MM, leukemia overall and AML in both sexes, as well as with higher DLBCL risk in women; the dose–response meta-regression analysis confirmed these associations. Less pronounced effects were observed regarding overweight, as it was associated with increased MM risk in both sexes, NHL risk in males, DLBCL and overall leukemia risk in females. Taller men presented with significantly higher risk of NHL and taller women were affected by higher risk of NHL, DLBCL, FL, CLL/SLL, MM, leukemia and AML. On the other hand, physical activity and abdominal fatness were not associated with the risk of hematological malignancies. In conclusion, this meta-analysis highlights the pivotal role of anthropometric measures in shaping the risk of hematological malignancies in adults. Additional, well-designed studies stemming from all the continents are needed for the further substantiation and generalization of the results.     

Challenges in assessing the real incidence of chronic lymphocytic leukemia: 16 years of epidemiological data from the province of Girona,Spain

Determining chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) incidence is challenging for two reasons: cancer registries tend to underreport CLL cases and its diagnostic criteria changed markedly in 2008. No studies have reported incidence rates dealing with both difficulties, and thus CLL/SLL burden in Europe is currently uncertain. Herein, we present accurate CLL/SLL incidence in a Spanish region during 1998–2013, using the population-based Girona Cancer Registry (GCR). We detected an 18.2% under-reporting of CLL/SLL cases when combining records from the GCR and additional information sources (i.e., records of flow cytometry laboratories, hospital registries and hematologists’ databases). In addition, age-adjusted rates (using the 2013 European population) changed from 7.57 (95% CI 6.87; 8.30) in 1998–2008 to 6.35 (95% CI 5.51; 7.30) in 2009–2013. Overall, completeness of CLL/SLL data requires accurate diagnosis and reporting of cases. Revision of cancer registry operations to include CLL/SLL-specific surveillance is likely to ensure that the monitoring of this malignancy is entirely accurate.     

Body mass index and risk of non-Hodgkin's and Hodgkin's lymphoma: a meta-analysis of prospective studies

We conducted a meta-analysis of prospective studies to summarise the epidemiologic evidence regarding the association of body mass index (BMI) with non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) incidence and NHL mortality. Pertinent studies were identified by searching PubMed (1966-May 2011) and the reference lists of retrieved articles. For each study, we estimated a relative risk (RR) for a 5 kg/m(2) increase in BMI. A random-effects model was used to combine the RR estimates from individual studies. The summary RRs for a 5 kg/m(2) increase in BMI were 1.07 (95% confidence intervals (CI), 1.04-1.10) for NHL incidence (16 studies, n=17,291 cases) and 1.14 (95% CI, 1.04-1.26) for NHL mortality (five studies, n=3407 cases). BMI was significantly positively associated with risk of diffuse large B-cell lymphoma (RR, 1.13; 95% CI, 1.02-1.26), but not other NHL subtypes. The difference in risk estimates for subtypes was not statistically significant (P=0.10). There was evidence of a nonlinear association between BMI and HL (P for nonlinearity=0.01) (five studies, n=1557 cases). The summary RRs of HL were 0.97 (95% CI, 0.85-1.12) for overweight and 1.41 (95% CI, 1.14-1.75) for obesity. These results indicate that BMI is positively associated with risk of NHL and HL as well as with NHL mortality.     

Prediagnostic serum sCD27 and sCD30 in serial samples and risks of non-Hodgkin lymphoma subtypes

Elevated prediagnostic serum levels of the immune activation markers sCD27 and sCD30 have been associated with non-Hodgkin lymphoma (NHL). However, the use of a single sample per participant in these studies has limited etiologic inferences. We report findings, overall and by NHL subtype, from a case–control analysis (422 cases, 434 controls) within the Janus Serum Bank with two samples per subject collected on average 5 years apart. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was associated with elevated sCD27 in the later, but not earlier, prediagnostic sample (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5–11.6 and 1.7, 0.7–4.7 per log increase, respectively) in analyses adjusting for both analytes, while follicular lymphoma (FL) was associated with elevated sCD30 in both the later and earlier samples (OR 2.9, 95% CI 1.4–4.4 and 2.3, 1.2–4.4, respectively). CLL/SLL cases were significantly more likely than controls to have higher sCD27 in the later vs. earlier sample (OR 1.4, 95% CI 1.1–1.9 per standard deviation increase); no such difference in sCD30 was apparent for FL. In a joint analysis, NHL cases were more likely than controls to have below-median sCD27 in the earlier sample and above-median sCD27 in the later sample (OR 1.5, 95% CI 1.0–2.3). For sCD30, the association between sCD30 and FL was confined to subjects with above-median analyte levels in both samples (OR 2.5, 95% CI 1.1–5.9). Our findings are compatible with elevated sCD27 representing a disease-induced effect and sCD30 representing a marker of increased FL susceptibility.     

Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richter's transformation and 1 Hodgkin's disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84 - 4.55) for second malignancy and 2.69 (95% CI 1.62 - 4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).     

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (OR_T3) = 2.2, 95% CI = 1.6-3.1], sCD30 (OR_T3 = 2.0, 95% CI = 1.6-2.5) and CXCL13 (OR_T3 = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (OR_T3 = 3.3, 95% CI = 2.4-4.6), MZL (OR_T3 = 7.7, 95% CI = 3.0-20.1) and TCL (OR_T3 = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (OR_T3 = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.     

Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma

Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, seem to have chemopreventive properties against several types of cancer, particularly colon cancer. Persons with rheumatoid arthritis, an autoimmune disease for which NSAIDs are used commonly, have been reported to be at lower risk of colon cancer but at elevated risk of non-Hodgkin lymphoma (NHL), raising the possibility that NSAIDs may be a risk factor for NHL. We evaluated the association of use of NSAIDs, arthritis history, and risk of NHL in a prospective cohort of 27,290 postmenopausal women from the state of Iowa. The frequency of use of aspirin and of other NSAIDs excluding aspirin (e.g., ibuprofen), as well as a physician diagnosis of rheumatoid arthritis (RA) or osteoarthritis (OA), were self-reported on a questionnaire mailed in 1992. The incidence of NHL was ascertained through annual linkages to the Iowa SEER Cancer Registry. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. Through 7 years of follow-up, 131 cases of NHL were identified. Compared to women who did not use either aspirin or other non-aspirin NSAIDs, women using aspirin exclusively (RR = 1.71; 95% CI = 0.94-3.13), non-aspirin NSAIDs exclusively (RR = 2.39; 95% CI = 1.18-4.83), or both types of drugs (RR = 1.97; 95% CI = 1.06-3.68) were at increased risk of NHL. A diagnosis of RA (RR = 1.75; 95% CI = 1.09-2.79), but not OA (RR = 1.06; 95% CI = 0.67-1.68), was associated with risk of NHL, but the positive association of use of aspirin and other NSAIDs with NHL was independent of RA history. Multivariate adjustment for other NHL risk factors only attenuated slightly these associations, whereas exclusion of cases occurring during the first 2 years of follow-up strengthened the associations. These data suggest that use of NSAIDs, either aspirin or other non-aspirin NSAIDs, are associated positively with risk of NHL, and that this association is independent of RA history.     

Lack of Association between Using Aspirin and Development of Non-Hodgkins Lymphoma: A Meta-analysis

Background: Non-Hodgkins lymphoma (NHL) is a heterogeneous group of malignancies, originating in thelymphatic organs, whose incidence is increasing in developed as well as developing countries. Epidemiologicalevidence suggests that aspirin may reduce the incidence and mortality of several cancers. The main objectiveof this study was to evaluate the potential relationship between using aspirin and development of NHL with ameta-analysis. Materials and Methods: A total of 7 studies were included. Outcome was calculated and reportedas odds ratios (ORs). Heterogeneity was assessed with Cochrane Q and I2 statistics. Dissemination bias wasevaluated by funnel plot visualization and trim-and-fill analysis. Results: Our analysis showed OR of developingNHL overall of 1(95% CI: 0.87-1.16, p=0.9), and in females this was 0.81 (95%CI: 0.72-.92, p=0.001) and inmales 1.01 (95%CI: 0.82-1.26, p=0.86). The odds ratio (OR) of chronic lymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL) was 0.85 (95%CI: 0.75-0.97, p=0.02), The ORs of follicular lymphoma (FL) and largeB-cell lymphoma (DLBCL) in individuals exposed to aspirin were 1.12 (95%CI: 0.86-1.45, p=0.37) and 1.03(95%CI: 0.9-1.19, p=0.6) respectively. Conclusions: In conclusion, individuals taking aspirin do not demonstrateany change in risk of Non-Hodgkins lymphoma.