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1.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
2.  Diet and Risk of Ovarian Cancer in the California Teachers Study Cohort 
American journal of epidemiology  2007;165(7):802-813.
Dietary phytochemical compounds, including isoflavones and isothiocyanates, may inhibit cancer development but have not yet been examined in prospective epidemiologic studies of ovarian cancer. The authors have investigated the association between consumption of these and other nutrients and ovarian cancer risk in a prospective cohort study. Among 97,275 eligible women in the California Teachers Study cohort who completed the baseline dietary assessment in 1995–1996, 280 women developed invasive or borderline ovarian cancer by December 31, 2003. Multivariable Cox proportional hazards regression, with age as the timescale, was used to estimate relative risks and 95% confidence intervals; all statistical tests were two sided. Intake of isoflavones was associated with lower risk of ovarian cancer. Compared with the risk for women who consumed less than 1 mg of total isoflavones per day, the relative risk of ovarian cancer associated with consumption of more than 3 mg/day was 0.56 (95% confidence interval: 0.33, 0.96). Intake of isothiocyanates or foods high in isothiocyanates was not associated with ovarian cancer risk, nor was intake of macronutrients, antioxidant vitamins, or other micronutrients. Although dietary consumption of isoflavones may be associated with decreased ovarian cancer risk, most dietary factors are unlikely to play a major role in ovarian cancer development.
PMCID: PMC2093945  PMID: 17210953
antioxidants; cohort studies; diet; isoflavones; isothiocyanates; nutrition; ovarian neoplasms; women's health
3.  Reproductive Factors and Non-Hodgkin Lymphoma Risk in the California Teachers Study 
PLoS ONE  2009;4(12):e8135.
Non-Hodgkin lymphoma (NHL) is a malignancy etiologically linked to immunomodulatory exposures and disorders. Endogenous female sex hormones may modify immune function and influence NHL risk. Few studies have examined associations between reproductive factors, which can serve as surrogates for such hormonal exposures, and NHL risk by subtype.
Methodology/Principal Findings
Women in the California Teachers Study cohort provided detailed data in 1995–1996 on reproductive history. Follow-up through 2007 identified 574 women with incident B-cell NHL. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models to assess associations between reproductive factors and all B-cell NHL combined, diffuse large B-cell lymphomas, follicular lymphomas, and B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas. Pregnancy was marginally associated with lower risk of B-cell NHL (RR = 0.84, 95% CI = 0.68–1.04). Much of the reduction in risk was observed after one full-term pregnancy relative to nulligravid women (RR = 0.75, 95% CI = 0.54–1.06; P for trend <0.01), particularly for diffuse large B-cell lymphomas (P for trend = 0.13), but not among women who had only incomplete pregnancies. Age at first full-term pregnancy was marginally inversely associated with B-cell NHL risk overall (P for trend = 0.08) and for diffuse large B-cell lymphomas (P for trend = 0.056). Breast feeding was not associated with B-cell NHL risk overall or by subtype.
Full-term pregnancy and early age at first full-term pregnancy account for most of the observed reduction in B-cell NHL risk associated with gravidity. Pregnancy-related hormonal exposures, including prolonged and high-level exposure to progesterone during a full-term pregnancy may inhibit development of B-cell NHL.
PMCID: PMC2780313  PMID: 19956586
4.  Obesity, Diet and Risk of Non-Hodgkin Lymphoma 
Non-Hodgkin lymphoma (NHL) represents a group of heterogeneous diseases that significantly vary in their causes, molecular profiles, and natural progression. In 2006, there will be ~59,000 newly diagnosed NHL cases in the U.S. and over 300,000 cases worldwide. While new therapeutic regimens are minimizing the number of deaths related to NHL, causes for the majority of lymphomas remain undetermined. Recent studies suggest that dietary factors may contribute to the rising rates of NHL. This review will summarize epidemiological reports that have studied the relationship between obesity, physical activity, diet and risk of NHL.
Based on a number of case-control and prospective cohort studies, overweight/obesity likely increases the risk of NHL; whereas, moderate physical activity may reduce risk. Several studies support an inverse association between intakes of vegetables and NHL risk, particularly for the consumption of cruciferous vegetables. This may relate to the induction of apoptosis and growth arrest in pre-neoplastic and neoplastic cells, two important actions of isothiocyanates found in cruciferous vegetables. Studies also suggest that fish intake may be inversely associated with risk of NHL, though findings have not been entirely consistent. This may relate to the high organochlorine content in some fish that could override a protective effect. High consumption of fats, meat and dairy products also may increase lymphoma risk. The accumulated scientific evidence concerning the associations between obesity, diet, and NHL suggests several identified modifiable risk factors that might be recommended to decrease lymphoma risk.
PMCID: PMC2819159  PMID: 17337642
5.  Prediagnostic serum tocopherol levels and the risk of Non-Hodgkin Lymphoma: The Multiethnic Cohort 
Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology.
This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high pressure liquid chromatography/photodiode-array detection with NHL risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).
We observed U-shaped associations with NHL for total and α-tocopherols (Ptrend<0.01 for polynomial terms [3 df]). The ORs (95% CI) for total tocopherols, which consisted primarily of α-tocopherol, were 0.41 (0.25–0.68), 0.52 (0.32–0.85), 0.39 (0.23–0.65), and 0.78 (0.47–1.29) for the 2nd-5th quintiles as compared to the 1st. The risk estimates were similar for α-tocopherol but non-significant for β- and γ-tocopherol combined and for δ-tocopherol. Adjustment for serum lipids strengthened the non-linear associations for total and α-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than non-users (21.32±9.04 vs 17.72±7.43 μg/mL; P <0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype.
Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial.
The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL.
PMCID: PMC3819232  PMID: 24045922
non-Hodgkin lymphoma; tocopherols; ethnicity; prospective cohort; nested case-control study
6.  Food-Frequency Questionnaire Based Estimates of Total Antioxidant Capacity and Risk of Non-Hodgkin Lymphoma 
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
PMCID: PMC3306533  PMID: 22038870
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
7.  Alcohol Consumption Over Time and Risk of Lymphoid Malignancies in the California Teachers Study Cohort 
American Journal of Epidemiology  2010;172(12):1373-1383.
Several previous studies found inverse associations between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) and multiple myeloma. However, most studies were retrospective, and few distinguished former drinkers or infrequent drinkers from consistent nondrinkers. Therefore, the authors investigated whether history of alcohol drinking affected risks of NHL and multiple myeloma among 102,721 eligible women in the California Teachers Study, a prospective cohort study in which 496 women were diagnosed with B-cell NHL and 101 were diagnosed with multiple myeloma between 1995–1996 and December 31, 2007. Incidence rate ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Risk of all types of B-cell NHL combined or multiple myeloma was not associated with self-reported past consumption of alcohol, beer, wine, or liquor at ages 18–22 years, at ages 30–35 years, or during the year before baseline. NHL subtypes were inconsistently associated with alcohol intake. However, women who were former alcohol drinkers at baseline were at elevated risk of overall B-cell NHL (rate ratio = 1.46, 95% confidence interval: 1.08, 1.97) and follicular lymphoma (rate ratio = 1.81, 95% confidence interval: 1.00, 3.28). The higher risk among former drinkers emphasizes the importance of classifying both current and past alcohol consumption and suggests that factors related to quitting drinking, rather than alcohol itself, may increase B-cell NHL risk.
PMCID: PMC3105275  PMID: 20952595
alcohol drinking; cohort studies; lymphoma, non-Hodgkin; multiple myeloma
8.  Risk of Non-Hodgkin Lymphoma and Nitrate and Nitrite from the Diet in Connecticut Women 
Cancer causes & control : CCC  2010;21(6):889-896.
The incidence of non-Hodgkin lymphoma has substantially increased during the past several decades, and although established risk factors such as immunodeficiency and viral infection may be responsible for a portion of the cases, the vast majority of the NHL cases remain unexplained. Dietary nitrate and nitrite intake are exposures of particular interest for non-Hodgkin lymphoma risk as they have been shown to cause lymphomas in animal studies and there is growing evidence of adverse impact in the epidemiological literature. We investigated NHL risk in general and by subtype in relation to dietary nitrate and nitrite intake in a population-based case-control study of 1,304 women in Connecticut. Nitrate and nitrite intake was assessed using a 120-item food frequency questionnaire. We found no association between risk of NHL and dietary nitrate and a slightly increased risk of NHL for higher dietary nitrite intake (OR = 1.37; 95% CI: 1.04–1.79). The risk was significantly increased for diffuse large B-cell lymphoma (OR = 1.61; 95% CI: 1.08–2.42), follicular lymphoma (OR = 1.61; 95% CI: 1.02–2.54), and T-cell lymphoma (OR = 2.38; 95% CI: 1.12–5.06). Animal products containing nitrite appear to be driving the risk for DLBC lymphoma and follicular lymphoma, whereas the risk for T-cell lymphoma is being driven by plant products. Our results confirm a previous finding for nitrite intake and highlight the importance of evaluating NHL risk by histologic type. We conclude that these results should be replicated in a larger study with data on water consumption as well as diet.
PMCID: PMC3086573  PMID: 20204494
Non-Hodgkin lymphoma; nitrate and nitrite; diet
9.  Dietary nitrate and nitrite intake and risk of non-Hodgkin lymphoma 
Leukemia & lymphoma  2012;54(5):945-950.
Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of non-Hodgkin lymphoma (NHL) cases, the vast majority of NHL cases remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds and nitrosoureas have been shown to induce B and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite intake and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case-control study of 348 cases and 470 controls conducted in Nebraska in 1999–2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (OR = 1.6; 95% CI: 0.8–2.9), particularly nitrite from animal sources (OR=1.9; 95% CI: 1.0–3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association.
PMCID: PMC4454474  PMID: 23013327
Non-Hodgkin lymphoma; nitrate; nitrite; diet
10.  Body Size, Recreational Physical Activity, and B-Cell Non-Hodgkin Lymphoma Risk Among Women in the California Teachers Study 
American Journal of Epidemiology  2009;170(10):1231-1240.
Nutritional status and physical activity are known to alter immune function, which may be relevant to lymphomagenesis. The authors examined body size measurements and recreational physical activity in relation to risk of B-cell non-Hodgkin lymphoma (NHL) in the prospective California Teachers Study. Between 1995 and 2007, 574 women were diagnosed with incident B-cell NHL among 121,216 eligible women aged 22–84 years at cohort entry. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models for all B-cell NHL combined and for the 3 most common subtypes: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Height was positively associated with risk of all B-cell NHLs (for >1.70 vs. 1.61–1.65 m, relative risk = 1.50, 95% confidence interval: 1.16, 1.96) and chronic lymphocytic leukemia/small lymphocytic lymphoma (relative risk = 1.93, 95% confidence interval: 1.09, 3.41). Weight and body mass index at age 18 years were positive predictors of B-cell NHL risk overall. These findings indicate that greater height, which may reflect genetics, early life immune function, infectious exposures, nutrition, or growth hormone levels, may play a role in NHL etiology. Adiposity at age 18 years may be more relevant to NHL etiology than that in later life.
PMCID: PMC2781760  PMID: 19822569
body mass index; body size; cohort studies; exercise; hip; lymphoma, non-Hodgkin; waist-hip ratio
11.  Antioxidant Intake from Fruits, Vegetables and Other Sources and Risk of Non-Hodgkin Lymphoma: The Iowa Women's Health Study 
Antioxidant nutrients found in fruits, vegetables, and other foods are thought to inhibit carcinogenesis and to influence immune status. We evaluated the association of these factors with risk of NHL overall and for diffuse large B-cell (DLBCL) and follicular lymphoma specifically in a prospective cohort of 35,159 Iowa women aged 55–69 years when enrolled at baseline in 1986. Diet was ascertained using a validated semi-quantitative food frequency questionnaire. Through 2005, 415 cases of NHL (including 184 DLBCL and 90 follicular) were identified. Relative risks (RRs) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for age and total energy. The strongest associations of antioxidants with risk of NHL (RR for highest versus lowest quartile; p for trend) were observed for dietary vitamin C (RR=0.78; p=0.044), α-carotene (RR=0.71; p=0.015), proanthocyanidins (RR=0.70; p=0.0024), and dietary manganese (RR=0.62; p=0.010). There were no associations with multivitamin use or supplemental intake of vitamins C, E, selenium, zinc, copper or manganese. From a food perspective, greater intake of total fruits and vegetables (RR=0.69; p=0.011), yellow/orange (RR=0.72; p=0.015) and cruciferous (RR=0.82; p=0.017) vegetables, broccoli (RR=0.72; p=0.018), and apple juice/cider (RR=0.65; p=0.026) were associated with lower NHL risk; there were no strong associations for other antioxidant-rich foods, including whole grains, chocolate, tea or nuts. Overall, these associations were mainly observed for follicular lymphoma, and were weaker or not apparent for DLBCL. In conclusion, these results support a role for vegetables and perhaps fruits, and associated antioxidants from food sources, as protective factors against the development of NHL and follicular lymphoma in particular.
PMCID: PMC2798902  PMID: 19685491
antioxidants; cohort studies; fruits; non-Hodgkin lymphoma; vegetables
12.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
PMCID: PMC4155467  PMID: 25174034
13.  Non-Hodgkin Lymphoma Risk and Insecticide, Fungicide and Fumigant Use in the Agricultural Health Study 
PLoS ONE  2014;9(10):e109332.
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
PMCID: PMC4206281  PMID: 25337994
14.  Phytanic acid and the risk of non-Hodgkin lymphoma 
Carcinogenesis  2012;34(1):170-175.
Greater consumption of red meat, processed meat and dairy products has been associated with an increased risk of non-Hodgkin lymphoma (NHL) in several previous reports. Phytanic acid, a saturated fatty acid obtained primarily through the consumption of ruminant meat and dairy products, may offer a potential underlying mechanism for these associations. In a population-based case–control study of 336 cases and 460 controls conducted in Nebraska during 1999–2002, we examined whether phytanic acid-containing foods or total phytanic acid intake, estimated from a food frequency questionnaire and the published phytanic acid values of 151 food items, were associated with increased NHL risk. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for overall NHL and the common NHL histologic subtypes. In multivariable models, higher intakes of density-adjusted beef [ORT3 vs. T1 = 1.5 (1.1–2.2); Ptrend = 0.02], total dairy products [OR = 1.5 (1.1–2.2); Ptrend = 0.02) and milk [OR = 1.6 (1.1–2.3); Ptrend = 0.01] were associated with an increased risk of NHL. Intake of total phytanic acid was positively associated with NHL risk [OR = 1.5 (1.0–2.1); Ptrend = 0.04]. In analyses stratified by NHL subtype, greater consumption of beef was associated with an increased risk of diffuse large B-cell lymphoma, and greater consumption of milk was associated with an increased risk of follicular lymphoma (FL). Total phytanic acid intake was associated with an increased risk of FL and small lymphocytic lymphoma/chronic lymphocytic leukemia. Our results provide support that total phytanic acid and phytanic acid-containing foods may increase NHL risk.
PMCID: PMC3534193  PMID: 23042099
15.  The Relationship Between Dietary Phytoestrogens and Development of Urinary Incontinence in Midlife Women 
Menopause (New York, N.Y.)  2013;20(4):428-436.
Because exogenous estrogen treatment has been associated with a higher risk of urinary incontinence, our objective was to evaluate the longitudinal relationships of dietary phytoestrogen intakes (isoflavones, coumestans and lignans) and the development of incontinence in midlife women transitioning through menopause.
The Study of Women’s health Across the Nation (SWAN) Phytoestrogen Study was developed within SWAN, a community-based, multisite, multi-racial/ethnic, prospective cohort study. SWAN interviewers administered a food consumption assessment at baseline and at follow-up visits 5 and 9. The SWAN Phytoestrogen study created a phytonutrient data base that allowed estimation of usual daily intakes of four isoflavones, four lignans and coumestrol. On an annual self-administered questionnaire, participants reported on frequency and type of incontinence. We used discrete proportional hazards models to evaluate whether estimated daily intake of each phytoestrogen class at the visit previous to the first report of incontinence was associated with the development of monthly or more incontinence compared to remaining continent.
We found no association or patterns of association between developing any, stress or urge incontinence and the reported daily dietary intake of isoflavones, coumestrol, and lignans in the visit previous to the onset of incontinence.
The results of this longitudinal study provide important information to better understand estrogen-like substances on the continence mechanism in midlife women. Our study shows that neither high nor low dietary intakes of isoflavones, coumestrol and lignans prevent stress or urge incontinence. Future studies should evaluate whether serum levels of phytoestrogens or their metabolites impact incontinence symptoms.
PMCID: PMC3568456  PMID: 23096248
Phytoestrogen; isoflavone; coumestrol; lignan; urinary incontinence
16.  Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project 
Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design.
We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control.
The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes.
The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.
PMCID: PMC4155460  PMID: 25174022
17.  Survival of Non-Hodgkin Lymphoma Patients with and without HIV-Infection in the Era of Combined Antiretroviral Therapy 
AIDS (London, England)  2010;24(11):1765-1770.
To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. -uninfected patients from the same integrated health care system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy (cART).
Cohort study.
Incident NHL diagnosed between 1996–2005 were identified from members of Kaiser Permanente (KP) California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma- and HIV-related characteristics for the same outcomes were also examined.
A total of 259 HIV-infected and 8,230 HIV-uninfected incident NHL cases were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis, compared to 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (Relative Risk=2.0, 95% Confidence Interval=1.7–2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages and histologic subtypes. HIV-infected patients with CD4 cell count <200/mm3 and/or prior AIDS-defining illness were also at increased risk for lymphoma-specific mortality compared to HIV-uninfected patients. Among HIV-infected NHL cases, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt’s subtype.
HIV-infected patients with NHL in the cART era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.
PMCID: PMC2895006  PMID: 20453630
HIV infection; non-Hodgkin lymphoma; prognostic factors; antiretroviral therapy; mortality
18.  Dairy Product Consumption and Risk of Non-Hodgkin Lymphoma: A Meta-Analysis 
Nutrients  2016;8(3):120.
Many epidemiologic studies have explored the association between dairy product consumption and the risk of non-Hodgkin lymphoma (NHL), but the results remain controversial. A literature search was performed in PubMed, Web of Science and Embase for relevant articles published up to October 2015. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. The dose-response relationship was assessed by restricted cubic spline. A total of 16 articles were eligible for this meta-analysis. The pooled RRs (95% CIs) of NHL for the highest vs. lowest category of the consumption of total dairy product, milk, butter, cheese, ice cream and yogurt were 1.20 (1.02, 1.42), 1.41 (1.08, 1.84), 1.31 (1.04, 1.65), 1.14 (0.96, 1.34), 1.57 (1.11, 2.20) and 0.78 (0.54, 1.12), respectively. In subgroup analyses, the positive association between total dairy product consumption and the risk of NHL was found among case-control studies (RR = 1.41, 95% CI: 1.17–1.70) but not among cohort studies (RR = 1.02, 95% CI: 0.88–1.17). The pooled RRs (95% CIs) of NHL were 1.21 (1.01, 1.46) for milk consumption in studies conducted in North America, and 1.24 (1.09, 1.40) for cheese consumption in studies that adopted validated food frequency questionnaires. In further analysis of NHL subtypes, we found statistically significant associations between the consumption of total dairy product (RR = 1.73, 95% CI: 1.22–2.45) and milk (RR = 1.49, 95% CI: 1.08–2.06) and the risk of diffuse large B-cell lymphoma. The dose-response analysis suggested that the risk of NHL increased by 5% (1.05 (1.00–1.10)) and 6% (1.06 (0.99–1.13)) for each 200 g/day increment of total dairy product and milk consumption, respectively. This meta-analysis suggested that dairy product consumption, but not yogurt, may increase the risk of NHL. More prospective cohort studies that investigate specific types of dairy product consumption are needed to confirm this conclusion.
PMCID: PMC4808850  PMID: 26927171
dairy product; milk; non-Hodgkin lymphoma; meta-analysis
19.  Dietary Phytoestrogen Intake Is Associated with Reduced Colorectal Cancer Risk1 
The Journal of nutrition  2006;136(12):3046-3053.
Evidence suggests dietary phytoestrogens may reduce the risk of certain hormonal cancers (e.g. breast and prostate). There is a paucity of data regarding phytoestrogens and colorectal cancer risk. Phytoestrogens are plant compounds with estrogen-like activities. Main classes include isoflavones (found in legumes such as soy) and lignans (found in grains, seeds, nuts, fruits, and vegetables). Although isoflavones have dominated phytoestrogen cancer research, lignans may be more relevant to North American diets. Food questionnaires and analytic databases have recently been modified to incorporate some lignan information. We conducted a case-control study to evaluate the association between phytoestrogen intake and colorectal cancer risk. Colorectal cancer cases were diagnosed in 1997–2000, aged 20–74 y, identified through the population-based Ontario Cancer Registry, and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex and age-group matched random sample of the population of Ontario. Epidemiologic and food frequency questionnaires were completed by 1095 cases and 1890 control subjects. Multivariate logistic regression analysis was used to obtain adjusted odds ratio (OR) estimates. Dietary lignan intake was associated with a significant reduction in colorectal cancer risk [OR (T3 vs. T1) = 0.73; 95% CI: 0.56, 0.94], as was isoflavone intake [OR (T3 vs. T1) = 0.71; 95% CI: 0.58, 0.86]. We evaluated interactions between polymorphic genes that encode enzymes possibly involved in metabolism of phytoestrogens (CYPs, catechol O-methyl transferase, GSTs, and UGTs) and found no significant effect modification with respect to phytoestrogen intake. This finding that phytoestrogen intake may reduce colorectal cancer risk is important, because dietary intake is potentially modifiable.
PMCID: PMC1850957  PMID: 17116718
20.  Dietary Vitamin D and Risk of Non-Hodgkin Lymphoma: The Multiethnic Cohort 
The British journal of nutrition  2009;103(4):581-584.
This study explored the association between dietary vitamin D and non-Hodgkin lymphoma (NHL) risk. The Multiethnic Cohort (MEC) includes more than 215,000 Caucasians, African Americans, Native Hawaiians, Japanese Americans, and Latinos, aged 45-75. After 10 years of follow-up, 939 incident NHL cases were identified. Risk was estimated using Cox proportional hazards models adjusted for possible confounders. Vitamin D intake was not associated with NHL risk in the entire cohort (Ptrend=0.72 for men and Ptrend=0.83 for women), but significantly lowered disease risk in African American women (HR=0.50, 95% CI: 0.28-0.90, Ptrend=0.03) and was borderline protective in African American men (HR=0.68; 95% CI: 0.39-1.19; Ptrend=0.31) when the highest to the lowest tertile was compared. In NHL subtype analyses, a 19%, 36%, and 32% lowered risk, although not significant, was observed for diffuse large B-cell lymphoma, follicular lymphoma, and small lymphocytic lymphoma/chronic lymphocytic leukemia in women, respectively. High dietary intake of vitamin D did not show a protective effect against NHL within the MEC except among African Americans, possibly because vitamin D production due to sun exposure is limited in this population.
PMCID: PMC2935689  PMID: 19781122
non-Hodgkin lymphoma; dietary vitamin D; prospective studies; ethnicity
21.  Cohort study of non-Hodgkin lymphoma risk in association with hepatitis B virus infection in South Korea 
The lancet oncology  2010;11(9):827-834.
Hepatitis B virus (HBV) infection is common throughout Asia and Africa. Evidence is inconclusive regarding whether chronic HBV infection increases risk for non-Hodgkin lymphoma (NHL).
We conducted a cohort study of 603,585 South Korean workers and their dependents enrolled during 1992–1995. Serum hepatitis B surface antigen (HBsAg) measured at baseline indicated the presence of chronic HBV infection. We ascertained hematologic malignancies using national inpatient, outpatient, and mortality databases through 2006. Cox regression was used to evaluate associations with HBsAg status, adjusting for sex, age, and enrollment year.
53,045 subjects (8.8%) were HBsAg positive at baseline. Subsequently, 133 HBsAg positive and 905 HBsAg negative individuals developed NHL. HBsAg positive subjects had elevated risk of NHL overall (incidence 19.4 vs. 12.3 per 100,000 person-years; adjusted hazard ratio [HR] 1.74, 95%CI 1.45–2.09). Among NHL subtypes, risk was significantly elevated in association with HBsAg positivity for diffuse large B cell lymphoma (N=325 cases; adjusted HR 2.01, 95%CI 1.48–2.75) and non-significantly elevated for follicular NHL (N=47; 1.67, 0.71–3.95) and T-cell NHL (N=75; 1.40, 0.67–2.92); risk was also elevated for other/unknown NHL subtypes (N=591; 1.65, 1.29–2.11). Elevated risk was also observed for malignant immunoproliferation (N=14; adjusted HR 3.79, 95%CI, 1.05–13.7), a category that includes Waldenström macroglobulinemia. Risk of these malignancies was consistently elevated in HBsAg positive subjects throughout 14 years of follow-up. HBsAg positivity was not associated with Hodgkin lymphoma, multiple myeloma, or various leukemias.
During extended follow-up, HBsAg positive individuals manifested an elevated risk of NHL, suggesting that chronic infection promotes lymphomagenesis.
PMCID: PMC2933963  PMID: 20688564
22.  Common Immune-Related Risk Factors and Incident Non-Hodgkin Lymphoma: The Multiethnic Cohort 
Severe immune dysfunction is an established risk factor of lymphoma, but the role of moderate alterations of immunity is not clear and prospective investigations are needed. We examined several immune-related disorders and medications in relation to non-Hodgkin lymphoma (NHL) in the Multiethnic Cohort. Over 215,000 subjects of African American, Caucasian, Japanese American, Latino, and Native Hawaiian ancestry aged 45–75 years completed a questionnaire, including information on medical history, in 1993–1996. After exclusions, we performed Cox regression among 193,050 cohort members including 939 incident NHL cases while adjusting for sex, age, ethnicity, education, body mass index, and alcohol intake. Self-reported diabetes was not associated with NHL overall, but was positively associated with risk among Japanese Americans (hazard ratio (HR) = 1.55; 95% confidence interval (CI): 1.10–2.17). Participants with a history of blood transfusion were at increased risk with HR = 1.39 (95% CI: 1.06–1.84) in men and HR = 1.22 (95% CI: 0.94–1.58) in women, especially for the diffuse large B-cell lymphoma subtype. History of asthma or other allergies was associated with elevated risk only among Latinos (HR = 1.46; 95% CI: 1.07–2.00) who also showed a significant relation between current use of antihistamines and NHL (HR = 1.80; 95% CI: 1.09–2.97). Use of non-steroidal anti-inflammatory drugs was not associated with NHL. Our findings from this large prospective study support a moderate risk for NHL related to blood transfusions, current long-term antihistamine use, and diabetes, but the associations were limited to a certain ethnic groups and require further replications.
PMCID: PMC2734966  PMID: 19444913
allergy; blood transfusion; diabetes mellitus; lymphoma, non-Hodgkin; NSAIDs
23.  Increased Risk of Stomach and Esophageal Malignancies in People With AIDS 
Gastroenterology  2012;143(4):943-950.e2.
People infected with human immunodeficiency virus (HIV) have an increased risk of some malignancies, but little is known about the effects of infection on risk of cancers of the upper gastrointestinal tract. We evaluated the risks of different histologic and anatomic subtypes of carcinomas and non-Hodgkin lymphomas (NHLs) of the stomach and esophagus in people with acquired immunodeficiency syndrome (AIDS).
We analyzed data from the HIV/AIDS Cancer Match Study, which links data collected from 1980 to 2007 for 16 US population-based HIV and AIDS and cancer registries. We compared risks of stomach and esophageal malignancies in people with AIDS (N = 596,955) with those of the general population using standardized incidence ratios (SIRs). We assessed calendar trends using Poisson regression.
People with AIDS had increased risks of carcinomas of the esophagus (SIR, 1.69; 95% confidence interval [CI], 1.37–2.07; n = 95) and stomach (SIR, 1.44; 95% CI, 1.17–1.76; n = 96). Risk was increased for esophageal adenocarcinoma (SIR, 1.91; 95% CI, 1.31–2.70) and squamous cell carcinoma (SIR, 1.47; 95% CI, 1.10 –1.92). People with AIDS had greater risks of carcinomas of the gastric cardia (SIR, 1.36; 95% CI, 0.83–2.11) and noncardia (SIR, 1.53; 95% CI, 1.12–2.05) than the general population. Although most stomach and esophageal NHLs that developed in people with AIDS were diffuse large B-cell lymphomas, these individuals also had an increased risk of stomach mucosa–associated lymphoid tissue lymphoma (SIR, 5.99; 95% CI, 3.19 –10.2; n = 13). The incidence of carcinomas remained fairly constant over time, but rates of NHL decreased from 1980 to 2007 (Ptrend < .0001).
People with AIDS are at increased risk for developing esophageal and stomach carcinomas and NHLs. Although the incidence of NHL decreased from 1980 to 2007 as treatments for HIV infection improved, HIV-infected individuals face continued risks of esophageal and stomach carcinomas.
PMCID: PMC4236003  PMID: 22796240
MALT Lymphoma; Epidemiology; Virus-Associated Cancers; Immunosuppression
24.  Body Mass Index and Non-Hodgkin's Lymphoma Survival in an Ethnically Diverse Population: The Multiethnic Cohort Study 
Obesity increases the risk of death from several malignancies including breast and colon cancer. However, for non-Hodgkin's lymphoma (NHL), the association between pre-diagnostic body mass index (BMI) and survival is unclear. We examined the association between pre-diagnostic BMI overall and NHL-specific survival in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians.
MEC participants free of NHL at cohort entry and diagnosed with NHL during follow-up were included in the analyses (N=1348). Body mass index (BMI) was based on self-reported weight and height at cohort entry. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for pre-diagnostic BMI categories in relation to all-cause and NHL-specific mortality while adjusting for known confounders.
The mean time from cohort entry to NHL diagnosis was 7.2±3.9 years (range: 0.0–15.0 years). The mean age at NHL diagnosis was 70.6 (range 45–89) years and the mean BMI at cohort entry was 26.5±4.7 kg/m2. After a mean follow-up of 4.3±3.5 years, 679 deaths including 457 NHL-specific deaths occurred. In multivariable models, obese patients (BMI ≥ 30.0) had higher all-cause (HR = 1.55, 95%CI = 1.21 −2.00) and NHL-specific (HR = 1.84, 95%CI = 1.35 – 2.52) mortality compared to patients with high-normal BMI (22.5–24.9 kg/m2). For overweight patients (BMI 25.0 – 29.9), the respective HRs were 1.29 (95%CI = 1.05 – 1.58) and 1.47 (95%CI = 1.14 – 1.89). Stratification by NHL type suggested higher NHL-specific mortality risk for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) than for diffuse large B-cell lymphoma (DLBCL).
Pre-diagnostic obesity may be related to poorer overall and NHL-specific survival in NHL patients. Therefore, pre-diagnostic BMI may be a suitable prognostic marker for NHL patients.
PMCID: PMC4175946
25.  Intake of vitamins D and A, and calcium and risk of non-Hodgkin lymphoma: San Francisco Bay Area population-based case-control study 
Nutrition and Cancer  2012;64(5):674-684.
Several nutrients identified as potentially cancer protective have been inconsistently associated with non-Hodgkin lymphoma (NHL) risk. Dietary history data, including use of vitamin supplements, were collected using a semi-quantitative food frequency questionnaire administered during in-person interviews with 4,133 participants (2052 cases, 2081 controls) in a San Francisco Bay Area population-based case-control. Data were used to determine the association of intake levels of vitamins D, A and calcium with risk of NHL and NHL subtypes. Odds ratios (OR) and 95% confidence intervals (CI) were computed as estimates of relative risk using adjusted unconditional logistic regression. Increasing vitamin D intake from food and supplements was positively associated with NHL risk in men (5th quintile: OR=1.6, 95% CI= 1.0-2.4, Ptrend=0.07) and with diffuse large B-cell lymphoma (DLBCL) in women and men (5th quintile: OR=1.6, 95% CI=1.0-2.5, Ptrend=0.02), that was largely due to the effect in men (Ptrend=0.03). These results do not support a strong role for vitamin D intake with NHL risk with the exception of a potential association for DLBCL risk in men. Our results should be interpreted conservatively until further investigation in larger pooled studies can be conducted to better assess the role of vitamin D intake in lymphomagenesis.
PMCID: PMC3403694  PMID: 22697504
lymphoma, non-Hodgkin; case-control studies; vitamin D; vitamin A; calcium

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