Wine Drinking and Risk of Non-Hodgkin’s Lymphoma among Men in the United States: A Population-based Case-Control Study

Nathaniel C. Briggs1, Robert S. Levine1, Linda D. Bobo2, William P. Haliburton3, Edward A. Brann4 and Charles H. Hennekens5

1 Division of Preventive Medicine, Department of Internal Medicine, Meharry Medical College, Nashville, TN.
2 Uniformed Services University of the Health Sciences, Bethesda, MD.
3 Center for Mental Health Policy, Vanderbilt University, Nashville, TN.
4 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.
5 Departments of Medicine and Epidemiology and Public Health, University of Miami School of Medicine and Mount Sinai Medical Center–Miami Heart Institute, Miami, FL.

Received for publication November 14, 2002; accepted for publication May 7, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relation between wine consumption and non-Hodgkin’s lymphoma (NHL) was investigated using data from the Selected Cancers Study. Cases (n = 960) were men aged 32–60 years diagnosed with NHL from 1984 to 1988 and identified from eight US population-based cancer registries. Controls (n = 1,717) were men recruited by random digit dialing and frequency matched to cases by age and registry. Logistic regression was used to calculate odds ratios and 95% confidence intervals adjusted for age, registry, race/ethnicity, education, and smoking. Odds ratios for men who consumed less than one and those who consumed one or more wine drinks per day were 0.8 (95% confidence interval: 0.5, 1.3) and 0.4 (95% confidence interval: 0.2, 0.9) compared with nondrinkers, respectively (p for trend = 0.02). Among wine drinkers who consumed alcohol beverages from ages 16 years or less, odds ratios for intakes of less than one and one or more wine drinks per day were 0.4 (95% confidence interval: 0.2, 0.97) and 0.3 (95% confidence interval: 0.1, 0.8), respectively (p for trend = 0.004). No associations were evident for beer or spirits. These data show that consumption of wine, but not of beer or spirits, is associated with a reduced NHL risk.

alcohol drinking; alcoholic beverages; epidemiologic factors; lymphoma, non-Hodgkin’s; preventive medicine; public health; risk factors; wine

Abbreviations: Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; NHL, non-Hodgkin’s lymphoma; NLAES, National Longitudinal Alcohol Epidemiologic Survey.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Non-Hodgkin’s lymphoma (NHL) comprises a heterogeneous group of diseases arising from lymphoid tissue (1). Although NHL is the fifth most common cancer in the United States (2), the etiology of most cases remains unexplained, and apart from immunodeficiency states or an occupational exposure to chemicals, risk factors are obscure (3). Given the paucity of established risk factors for NHL, identification of protective factors might provide valuable information. Several reports have described decreased NHL risks for wine drinkers (47). However, findings have been inconclusive due to methodological limitations, including small sample sizes, limited data on dose-response relations, and lack of adjustment for potential confounding from consumption of beer and spirits. In this study, the association between risk of NHL and consumption of wine, beer, and spirits is investigated among men aged 32–60 years by using data from the Selected Cancers Study (8, 9).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Selected Cancers Study was a large case-control study designed to investigate associations between exposure to Agent Orange during US military service in Vietnam and the development of several cancers, including NHL and Hodgkin’s disease. Methods have been described in detail elsewhere (8, 9). Briefly, eligible cases were men born between 1929 and 1953 who were presumptively diagnosed with lymphoma between 1984 and 1988. Cases were identified from eight population-based US cancer registries—five covered US metropolitan areas (Atlanta, Georgia; Miami, Florida; Detroit, Michigan; Seattle, Washington; and San Francisco, California), and three covered US states (Connecticut, Iowa, and Kansas). All registries except those in Miami and Kansas were part of the Surveillance, Epidemiology, and End Results Program. A rapid case-reporting scheme was used to obtain interviews promptly after diagnosis. Controls were identified by random digit dialing (10) and frequency matched to presumptive lymphoma cases by 5-year date-of-birth intervals and within geographic strata corresponding to cancer registries.

Of 2,354 cases with a presumptive diagnosis of NHL, Hodgkin’s disease, or "lymphoma not otherwise specified," 2,073 (88 percent) participated (table 1). For 97 percent of the study participants, microscopic slides or tissue blocks were available for confirmation of the original diagnosis by a panel of three hematopathologists. After independent and blinded review of tissue specimens, a consensus diagnosis was reached for 1,511 NHL cases, 343 Hodgkin’s disease cases, and 14 unclassifiable lymphomas. Confirmed NHL cases were further classified by histologic subtype (table 2) using the Working Formulation (11). Of 15,768 households contacted for screening to select potential controls, 14,328 (91 percent) provided eligibility information, 4,381 of 4,822 households with eligible men provided a name and address, 2,299 men were randomly selected for interview, and 1,910 (83 percent) selected men completed interviews.


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TABLE 1. Selection of non-Hodgkin’s lymphoma cases and controls, Selected Cancers Study, 1984–1988
 

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TABLE 2. Frequency of non-Hodgkin’s lymphoma cases by histologic subtype as classified under the Working Formulation, Selected Cancer Study, 1984–1988
 
For this analysis, the study population was restricted to living cases and controls (12) with no history of acquired immunodeficiency virus (AIDS) or major AIDS risk factors (injecting drug use, bisexual/homosexual orientation), for whom interviewers rated interview quality and interviewee cooperation as good and for whom information on history of alcohol consumption was available. Altogether, 334 of 551 (61 percent) excluded cases had histories of AIDS (n = 290) or a major AIDS risk factor (n = 44). The final study population included 960 NHL cases and 1,717 controls.

Data collection
A standardized questionnaire was used to collect information on sociodemographics, medical history, occupation, and lifestyle, including alcohol beverage consumption and cigarette smoking. Questionnaires were administered by professional interviewers, generally through telephone interviews that required about 50 minutes to complete. In-person interviews were conducted when necessary to secure participation (36 cases and 31 controls). Study participants were classified as drinkers or nondrinkers based on the question, "Did you ever have an average of one drink or more a week for a year or longer?" Drinkers were queried about current and past alcohol use, including average weekly consumption of 12-ounce (360-ml) cans/bottles of beer, 4-ounce (120-ml) glasses of wine, 1-ounce (45-ml) shots of liquor, and age of onset of alcohol beverage consumption.

Statistical analysis
All analyses were performed using SAS software (13). Logistic regression was used to calculate odds ratios and 95 percent confidence intervals. To account for the frequency-matched design, indicator variables for the five age categories and eight cancer registries were used in unconditional models; year of birth within age categories was included as a covariate to adjust for residual confounding. Each model also included indicator variables to adjust for the potential confounders of race/ethnicity (White non-Hispanic, Black non-Hispanic, Hispanic, other), cigarette smoking (ever smoked vs. never smoked), and education (high school or less vs. more than high school). In models for each type of alcohol beverage (wine, beer, spirits), the other two types were included as covariates.

Analyses were performed with stratification for current versus past alcohol consumption (<=2 vs. >=3 years before interview date) and for type of alcohol beverage (wine, beer, or spirits) stratified by quantity and preference. Categories for quantity of wine intake were nondrinker (lifetime abstainers plus occasional drinkers of less than one drink per week), one to six drinks per week, and one drink or more per day. For beer and spirits, two categories, one to two and three drinks or more per day, were used in lieu of one drink or more per day. Tests for linear trend were performed by using each category as an ordinal variable in the logistic regression models; p values were based on the Wald test. A beverage preference was assigned if the percentage of weekly alcohol consumption for one beverage was greater than for any other after adjustment for differences in alcohol content using National Longitudinal Alcohol Epidemiologic Survey (NLAES) conversion guidelines (14). Ages of onset of drinking were grouped by using NLAES age categories (<=16, 17–18, 19–20, and >=21 years) (14). After preliminary analysis suggested decreased NHL risks for consumption of one or more wine drinks per day and for ages of onset of drinking of 16 years or less, risks were investigated for drinkers stratified by history of wine consumption (wine vs. nonwine drinkers) and age of onset of alcohol beverage consumption (<=16 vs. >=17 years).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In table 3, exposure proportions among cases and controls are shown for the matching variables of cancer registry and age by 5-year birth date intervals and for race/ethnicity, education, and cigarette smoking. NHL cases were slightly older than controls (mean, 2 years) because controls were frequency matched on age to the group of all men with a presumptive lymphoma diagnosis, which included a comparatively younger subgroup of men with Hodgkin’s disease. Men with NHL were more likely to be White than were controls, which is consistent with the greater incidence of NHL among White men compared with Black, Hispanic, and Asian men (15). Compared with controls, men with NHL also tended to have a somewhat lower level of educational attainment and were more likely to have ever smoked cigarettes.


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TABLE 3. Demographic and lifestyle characteristics of non-Hodgkin’s lymphoma cases and controls, Selected Cancers Study, 1984–1988
 
The distribution of study participants by history of alcohol consumption is shown in table 4. There were 1,867 (70 percent) drinkers and 810 (30 percent) nondrinkers. The overall proportion of drinkers was comparable for the case (69 percent) and control (70 percent) groups. Wine was consumed by 34 percent of the cases and 39 percent of the controls, beer by 81 percent of the cases and 79 percent of the controls, and spirits by 60 percent of the cases and 58 percent of the controls.


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TABLE 4. Distribution of non-Hodgkin’s lymphoma cases and controls by type of alcohol beverage consumption, Selected Cancers Study, 1984–1988
 
The adjusted risk of NHL for all drinkers was slightly less than that for nondrinkers (table 5), with similar risks for current and former drinkers. Among wine drinkers, there was a significant linear decrease in risk of NHL with increasing quantity of wine intake. A more than twofold decrease in risk was seen for consumption of one wine drink or more per day. There was also a significant linear decrease in NHL risk for wine drinkers who preferred wine to beer or spirits (table 6), but not for wine drinkers without a preference for wine. No associations were evident for consumption of beer or spirits.


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TABLE 5. Adjusted odds ratios and 95% confidence intervals for risk of developing non-Hodgkin’s lymphoma by type, quantity, and age of onset of alcohol beverage consumption, Selected Cancers Study, 1984–1988
 

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TABLE 6. Adjusted odds ratios and 95% confidence intervals for risk of developing non-Hodgkin’s lymphoma by alcohol beverage preference*, Selected Cancers Study, 1984–1988
 
An age of onset of drinking of 16 years or less was associated with a significantly decreased risk of NHL, but no associations were evident for older ages of onset (table 5). Stratification by type of alcohol beverages consumed revealed that this association was specific for wine drinkers (table 7). Among wine drinkers with an age of onset of drinking of 16 years or less, there was a significant linear decrease in risk of NHL with increasing quantity of wine intake. A more than threefold reduction in NHL risk was associated with consumption of one wine drink or more per day. Among wine drinkers with an age of onset of drinking of 17 years or more, there was a linear decrease in NHL risk of borderline significance and a nonsignificant decrease in risk with daily consumption of one or more wine drinks.


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TABLE 7. Adjusted odds ratios and 95% confidence intervals for risk of developing non-Hodgkin’s lymphoma among drinkers by type and quantity of alcohol beverage consumption stratified by age of onset of drinking, Selected Cancers Study, 1984–1988
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Wine consumption was associated with a decreased risk of NHL, but no associations were evident for beer or spirits. The reduction in risk for wine drinkers was linearly associated with increasing wine intake, achieving significance with an average consumption of one or more wine drinks per day. This trend was quite strong for wine drinkers who regularly consumed alcohol from ages 16 years or less, but relatively modest for wine drinkers who began drinking at age 17 years or more.

Limited support for a decreased risk of NHL with wine consumption is provided by data from several previous reports (47). In a prospective study of women (4), significantly decreased NHL risks were associated with monthly consumption of more than two drinks of red wine and white wine, respectively, but not for two or fewer drinks monthly of either wine type. In contrast, no significant associations were found for consumption of beer or spirits. However, sample sizes were very small, and the range of intake quantities was limited. In a population-based case-control study of homosexual men (6), a significant linear decrease in NHL risk with increasing tertiles of lifetime alcohol consumption was reported for human immunodeficiency virus (HIV)-negative men who drank wine, while no significant associations were seen for those who drank other alcohol beverages. However, risks were not adjusted for lifetime consumption of beer or spirits, and no data were shown for NHL risks stratified by the percentage of lifetime alcohol intake from wine relative to alcohol intake from beer and spirits or for HIV-positive homosexual men who drank wine. In a population-based case-control study of HIV-negative men and women (7), nonsignificant decreases in NHL risk were reported for consumption of wine and spirits among both sexes. Men who drank beer had an increased risk of NHL, and women who drank beer had a risk close to unity. In analyses for each subgroup of drinkers, no adjustments were made for confounding due to consumption of other alcohol beverages or for bias that could have arisen from matching on age, race/ethnicity, language of interview, and neighborhood of residence of cases. For unexplained reasons, the case population was limited to cases with high- or intermediate-grade NHL. Data from a hospital-based case-control study in Uruguay (5) revealed a nonsignificant linear decrease in NHL risk with increasing daily ethanol intake among men who drank wine, after adjustment for several confounders, including consumption of beer and spirits, age, smoking, and region of residence. In contrast, for the highest daily ethanol intake level (>60 ml of ethanol per day), at which the greatest decrease in NHL risk was evident for wine drinkers, there was a significant increase in the adjusted risk of NHL among beer drinkers and a nonsignificantly increased adjusted risk among drinkers of spirits. The authors did not report data for women because only 5 percent were drinkers.

Decreases in cancer-specific mortality attributable to wine have also been reported for lung cancer (16) and for upper digestive tract cancers (17). Although the evidence that wine drinking affects carcinogenesis independently of nonspecific effects for alcohol has been considered inconclusive (18), an increasing amount of data from observational studies indicates that wine consumption may be associated with decreases in all-cause cancer mortality not seen for beer or spirits (1921).

Our finding that wine drinkers who consumed alcohol from ages 16 years or less had a much greater reduction in NHL risk than did wine drinkers who started drinking at later ages is novel. However, biologic plausibility for such an anticarcinogenic effect is enhanced by reports that resveratrol, a phytoestrogen produced by grapes and a natural ingredient in wine, can inhibit the initiation as well as the promotion and progression of cancer (22). Accordingly, an increased protective effect from wine consumption at an early age could be due to resveratrol-associated inhibitory effects on initiation that are additive with inhibitory effects on promotion and progression at a later age. If the association is real, nontoxic NHL prevention strategies, such as resveratrol-enriched table grapes or grape jelly (23), are conceivable.

Resveratrol has been reported to have anticarcinogenic effects on human lymphoma cells (25) and human leukemia cells (22). It is noteworthy that one mechanism by which resveratrol appears to inhibit carcinogenesis involves a modulatory effect on the lymphomagenic antiapoptosis protein BCL–2 (25). The two most common subtypes of NHL, follicular and diffuse, are both associated with a t(14;18) chromosomal translocation that leads to overexpression of the BCL–2 proto-oncogene and increased levels of the BCL–2 protein (26). Increased levels of the BCL–2 protein may induce progression of follicular NHL to diffuse NHL and other more aggressive subtypes (27), a transformation that occurs in 50 percent of follicular NHL cases. Other NHL subtypes have also been associated with BCL–2 dysregulation, including small noncleaved cell lymphoma (26), small lymphocytic lymphoma (28), and mantle zone lymphoma (28). Therefore, if wine is protective for NHL due to modulation of the BCL–2 protein by resveratrol, the effect may be relatively nonspecific. Nevertheless, given the marked heterogeneity of NHL, such an effect might not be generalizable to all subtypes.

Limitations on sample size precluded a meaningful analysis of NHL subtype-specific associations relative to the significant linear decrease in overall NHL risk seen with an increasing quantity of daily wine intake among men who began drinking at an early age. However, among men who consumed alcohol beverages starting at ages 16 years or less and who regularly drank wine in any quantity, risks were decreased more than twofold for the follicular, diffuse, and small lymphocytic NHL subtypes, as classified by the Working Formulation (11), although only the decrease for diffuse NHL was significant (data not shown). This is consistent with prospective data from the Iowa Women’s Health Study (4), which revealed decreased risks for the follicular, diffuse, and small lymphocytic subtypes of NHL among women who drank wine, although there were very few exposed cases and the associations were nonsignificant.

Salutary effects of wine and other alcohol beverages have also been ascribed to limitations in study design that overlook confounding due to unique risk factors among lifetime abstainers, protective factors specific to occasional drinkers, and a cessation of drinking with declining health (29). The resultant potential for artifactual increases in the number of unhealthy drinkers has raised questions about validity of studies using lifetime abstainers as a reference group or combining former drinkers with nondrinkers for analysis. Because current and former drinkers were combined for analysis, after initial stratification revealed little difference between these groups, any migration of unhealthy drinkers to the nondrinking category would have decreased the strength of association for wine in relation to decreased risk for NHL. Protective factors unique to occasional drinkers would also have attenuated the salutary effect observed for wine drinking because occasional drinkers were grouped with nondrinkers for analysis.

Several study limitations must also be considered. First, although our findings could be due to chance, this seems unlikely because of the magnitude, consistency, and significance of the results. Second, residual confounding may have occurred in relation to factors such as dietary intake, ethnicity, and various measures of socioeconomic status that could not be addressed in multivariate analyses due to lack of information. Third, because the study population was restricted to men aged 32–60 years, our findings may not be generalizable to men in other age groups or to women. Fourth, although study participants were asked about consumption of alcohol beverages and age at onset of drinking, specific inquiries were not made with regard to ages at onset of drinking for each type of alcohol beverage. Consequently, apparent beneficial effects for wine may be due to other factors associated with a younger age at onset of drinking, alone or in combination with wine consumption at a later age. Fifth, study participants were queried about average intakes of specific alcohol beverages. Therefore, it was not possible to investigate temporal patterns such as binge drinking, which may have an effect on health that is independent of lifetime alcohol consumption (30). If binging on beer or spirits were more common than binging on wine, protective effects for beer and spirits among nonbingers could have been masked. Sixth, the linear decrease in NHL risk observed for increasing wine consumption cannot be extrapolated to consumption of more than one wine drink per day, as there were too few heavy wine drinkers to investigate risk at higher levels. Last, because no information was obtained about types of wine consumed, type-specific differences in NHL risk could not be assessed. Because red wine has greater concentrations of resveratrol than does white wine (31), a resveratrol-associated anticarcinogenic effect might be attributable largely to red wine.

Despite limitations of this study, the authors believe the most plausible interpretation of the data is a linear decrease in risk for NHL with consumption of wine in quantities of up to one drink per day. The strength of the association, the presence of a dose-response relation, consistent findings from smaller studies, and a biologically plausible mechanism all increase the likelihood of causality.


    ACKNOWLEDGMENTS
 
The authors thank the Centers for Disease Control and Prevention and the Selected Cancers Cooperative Study Group for collecting all of the original data.


    NOTES
 
Reprint requests to Dr. Nathaniel C. Briggs, Division of Preventive Medicine, Department of Internal Medicine, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd., Nashville, TN 37208-3599 (e-mail: nbriggs{at}mmc.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Herrinton LJ. Epidemiology of the revised European-American lymphoma classification subtypes. Epidemiol Rev 1998;20:187–203.[ISI][Medline]
  2. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47.[Abstract/Free Full Text]
  3. Scherr PA, Mueller NE. Non-Hodgkin’s lymphomas. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention. New York, NY: Oxford University Press, 1996:920–45.
  4. Chiu BC, Cerhan JR, Gapstur SM, et al. Alcohol consumption and non-Hodgkin lymphoma in a cohort of older women. Br J Cancer 1999;80:1476–82.[ISI][Medline]
  5. De Stefani E, Fierro L, Barrios E, et al. Tobacco, alcohol, diet and risk of non-Hodgkin’s lymphoma: a case-control study in Uruguay. Leuk Res 1998;22:445–52.[ISI][Medline]
  6. Holly EA, Lele C. Non-Hodgkin’s lymphoma in HIV-positive and HIV-negative homosexual men in the San Francisco Bay Area: allergies, prior medication use, and sexual practices. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:211–22.[ISI][Medline]
  7. Nelson RA, Levine AM, Marks G, et al. Alcohol, tobacco and recreational drug use and the risk of non-Hodgkin’s lymphoma. Br J Cancer 1997;76:1532–7. [ISI][Medline]
  8. Selected Cancers Cooperative Study Group. The association of selected cancers with service in the US military in Vietnam. I. Non-Hodgkin’s lymphoma. Arch Intern Med 1990;150:2473–83.[Abstract]
  9. Centers for Disease Control. The association of selected cancers with service in the U.S. military in Vietnam: final report. Atlanta, GA: US Department of Health and Human Services, 1990.
  10. Lele C, Holly EA, Roseman DS, et al. Comparison of control subjects recruited by random digit dialing and area survey. Am J Epidemiol 1994;140:643–8.[Abstract]
  11. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage: the Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982;49:2112–35.[ISI][Medline]
  12. . Boyle CA, Brann EA. Proxy respondents and the validity of occupational and other exposure data. The Selected Cancers Cooperative Study Group. Am J Epidemiol 1992;136:712–21.[Abstract]
  13. SAS Institute, Inc. SAS/STAT user’s guide. Version 6. Vol 2. 4th ed. Cary, NC: SAS Institute, Inc, 1989.
  14. National Institute on Alcohol Abuse and Alcoholism. Drinking in the United States: main findings from the 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES). US alcohol epidemiologic data reference manual. Vol 6. First ed. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism, 1998.
  15. Horm JW, Devesa SS, Burhansstipanov L. Cancer incidence, mortality, and survival among racial and ethnic minority groups in the United States. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention. New York, NY: Oxford University Press, 1996:192–235.
  16. Prescott E, Gronbaek M, Becker U, et al. Alcohol intake and the risk of lung cancer: influence of type of alcohol beverage. Am J Epidemiol 1999;149:463–70.[Abstract]
  17. Gronbaek M, Becker U, Johansen D, et al. Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. BMJ 1998;317:844–7.[Abstract/Free Full Text]
  18. Sabroe S. Alcohol and cancer. Still no clear evidence to link specific beverages to specific cancers. BMJ 1998;317:827.
  19. Gronbaek M, Becker U, Johansen D, et al. Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med 2000;133:411–19.[Abstract/Free Full Text]
  20. Renaud SC, Gueguen R, Siest G, et al. Wine, beer, and mortality in middle-aged men from eastern France. Arch Intern Med 1999;159:1865–70.[Abstract/Free Full Text]
  21. Tsugane S, Fahey MT, Sasaki S, et al. Alcohol consumption and all-cause and cancer mortality among middle-aged Japanese men: seven-year follow-up of the JPHC Study Cohort I. Am J Epidemiol 1999;150:1201–7.[Abstract]
  22. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;275:218–20.[Abstract/Free Full Text]
  23. Cantos E, Espin JC, Tomas-Barberan FA. Postharvest induction modeling method using UV irradiation pulses for obtaining resveratrol-enriched table grapes: a new "functional" fruit? J Agric Food Chem 2001;49:5052–8.[ISI][Medline]
  24. Park JW, Choi YJ, Jang MA, et al. Chemopreventive agent resveratrol, a natural product derived from grapes, reversibly inhibits progression through S and G2 phases of the cell cycle in U937 cells. Cancer Lett 2001;163:43–9.[ISI][Medline]
  25. Tinhofer I, Bernhard D, Senfter M, et al. Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl–2. FASEB J 2001;15:1613–15.[Abstract/Free Full Text]
  26. Harris NH, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361–92.[Free Full Text]
  27. Matolcsy A, Casali P, Warnke RA, et al. Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl–2 gene. Blood 1996;88:3937–44. [Abstract/Free Full Text]
  28. Zutter M, Hockenbery D, Silverman GA, et al. Immunolocalization of the Bcl–2 protein within hematopoietic neoplasms. Blood 1991;78:1062–8.[Abstract]
  29. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet 1988;2:1267–73.[ISI][Medline]
  30. Kauhanen J, Kaplan GA, Goldberg DE, et al. Beer binging and mortality: results from the Kuopio Ischaemic Heart Disease Risk Factor Study, a prospective population based study. BMJ 1997;315:846–51.[Abstract/Free Full Text]
  31. Sato M, Suzuki Y, Okuda T, et al. Contents of resveratrol, piceid, and their isomersin commercially available wines made from grapes cultivated in Japan. Biosci Biotechnol Biochem 1997;61:1800–5.