Dominik D. Alexander

The non‐Hodgkin lymphomas: A review of the epidemiologic literature

The non‐Hodgkin lymphomas (NHL) are a heterogeneous group of B‐cell and T‐cell neoplasms that arise primarily in the lymph nodes. NHL incidence rates in the US doubled between about 1970 and 1990, and stabilized during the 1990s. NHL accounts for ∼3.4% of cancer deaths in the US. Although some of the observed patterns in NHL have been related to HIV/AIDS, these conditions cannot fully explain the magnitude of the changes; neither do changes in classification systems nor improved diagnostic capabilities. Studies of occupational and environmental exposures (e.g., pesticides, solvents) have produced no consistent pattern of significant positive associations. Inverse associations with ultraviolet radiation exposure and alcohol and fish intake, and positive associations with meat and saturated fat intake have been reported in several studies; additional studies are needed to confirm or refute these associations. Family history of NHL or other hematolymphoproliferative cancers and personal history of several autoimmune disorders are associated with increased risk of NHL, but are not likely to account for a large proportion of cases. HIV and other infectious agents, such as human herpesvirus 8 and Epstein–Barr, appear to be associated with differing types of NHL, such as some B‐cell lymphomas. Future epidemiologic studies should evaluate associations by NHL type, enhance exposure information collected, and elucidate factors that may identify susceptible (or resistant) subpopulations because of genetic, immunologic or other characteristics. The extent to which the etiology of NHL types may differ is important to resolve in ongoing and future studies.

Multiple myeloma: A review of the epidemiologic literature

Multiple myeloma, a neoplasm of plasma cells, accounts for ∼∼15% of lymphatohematopoietic cancers (LHC) and 2% of all cancers in the US. Incidence rates increase with age, particularly after age 40, and are higher in men, particularly African American men. The etiology is unknown with no established lifestyle, occupational or environmental risk factors. Although several factors have been implicated as potentially etiologic, findings are inconsistent. We reviewed epidemiologic studies that evaluated lifestyle, dietary, occupational and environmental factors; immune function, family history and genetic factors; and the hypothesized precursor, monoclonal gammopathies of undetermined significance (MGUS). Because multiple myeloma is an uncommon disease, etiologic assessments can be difficult because of small numbers of cases in occupational cohort studies, and few subjects reporting exposure to specific agents in case–control studies. Elevated risks have been reported consistently among persons with a positive family history of LHC. A few studies have reported a relationship between obesity and multiple myeloma, and this may be a promising area of research. Factors underlying higher incidence rates of multiple myeloma in African Americans are not understood. The progression from MGUS to multiple myeloma has been reported in several studies; however, there are no established risk factors for MGUS. To improve our understanding of the causes of multiple myeloma, future research efforts should seek the causes of MGUS. More research is also needed on the genetic factors of multiple myeloma, given the strong familial clustering of the disease.

Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors

Background Hepatic metastases develop in approximately 50% of colorectal cancer (CRC) cases. We performed a review and meta-analysis to evaluate survival after resection of CRC liver metastases (CLMs) and estimated the summary effect for seven prognostic factors. Methods Studies published between 1999 and 2010, indexed on Medline, that reported survival after resection of CLMs, were reviewed. Meta-relative risks for survival by prognostic factor were calculated, stratified by study size and annual clinic volume. Cumulative meta-analysis results by annual clinic volume were plotted. Results Five- and 10-year survival ranged from 16% to 74% (median 38%) and 9% to 69% (median 26%), respectively, based on 60 studies. The overall summary median survival time was 3.6 (range: 1.7–7.3) years. Meta-relative risks (95% confidence intervals) by prognostic factor were: node positive primary, 1.6 (1.5–1.7); carcinoembryonic antigen level, 1.9 (1.1–3.2); extrahepatic disease, 1.9 (1.5–2.4); poor tumor grade, 1.9 (1.3–2.7); positive margin, 2.0 (1.7–2.5); >1 liver metastases, 1.6 (1.4–1.8); and >3 cm tumor diameter, 1.5 (1.3–1.8). Cumulative meta-analyses by annual clinic volume suggested improved survival with increasing volume. Conclusion The overall median survival following CLM liver resection was 3.6 years. All seven investigated prognostic factors showed a modest but significant predictive relationship with survival, and certain prognostic factors may prove useful in determining optimal therapeutic options. Due to the increasing complexity of surgical interventions for CLM and the inclusion of patients with higher disease burdens, future studies should consider the potential for selection and referral bias on survival.

Ingested nitrate and nitrite and stomach cancer risk: An updated review

Nitrite and nitrate are naturally occurring molecules in vegetables and also added to cured and processed meats to delay spoilage and pathogenic bacteria growth. Research over the past 15 years has led to a paradigm change in our ideas about health effects of both nitrite and nitrate. Whereas, historically nitrite and nitrate were considered harmful food additives and listed as probable human carcinogens under conditions where endogenous nitrosation could take place, they are now considered by some as indispensible nutrients essential for cardiovascular health by promoting nitric oxide (NO) production. We provide an update to the literature and knowledge base concerning their safety. Most nitrite and nitrate exposure comes from naturally occurring and endogenous sources and part of the cell signaling effects of NO involve nitrosation. Nitrosation must now be considered broadly in terms of both S- and N-nitrosated species, since S-nitrosation is kinetically favored. Protein S-nitrosation is a significant part of the role of NO in cellular signal transduction and is involved in critical aspects of cardiovascular health. A critical review of the animal toxicology literature of nitrite indicates that in the absence of co-administration of a carcinogenic nitrosamine precursor, there is no evidence for carcinogenesis. Newly published prospective epidemiological cohort studies indicate that there is no association between estimated intake of nitrite and nitrate in the diet and stomach cancer. This new and growing body of evidence calls for a reconsideration of nitrite and nitrate safety.

Long-Chain Omega-3 Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid and Blood Pressure: A Meta-Analysis of Randomized Controlled Trials

BACKGROUND Although a large body of literature has been devoted to examining the relationship between eicosapentaenoic and docosahexaenoic acids (EPA+DHA) and blood pressure, past systematic reviews have been hampered by narrow inclusion criteria and a limited scope of analytical subgroups. In addition, no meta-analysis to date has captured the substantial volume of randomized controlled trials (RCTs) published in the past 2 years. The objective of this meta-analysis was to examine the effect of EPA+DHA, without upper dose limits and including food sources, on blood pressure in RCTs. METHODS Random-effects meta-analyses were used to generate weighted group mean differences and 95% confidence intervals (CIs) between the EPA+DHA group and the placebo group. Analyses were conducted for subgroups defined by key subject or study characteristics. RESULTS Seventy RCTs were included. Compared with placebo, EPA+DHA provision reduced systolic blood pressure (−1.52mm Hg; 95% confidence interval (CI) = −2.25 to −0.79) and diastolic blood pressure (−0.99mm Hg; 95% CI = −1.54 to −0.44) in the meta-analyses of all studies combined. The strongest effects of EPA+DHA were observed among untreated hypertensive subjects (systolic blood pressure = −4.51mm Hg, 95% CI = −6.12 to −2.83; diastolic blood pressure = −3.05mm Hg, 95% CI = −4.35 to −1.74), although blood pressure also was lowered among normotensive subjects (systolic blood pressure = −1.25mm Hg, 95% CI = −2.05 to −0.46; diastolic blood pressure = −0.62mm Hg, 95% CI = −1.22 to −0.02). CONCLUSIONS Overall, available evidence from RCTs indicates that provision of EPA+DHA reduces systolic blood pressure, while provision of ≥2 grams reduces diastolic blood pressure.

META-ANALYSIS OF PROSPECTIVE STUDIES OF RED MEAT CONSUMPTION AND COLORECTAL CANCER

The relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. To estimate the summary association between red meat intake and CRC and to examine sources of heterogeneity, a meta-analysis of prospective studies was conducted. Thirty-four prospective studies of red meat and CRC were identified, of which 25 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose–response relationships were calculated. In the high versus low intake meta-analysis, the SRRE was 1.12 (95% CI: 1.04–1.21) with significant heterogeneity (P=0.014). Summary associations were modified by tumor site and sex. The SRREs for colon cancer and rectal cancer were 1.11 (95% CI: 1.03–1.19) and 1.19 (95% CI: 0.97–1.46), respectively. The SRREs among men and women were 1.21 (95% CI: 1.04–1.42) and 1.01 (95% CI: 0.87–1.17), respectively. The available epidemiologic data are not sufficient to support an independent and unequivocal positive association between red meat intake and CRC. This conclusion is based on summary associations that are weak in magnitude, heterogeneity across studies, inconsistent patterns of associations across the subgroup analyses, and the likely influence of confounding by other dietary and lifestyle factors.

Meta-analysis of animal fat or animal protein intake and colorectal cancer

BACKGROUND In the recent World Cancer Research Fund/American Institute for Cancer Research report of diet and cancer, it was concluded that there is limited but suggestive evidence that animal fat intake increases the risk of colorectal cancer. OBJECTIVE To clarify this potential relation, we conducted meta-analyses across a variety of subgroups, incorporating data from additional studies. DESIGN Analyses of high compared with low animal fat intakes and categorical dose-response evaluations were conducted. Subgroup analyses, consisting of evaluations by study design, sex, and tumor site were also performed. RESULTS Six prospective cohort studies with comprehensive dietary assessments, contributing 1070 cases of colorectal cancer and approximately 1.5 million person-years of follow-up, were identified. The summary relative risk estimate (SRRE) for these studies was 1.04 (95% CI: 0.83, 1.31; P for heterogeneity = 0.221) on the basis of high compared with low intakes. When data from case-control studies were combined with the cohort data, the resulting SRRE was 1.15 (95% CI: 0.93, 1.42) with increased variability (P for heterogeneity = 0.015). In our dose-response analysis of the cohort studies, no association between a 20-g/d increment in animal fat intake and colorectal cancer was observed (SRRE: 1.02; 95% CI: 0.95, 1.09). In a separate analysis of 3 prospective cohort studies that reported data for animal protein or meat protein, no significant association with colorectal cancer was observed (SRRE: 0.90; 95% CI: 0.70, 1.15). CONCLUSION On the basis of the results of this quantitative assessment, the available epidemiologic evidence does not appear to support an independent association between animal fat intake or animal protein intake and colorectal cancer.

Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis.

Although exposure to high levels of arsenic in drinking water is associated with excess cancer risk (e.g., skin, bladder, and lung), lower exposures (e.g., <100-200 microg/L) generally are not. Lack of significant associations at lower exposures may be attributed to methodologic issues (e.g., inadequate statistical power, exposure misclassification), or to differences in the dose-response relationship at high versus low exposures. The objectives of this review and meta-analysis were to evaluate associations, examine heterogeneity across studies, address study design and sample size issues, and improve the precision of estimates. Eight studies of bladder cancer and low-level arsenic exposure met our inclusion criteria. Meta-analyses of never smokers produced summary relative risk estimates (SRREs) below 1.0 (highest versus lowest exposure). The SRRE for never and ever smokers combined was elevated slightly, but not significantly (1.11; 95% CI: 0.95-1.30). The SRRE was somewhat elevated among ever smokers (1.24; 95% CI: 0.99-1.56), and statistical significance was observed in some subgroup analyses; however, heterogeneity across studies was commonly present. Although uncertainties remain, low-level arsenic exposure alone did not appear to be a significant independent risk factor for bladder cancer. More studies with detailed smoking history will help resolve whether smoking is an effect modifier.

A REVIEW AND META-ANALYSIS OF PROSPECTIVE STUDIES OF RED AND PROCESSED MEAT INTAKE AND PROSTATE CANCER

Over the past decade, several large epidemiologic investigations of meat intake and prostate cancer have been published. Therefore, a meta-analysis of prospective studies was conducted to estimate potential associations between red or processed meat intake and prostate cancer. Fifteen studies of red meat and 11 studies of processed meat were included in the analyses. High vs. low intake and dose-response analyses were conducted using random effects models to generate summary relative risk estimates (SRRE). No association between high vs. low red meat consumption (SRRE = 1.00, 95% CI: 0.96-1.05) or each 100 g increment of red meat (SRRE = 1.00, 95% CI: 0.95-1.05) and total prostate cancer was observed. Similarly, no association with red meat was observed for advanced prostate cancer (SRRE = 1.01, 95% CI: 0.94-1.09). A weakly elevated summary association between processed meat and total prostate cancer was found (SRRE = 1.05, 95% CI: 0.99-1.12), although heterogeneity was present, the association was attenuated in a sub-group analysis of studies that adjusted for multiple potential confounding factors, and publication bias likely affected the summary effect. In conclusion, the results of this meta-analysis are not supportive of an independent positive association between red or processed meat intake and prostate cancer.

Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies.

A tremendous amount of scientific interest has been generated regarding processed meat consumption and cancer risk. Therefore, to estimate the association between processed meat intake and colorectal cancer (CRC), a meta-analysis of prospective studies was conducted. Twenty-eight prospective studies of processed meat and CRC were identified, of which 20 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose–response relationships were calculated. The SRRE for high (vs. low) processed meat intake and CRC was 1.16 [95% confidence interval (CI): 1.10–1.23] for all studies. Summary associations were modified considerably by sex; the SRRE for men was 1.23 (95% CI: 1.07–1.42) and the SRRE for women was 1.05 (95% CI: 0.94–1.16), based on nine and 13 studies, respectively. Sensitivity analyses did not indicate appreciable statistical variation by tumor site, processed meat groups, or study location. The SRRE for each 30-gram increment of processed meat and CRC was 1.10 (95% CI: 1.05–1.15) based on nine studies, and the SRRE for each incremental serving of processed meat per week was 1.03 (95% CI: 1.01–1.05) based on six studies. Overall, summary associations were weak in magnitude (i.e. most less than 1.20), processed meat definitions and analytical comparisons were highly variable across studies, and isolating the independent effects of processed meat intake is difficult, given the likely influence of confounding by other dietary and lifestyle factors. Therefore, the currently available epidemiologic evidence is not sufficient to support a clear and unequivocal independent positive association between processed meat consumption and CRC.