Nobuyuki Hamajima

Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, womens age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19–1.45, P<0.00001) for an intake of 35–44 g per day alcohol, and 1.46 (1.33–1.61, P<0.00001) for ⩾45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5–8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98–1.07, and for current smokers=0.99, 0.92–1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, womens age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19–1.45, P<0.00001) for an intake of 35–44 g per day alcohol, and 1.46 (1.33–1.61, P<0.00001) for ⩾45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5–8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98–1.07, and for current smokers=0.99, 0.92–1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia.

Background. Although colony-stimulating factors have been shown to accelerate recovery from severe neutropenia after intensive chemotherapy or bone marrow transplantation, their use in acute leukemia has been controversial because in vitro they stimulate leukemic colonies as well as normal granulocyte colonies. Methods. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of recombinant human granulocyte colony-stimulating factor (CSF) after a standard course of intensive therapy in 108 patients with relapsed or refractory acute leukemia (67 with acute myelogenous leukemia, 30 with acute lymphocytic leukemia, 9 in blast crisis from chronic myelogenous leukemia, and 2 with acute leukemia arising from myelodysplastic syndromes). Treatment with granulocyte CSF (200 micrograms per square meter of body-surface area per day in a 30-minute infusion) was begun two days after the end of the chemotherapy and continued until the neutrophil count rose above 1500 per cubic millimeter. Results. Treatment with granulocyte CSF accelerated the recovery of neutrophils significantly (P less than 0.01), shortening it by about a week, but it had no effect on platelet recovery. Although the incidence of febrile episodes was almost the same, documented infections were significantly less frequent in the group treated with granulocyte CSF (P = 0.028). There was no evidence that granulocyte CSF accelerated the regrowth of leukemic cells. Fifty percent of 48 patients in the CSF group who could be evaluated and 36 percent of 50 controls had complete remission. The rate of relapse was almost the same in the two groups. Conclusions. It appears that recombinant human granulocyte CSF is safe in acute leukemia, accelerating neutrophil recovery and thereby reducing the incidence of documented infection without affecting the regrowth of leukemic cells. It should be used with caution, however, pending further confirmation of these early results.

A Large-scale, Hospital-based Case-Control Study of Risk Factors of Breast Cancer According to Menopausal Status

We conducted a large‐scale, hospital‐based case‐control study to evaluate differences and similarities in the risk factors of female breast cancer according to menopausal status. This study is based on a questionnaire survey on life style routinely obtained from outpatients who first visited the Aichi Cancer Center Hospital between January 1, 1988 and December 31, 1992. Among 36,944 outpatients, 1,186 women with breast cancer detected by histological examination were taken as the case group (607 premenopausal women and 445 postmenopausal women) and 23,163 women confirmed to be free of cancer were selected as the control group. New findings and reconfirmed factors of breast cancer were as follows. 1) The risk of at least one breast cancer history among subjects’ first‐degree relatives was relatively high among pre‐ as well as post‐menopausal women. 2) A protective effect of physical activity against breast cancer was observed among both pre‐ and post‐menopausal women. 3) Dietary control decreased the risk of premenopausal breast cancer. 4) Current smoking and drinking elevated the risk of breast cancer in premenopausal women. 5) Decreasing trends of breast cancer risk were associated with intake of bean curd, green‐yellow vegetables, potato or sweet potato, chicken and ham or sausage in premenopausal women, while in postmenopausal women a risk reduction was associated with a more frequent intake of boiled, broiled and/or raw fish (sashimi). Further study will be needed to clarify the age group‐ and/or birth cohort‐specific risk factors for breast cancer among the young generation in Japan.

Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population

Dysfunctional genotype combinations of polymorphic adenosine 5′-triphosphate–binding cassette transporter gene ABCG2/BCRP, which encodes a high-capacity urate secretion transporter in human gut and kidney, are major causes of gout. Gout, the “Disease of Kings” as it is often known, is a painful medical condition characterized by sharp acute pain in bone joints, due to the high deposition of uric acid crystals from the blood serum into the surrounding cartilage. It affects approximately 1% of the U.S. population and remains a significant public health concern. The prevalence of gout is much higher in certain Asian ethnic groups, and is also reportedly rising in African Americans. Current medical treatments are aimed at ameliorating pain severity, but as the underlying genetic etiology of the disease unfolds, new targets for future therapies are likely to be found. Although genome-wide association studies (GWAS) have enabled the calculation of risk predispositions for a wide variety of complex diseases, the relation of gene function to the causality of disease-related mutations has remained largely unclear. A recent U.S. population–based study supported an association between urate levels and gout in individuals carrying variants in a multifunctional transporter gene, ABCG2. This study identified Q141K as a high-risk variant in nearly 10% of gout cases in Caucasians. Now, a team led by Hirotaka Matsuo report that in a Japanese population, another risk variant in ABCG2, namely the Q126X nonfunctional mutation, confers an even higher risk associated with an increase in uric acid deposition in the blood and may cause gout in Asians. Because this gene is responsible for giving rise to a protein that transports harmful waste products and metabolites out of the kidney and gut, they extensively validate the biological activity of ABCG2 using functional assays in vitro that effectively recapitulate human data obtained from Japanese individuals afflicted with the disease. These findings lend weight to previously reported GWAS; moreover, these newly identified specific high-risk variants that block urate secretion may serve as potential intervention points for quelling the disease. Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.

Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan

Objectives: The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. Methods: A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. Results: The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). Conclusions: The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity.

Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan

Experimental studies suggest various features of anticancer activity of green tea including inhibitory effect of tumor invasion and metastasis. This study was conducted to examine the association between regular green tea consumption prior to diagnosis and subsequent risk of breast cancer recurrence. The Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) was started in 1988, in which information on lifestyle has routinely been collected from all first-visit outpatients by questionnaire. A total of 1160 new surgical cases of female invasive breast cancers with HERPACC information diagnosed between June 1990 and August 1998 were followed up through December 1999, and the risk (hazard ratio: HR) of recurrence was assessed with reference to daily green tea consumption using a Cox proportional hazard model. During 5264 person-years of follow-up, 133 subjects (12%) were documented to suffer recurrence of breast cancer. A decreased HR for recurrence adjusted for stage was observed with consumption of three or more daily cups of green tea (HR=0.69, 95% confidence interval (95%CI)=0.47-1.00). Particularly in stage I, the HR was decreased statistically significantly (HR=0.43, 95%CI=0.22-0.84). A similar tendency was observed for stage II subjects, but was not present among more advanced stages. Although careful interpretation is needed, these results suggest the possibility that regular green tea consumption may be preventive against recurrence of breast cancer in early stage cases.

Interleukin 1 Polymorphisms, Lifestyle Factors, and Helicobacter pylori Infection

Associations between Helicobacter pylori (HP) infection and lifestyle factors have been reported by several authors, but little is known about the host factors associated with the infection. This study aims to examine the infection rate of HP according to gene polymorphisms of interleukin (TL)‐IA, IL‐1B, and IL‐1RN, and to investigate the interactions with lifestyle factors. Subjects were 241 non‐cancer outpatients who had participated in a HP eradication program. Polymorphisms at ‐889 (T to C) of IL‐1A, at ‐31 (C to T; T allele makes a TATA box) and ‐511 (C to T) of IL‐1B, and at intron 2 (86‐bp VNTR (variable number of tandem repeats)) of IL‐1RN were genotyped by PCR (polymerase chain reaction), PCR‐RFLP (restriction fragment length polymorphism) and PCR‐CTPP (PCR with confronting two‐pair primers). It was found that IL‐1B polymorphisms at ‐31 and ‐511 were near‐completely linked, but in the opposite way to that in Caucasians; ‐31C/ ‐511T and ‐31T/‐511C alleles were dominant in the present subjects. The HP infection rate was substantially different among the genotypes of IL‐1B C‐31T; 45.2% (19/42) for the C/C, 67.7% (90/133) for the C/T, and 63.6% (42/66) for the T/T. The age‐sex adjusted odds ratio (OR) relative to the C/C genotype was 2.32 (95%CI (confidence interval), 1.10‐4.92) for the T/C genotype and 2.46 (1.06‐5.74) for the T/T genotype. The OR for the T/T genotype was significantly modified by smoking status; interaction term=14.6 (1.12‐190). The polymorphisms of IL‐1A and IL‐1RN were not associated with the infection rate. The results suggested that the T allele of IL‐1B C‐31T is associated with vulnerability to persistent HP infection, and that the vulnerability is modified by smoking.

Epidemiological features of first-visit outpatients in Japan: Comparison with general population and variation by sex, age, and season

To evaluate the methodological issues in using first-visit outpatients as controls in epidemiological studies, the features of general lifestyles of non-cancer outpatients at Aichi Cancer Center Hospital (ACCH) were compared with those of the general population, and their variation by sex, age, and season was determined by using a self-administered questionnaire. The study included 1231 subjects randomly selected from the Nagoya electoral roll (CRG), and three groups of non-cancer ACCH outpatients living in Nagoya; 800 from the period September to December 1992 (OPG1), 2326 from January to December 1992 (OPG2), and 12,243 from January 1991 to December 1992 (OPG3). In the younger age group, the proportion of current smokers was higher in the CRG than in the OPGs. In the older age groups, the proportion of those who consumed fresh vegetables and fruit everyday was higher in the OPGs than in the CRG. For other items, the features of the OPGs were not significantly different from those of the CRG. Among the OPG3, there were differences in the features of general lifestyles between sexes and consumption of several food items varied with age. Seasonal variation, however, was only observed in the specific food items where supply varied seasonally. It was concluded that, with due consideration of age, sex, and season in the analysis, it is feasible to use non-cancer outpatients as controls in epidemiological studies.

Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver

BACKGROUND In many industrialized countries, non-alcoholic fatty liver disease (NAFLD) is recognized as an important disease that increases the risk of cardiovascular disease, type-2 diabetes, and metabolic syndrome. Most people with NAFLD are asymptomatic, and the disease is discovered incidentally during clinical laboratory tests. Present screening methods for NAFLD use ultrasound, and CT scans that are time-consuming, and a simple screening method for NAFLD is needed. In this study, we investigated whether serum miRNAs are associated with NAFLD and assessed the potential of serum miRNAs as a biomarker for NAFLD. METHODS We assessed intrahepatic fat by ultrasound scan, and the serum levels of five miRNAs (miR-21, miR-34a, miR-122, miR-145, and miR-451), which help regulate cholesterol and fatty acid homeostasis in liver tissue, by real-time PCR in a cross-sectional sample of 403 participants who attended health examinations. RESULTS Serum levels of miRNAs, miR-21, miR-34a, miR-122, and miR-451 were higher in participants with NAFLD. The serum level of miR-122 was correlated with the severity of liver steatosis. CONCLUSION Serum levels of miRNAs, particularly miR-122, may be a useful biomarker for NAFLD.

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese.

AbstractMethods. The cases were 102 patients with esophageal cancer, 143 with stomach cancer, 74 with colon cancer, 72 with rectal cancer, 192 with lung cancer, 237 with breast cancer, 56 with prostate cancer, and 108 with malignant lymphoma. Controls consisted of outpatients from two sources: 241 noncancer outpatients who underwent gastroscopy and 399 first-visit outpatients, expected to include about 20% with cancer. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Results. The TT genotype with null enzyme activity was found in 19.9% of the 241 noncancer gastroscopy examinees, 16.5% of the 399 first-visit outpatients, 12.7% of the esophageal cancer patients, 16.8% of the stomach cancer patients, 13.5% of the colon cancer patients, 9.7% of the rectal cancer patients, 17.7% of the lung cancer patients, 14.3% of the breast cancer patients, 16.1% of the prostate cancer patients, and 15.7% of the malignant lymphoma patients. The odds ratios (ORs) of the genotypes were not significant for any cancers combined or for any site of cancer, except for lung cancer (OR, 0.66; 95% confidence interval [CI], 0.46–0.96 for CT relative to CC). The OR of current smoking for cancers of the esophagus and lung combined was different between the CC genotype (OR, 2.06; 95% CI, 1.06–3.98) and TT genotype (OR, 5.11; 95% CI, 1.37–19.05), although the difference was not significant. Conclusion. This study suggests that the CC genotype of the NQO1 C609T polymorphism is associated with the risk of lung cancer, and that the TT genotype increases the risk of smoking for cancers of the esophagus and lung.