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Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users. Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

Summary Background & aims The associations between dietary magnesium intake and stroke and coronary heart disease (CHD) incidences are inconsistent and not established in Asian. We aimed to determine the association between dietary magnesium intake and the risk of stroke and CHD in a Japanese population. Subjects/Methods We studied 85,293 Japanese subjects by questionnaire at baseline (age 45–74 years, without cardiovascular disease or cancer in 1995 and 1998 for Cohorts I and II, respectively). The participants were followed until the end of 2009 and 2010 in Cohorts I and II, respectively. Dietary magnesium intake was estimated from a self-administered 138-item food-frequency questionnaire. Results After 1,305,738 person-years of follow-up, 4110 strokes and 1283 cases of CHD were documented. The multivariable-adjusted hazard ratios (HRs, 95% confidence intervals, 95%CIs) of CHD for the fourth and fifth quintiles of dietary magnesium intake were 0.70 (0.50–0.99) and 0.66 (0.44–0.97) in men (P for trend = 0.036), respectively, and third quintile of dietary magnesium intake was 0.61 (0.39–0.96) in women (P for trend = 0.241), compared with the lowest quintile in men and women. We observed no decreased risks of incident stroke in men or women with higher dietary magnesium intakes. Conclusions Higher dietary magnesium intake was associated with a reduced risk of CHD in Japanese men.

Aims Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. Methods and results The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000–04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50–79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality. The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73–1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55–0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64–0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01–4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07–11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03–1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40–0.99), respectively. Conclusion An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Background and aims Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). However, it is unclear whether increased blood levels of n-3 PUFAs are associated with reduced risk of CHD in the Japanese population. Methods The relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD was examined in a nested case-control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort. Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases (n = 209) comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years. Results Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79 (95% confidence interval [95% CI]: 0.41–1.51, p for trend = 0.51). Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n-3 PUFAs were 0.91 (95% CI: 0.43–1.89, p for trend = 0.90) for myocardial infarction, 0.08 (95% CI: 0.01–0.88, p for trend = 0.04) for sudden cardiac death, 0.89 (95% CI: 0.42–1.89, p for trend = 0.97) for nonfatal coronary events, and 0.12 (95% CI: 0.02–0.75, p for trend = 0.03) for fatal coronary events. Conclusions Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals.

Severe adverse events (SAE) and late hematological malignancies have been reported after PBSC donation. No prospective data on incidence and risk factors have been available for family donors so far. The Japan Society for Hematopoietic Cell Transplantation (JSHCT) introduced therefore in 2000 a mandatory registration system. It defined standards for donor eligibility and asked harvest centers to report any SAE immediately. All donors were examined at day 30 and were to be contacted once each year for a period of 5 years. Acute SAEs within day 30 were reported from 47/3264 donations (1.44%) with 14 events considered as unexpected and severe (0.58%). No donor died within 30 days. Late SAEs were reported from 39/1708 donors (2.3%). The incidence of acute SAEs was significantly higher among donors not matching the JSHCT standards (P=0.0023). Late hematological malignancies in PBSC donors were not different compared with a retrospective cohort of BM donors (N:1/1708 vs N:2/5921; P=0.53). In conclusion, acute and late SAEs do occur in PBSC donors at relatively low frequency but risk factors can be defined.

We examined the association between green tea consumption and mortality due to all causes, cancer, heart disease, cerebrovascular disease, respiratory disease, injuries, and other causes of death in a large-scale population-based cohort study in Japan.We studied 90,914 Japanese (aged between 40 and 69 years) recruited between 1990 and 1994. After 18.7 years of follow-up, 12,874 deaths were reported. The association between green tea consumption and risk of all causes and major causes of mortality was assessed using the Cox proportional hazards regression model with adjustment for potential confounders.Hazard ratios for all-cause mortality among men who consumed green tea compared with those who drank less than 1 cup/day were 0.96 (0.89-1.03) for 1-2 cups/day, 0.88 (0.82-0.95) for 3-4 cups/day, and 0.87 (0.81-0.94) for more than 5 cups/day (P for trend.001). Corresponding hazard ratios for women were 0.90 (0.81-1.00), 0.87 (0.79-0.96), and 0.83 (0.75-0.91; P for trend.001). Green tea was inversely associated with mortality from heart disease in both men and women and mortality from cerebrovascular disease and respiratory disease in men. No association was found between green tea and total cancer mortality.This prospective study suggests that the consumption of green tea may reduce the risk of all-cause mortality and the three leading causes of death in Japan.

To investigate the pharyngeal morphologic features and its pathogenic role on obstructive sleep apnoea syndrome in the elderly population.Prospective controlled, comparative cohort study.Territory referral centre.We enroled 320 consecutive patients with complaints of snoring who visited Nagoya University Hospital from January 2004 to December 2007. We also collected 26 control subjects aged over 60 years from community-dwelling people.We underwent a morphological evaluation, measurement of nasal resistance, assessment of daytime sleepiness and nocturnal polysomnography.Two hundred and ninety-two patients were analysed. The constitution ratio of men, the body mass index and Epworth sleepiness scale were decreased with ageing. Tonsil size was reduced progressively with ageing. Retroglossal space was wider, and soft palate was lower in ≥ 60 year group than in40 year group. Retroglossal space was wide in elderly patients with sleep apnoea compared with control subjects. Tonsil size was not correlated to apnoea/hypopnoea index in ≥ 60 year group unlike the other generations. Modified Mallampati Score and tongue size were significantly but mildly correlated only in ≥ 60 year group. Width of fauces was correlated in all the groups. Multiple regression analysis showed that body mass index, age, gender, tonsil size and width of fauces were independent factors for apnoea/hypopnoea index.Morphologically, the tonsil could play a minor role but the width of fauces could play relatively a major role. Additionally, wide retroglossal space, low positional soft palate and large tongue size may be characteristics for elderly patients of obstructive sleep apnoea syndrome.

Associations between Helicobacter pylori (HP) infection and lifestyle factors have been demonstrated by several studies, but there are very few reports on links with host factors, especially concerning genetic polymorphisms for inhabitants of large city. The present investigation was conducted to determine the HP infection rate with reference to the Interleukin-1 beta gene (IL-1B) polymorphism and assess the interactions with smoking reported for outpatients.The subjects were 468 participants in a health-check-up program of law of health for aged conducted by Nagoya Nishi Health Center. The participants were asked to permit use of their residual blood drawn during a health-check-up program and written informed consent was obtained for gene polymorphism tests. Data on smoking habit were obtained by self-administered questionnaire. The IL-1B C-to-T polymorphism at -31 was genotyped by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) and an anti-HP IgG antibody test was used for detecting HP infection. Differences in values were assessed by a chi 2 test. An unconditional logistic model was applied for estimating odds ratios with the computer program STATA Version 6. This study was approved by the Ethical Committee at Aichi Cancer Center in 2000 before it was commenced (Ethical Committee Approval Number 11-12)The HP infection rate was 52.6% (61/116) for the C/C genotype of IL-1B-31, 48.6% (89/183) for the C/T, and 63.2% (103/163) for T/T; the difference were not statistically significant. However, when non-current smokers were excluded, the rate were 47.8% (11/23), 52.9% (18/34), and 72.7% (16/22), respectively, indicating the T/T genotype to have a higher infection rate. The age-sex-smoking adjusted odds ratio (OR) relative to the C/C genotype were 0.97 (95% confidence interval, 0.59-1.57) for the T/C genotype and 1.73 (1.04-2.87) for the T/T genotype. Among current and former smokers the age-sex adjusted OR were 1.68 (0.50-5.71) for the T/C genotype and 5.29 (1.11-25.1) for the T/T genotype, suggesting a effect of this polymorphism prominent in smokers.An association between the IL-1B-31 polymorphism and persistent HP infection was observed for inhabitants with a smoking habit, indicating that this polymorphism is one genetic trait conferring an increased likelihood of persistent HP infection.

Helicobacter pylori attach to the gastric mucosa with adhesin, which binds to Lewis b (Le(b)) or H type I carbohydrate structures. The Secretor (Se) gene and Lewis (Le) gene are involved in type I Le antigen synthesis. The present study was performed to investigate the possibility that Se and Le gene polymorphisms alter the risk of H. pylori infection. Two hundred thirty-nine participants were genotyped for Se and Le and tested for the presence of anti-H. pylori IgG antibodies. Using the normal gastric mucosa from 60 gastric cancer patients, we assessed immunohistochemically whether type I Le antigen expression depended on the Se and Le genotypes. The H. pylori infection rate was positively associated with the number of Se alleles (se/se group, 45.1%; Se/se group, 64.6%; and Se/Se group, 73.3%) and negatively associated with the number of Le alleles (le/le group, 76.4%; Le/le group, 68.3%; and Le/Le group, 55.6%). When the subjects were classified into three groups [low risk, (se/se, Le/Le) genotype; high risk, (Se/Se, le/le), (Se/Se, Le/le), and (Se/se, le/le) genotypes; moderate risk, other than low- or high-risk group], the odds ratio relative to the low-risk group was 3.30 (95% confidence interval, 1.40-7.78) for the moderate-risk group and 10.33 (95% confidence interval, 3.16-33.8) for the high-risk group. Immunohistochemical analysis supported the finding that Se and Le genotypes affected the expression of H. pylori adhesin ligands. We conclude that Se and Le genotypes affect susceptibility to H. pylori infection.

To determine the impact of family history (FH) on anthropometric and reproductive risk factors for breast cancer, a case-referent study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan.In total, 1584 breast cancer cases were included and 15,331 women, confirmed as free of cancer, were recruited as the referents. Odds ratios and 95% confidence intervals were determined by logistic regression analysis. Separate analyses were performed for premenopausal and postmenopausal women.Height, weight, and current body mass index (BMI) were positively associated with postmenopausal breast cancer regardless of FH, while these anthropometric factors did not alter risk in premenopausal women. The impacts of height and weight on postmenopausal breast cancer were more pronounced among FH women. There was little association with reproductive risk factors for premenopausal or postmenopausal breast cancer in FH cases, in clear contrast to the non-FH cases.These findings suggest some differences in risk impact of common etiologic factors between familial breast cancer and sporadic cases that may give pointers to further analysis of host-specific factors. They imply that avoidance of obesity after menopause may reduce the risk of breast cancer, regardless of FH.

Recent studies suggest that smoking habit may relate to genetic traits. This study examines the association with a polymorphism (C-31T) of interleukin 1B (IL-1B), which encodes IL-1beta, a multifunctional pro-inflammatory cytokine. Since the T allele makes a TATA box, the allele is thought to be responsible for a higher potency of IL-1B expression, indicating that individuals harboring the T allele are prone to inflammation. The study subjects were two different populations; 241 non-cancer outpatients (118 males and 123 females) at a cancer hospital and 462 examinees (127 males and 335 females) of a health checkup program provided by a local government. Current smokers were 36.4% for the male outpatients, 9.8% for the female outpatients, 38.6% for the male examinees, and 5.6% for the female examinees. The sex-age-adjusted odds ratios of current smokers were calculated for the genotypes with the T allele relative to the CC genotype by an unconditional logistic model. The estimate was 0.45 (95% confidence interval, 0.21-0.97) for the outpatients, and 0.83 (0.42-1.61) for the examinees. Although not significant for the examinees, the observed associations suggest that this polymorphism may influence smoking behavior through an inflammatory response of the respiratory tract to cigarette smoke.

The functional polymorphisms regulating immunologic responses may influence the proliferation or suppression of malignant lymphoma. We examined the association between malignant lymphoma risk and the polymorphisms of the IL-1 gene family [IL-1B -31 C/T, IL-1A -889 C/T, and IL-1RN 86-bp variable number of terminal repeat (VNTR)] and myeloperoxidase (MPO -463 G/A).The hospital-based case-control study was conducted in Japan. Genotypes were examined in a total of 372 lymphoma cases and 241 non-cancer control subjects. The relative risks were estimated by unconditional logistic regression analysis.The overall allele distribution of these polymorphisms did not differ substantially between patients and controls; the odds ratios were 0.73 (95% confidence interval, 0.48-1.11) for the T allele carriers of IL-1B relative to the non-carriers, 1.01 (0.56-1.82) for the 2-repeat allele (allele 2) carriers of IL-1RN, 0.96 (0.62-1.48) for the T allele carriers of IL-1A, and 1.04 (0.70-1.57) for the A allele carriers of MPO. Subgroup analyses according to histology [diffuse large B-cell lymphoma (DLBL), follicular lymphoma, low-grade lymphoma of mucosa associated lymphoid tissue, and others] failed to illustrate differences except for DLBL which showed a possible association with IL-1A and IL-1B polymorphisms.Our data show a limited association between these polymorphisms and malignant lymphoma risk in total. The possible association of the IL-1A and IL-1B polymorphisms with DLB-needs further clarification.

For the study presented here, we investigated possible links between the dopamine D2 receptor (DRD2) TaqIA genotype (DRD2*A) and smoking behavior in a total of 332 Japanese individuals. For the first time, functional insertion/deletion polymorphism (-141C Ins/Del) in the DRD2 promoter was also examined in relation to smoking behavior. The distribution of the DRD2*A genotype was significantly different among current, former, and never-smokers (P = 0.001; chi(2) test), and smoking appeared to be associated with the DRD2 A2/A2 genotype, showing marked contrast to previous reports for non-Hispanic whites in the United STATES: Multivariate logistic regression analysis incorporating age, sex, genotype, and smoking status as variables revealed that DRD2 A2/A2 genotype was significantly associated with an increased risk of predisposition to smoking behavior in the Japanese (odds ratio, 3.680; 95% confidence interval, 1.499-9.052). In contrast, such an increased risk was not observed in terms of association with the -141C Ins/Del polymorphism. These findings suggest an association of the DRD2*A genotype with an increased risk of being predisposed to smoking behavior in the Japanese and suggest the possible existence of ethnic group-specific differences, which warrant additional studies on the underlying molecular mechanism.

There is great controversy as to whether alteration of the p53 gene adversely affects survival of non-small cell lung cancer patients. The aim of this study was to qualitatively review the association between p53 alterations and patient outcome by reviewing published papers. Forty-three articles were used. Survival difference was combined by use of the DerSimonian-Laird method. p53 alteration was either detected as overexpression by the protein studies or as mutation by the DNA studies. The incidence of p53 alteration in DNA studies (381 of 1031; 37%) was lower than that in protein studies (1725 of 3579; 48%; P0.0001, chi2 test). The incidence of p53 overexpression and mutation in adenocarcinoma (36 and 34%) was significantly lower than that in squamous cell carcinoma (54 and 52%; P0.0001). Combined survival differences at 5 years (survival in patients with alteration minus that in patients without alteration) by protein and DNA studies were -9.1% (P = 0.0091) and -22.0% (P = 0.0026), respectively. The negative prognostic effect of p53 alteration was highly significant in patients with adenocarcinoma [-21.8% at 5 years (P = 0.0000039) by protein studies and -48.0% (P = 0.000031) by DNA studies] but not in patients with squamous cell carcinoma [-15.6% (P = 0.4241) by protein studies and 2.0% (P = 0.8864) by DNA studies]. In the light of these results, p53 alteration was a significant marker of poor prognosis in patients with pulmonary adenocarcinoma. Whether p53 alteration also provides information that can alter treatment decisions should be asked in clinical trials.

In patients with multiple synchronous lung tumors, discrimination of multicentric lung cancers from intrapulmonary metastasis is important for treatment decision, but this is sometimes difficult. The aim of this study was to retrospectively distinguish multicentric lung cancers from intrapulmonary metastases in 14 such cases by loss of heterozygosity (LOH) and p53 mutational status. DNA was extracted from microdissected tumor cells in paraffin-embedded archival tissue, and 3p14.2, 3p21, 3p25, 9p21, and 18q21.1 were investigated for LOH. Exons 5-8 of the p53 gene were examined for mutations by the PCR, followed by single-strand conformation polymorphism analysis and DNA sequencing. For cases with the same LOH pattern, we calculated a clonality index, the probability of the given LOH pattern when these tumors were hypothesized to be independent in origin. Eleven of 14 cases (79%) were thus diagnosed as having pulmonary metastasis and only one case as having genuinely multicentric lung cancers. Two cases presented difficulty in diagnosis. In several cases, the LOH patterns conflicted with p53 mutation patterns, suggesting that clonal evolution is directly affected by certain genetic changes. The combination of p53 with LOH helped increase both the sensitivity and specificity of the assay.

Anaplastic large cell lymphoma (ALCL) is a distinct entity of non-Hodgkin lymphoma, characterized by a proliferation of pleomorphic large lymphoid cells that express CD30. Recent studies have found that a subset of ALCL aberrantly expresses a chimeric anaplastic lymphoma kinase (ALK) protein as a result of t(2;5)(p23;q35) or variant translocations. ALK-positive ALCLs feature good prognosis, but some of them lead to poor outcomes. Since CD56 is expressed in some ALCLs, its clinical significance was examined in a series of T/null cell type ALCLs. Of 143 patients, 83 (58%) showed ALK-positive staining, and of 140 patients, 25 (18%) expressed CD56. The ALK-positive subgroup was characterized by a younger age of onset (P.0001), lower serum lactate dehydrogenase level (P =.01), better performance status (P =.03), less frequent extranodal involvement (P =.01), lower international prognostic index (IPI) categories (P =.002), and superior survival (P =.0009) in comparison with the ALK-negative group, suggesting that ALK is a specific marker defining a distinct subtype. CD56(+) cases showed a significantly poor prognosis overall (P =.002) as well as in both ALK-positive and ALK-negative subgroups (P =.02 and P =.04, respectively). Multivariate analysis confirmed that CD56 is independent of other prognostic factors, including IPI. Although CD56(+) cases showed a higher incidence of bone involvement, no other differences in clinicopathologic parameters were found between the CD56(+) and CD56(-) groups. These findings suggest that CD56 is not a marker to identify a distinct subtype of ALCL, but a strong clinical prognostic factor. Effective therapeutic approaches should be explored for high-risk ALCL patients, who can be identified by means of a prognostic model, including CD56.

It is known that alkylating agents and topoisomerase II inhibitors can cause distinct forms of therapy-related leukemia and myelodysplastic syndrome (TRL/MDS). Although several reports have been made on each of these agents separately, no study has yet been conducted to evaluate the effect of these two types of agents in the same population. In a nationwide, large-scale population study, the clinical and cytogenetic features as well as the prognostic factors in 256 patients with TRL/MDS were assessed. Median age was 61 years, and the median period of latency from primary malignancies was 47.9 months. The latency period was significantly shorter in patients undergoing chemotherapy, especially that of topoisomerase II inhibitors, for primary cancer. The morphological diagnosis of TRL/MDS was acute myeloid leukemia in 59% and MDS in 41% of patients. Chromosome abnormalities that frequently involved chromosomes 5, 7 or 11 were documented in 77% of the 189 patients examined. MLL gene rearrangements were detected in 11 of 58 subjects and were correlated with a borderline significance (P = 0.072) with topoisomerase II inhibitor administration. Overall median survival was only 9.7 months. Survival was similar in cases with or without MLL gene rearrangement. Multivariate analysis identified chromosome 5 abnormalities, hypoproteinemia, poor therapy outcomes for primary cancer, C-reactive protein, and thrombocytopenia as being significantly poor prognostic factors (P0.05). This large-population study provided a comprehensive update of TRL/MDS status in Japan, identified significant prognostic factors, and enabled the clinical significance of MLL gene rearrangement to be assessed.

5-Fluorouracil (5-FU) is used widely in the treatment of several common neoplasms. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. Several recent studies have described a pharmacogenetic disorder in which cancer patients with decreased DPD activity develop life-threatening toxicity following exposure to 5-FU. We reported recently the first Japanese case of decreased DPD activity accompanied by severe 5-FU toxicity. The present study describes the results of molecular analysis of this patient and her family, in which three novel mutations (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were identified. We also revealed that Arg21Gln and Glu386Ter are on the same allele and that Val335Leu is on the other allele, on the basis of analysis of the family genome. Expression analysis in Escherichia coli showed that Val335Leu and Glu386Ter led to mutant DPD protein with significant loss of enzymatic activity and no activity, respectively. The Arg21Gln mutation, however, resulted in no decrease in enzymatic activity compared with the wild type. The present data represent the first molecular genetic analysis of DPD deficiency accompanied by severe 5-FU toxicity in a Japanese patient.

A randomized controlled trial was designed to investigate the therapeutic benefit of a combination chemotherapy consisting of MTX, 5-FU and THP in patients with advanced or recurrent gastric carcinoma. The patients were randomized into two groups; Group A patients (n = 37) underwent our combined chemotherapy, whereas Group B (n = 34) underwent chemotherapy with 5-FU alone as a control. There were no significant differences in various background factors between the groups. The median survival time was roughly 170 days after the randomization for the patients with advanced cancer (n = 26 for Group A and n = 25 for Group B), with no significant difference between the groups. Two long survivors, however, belonged to Group A. The median survival time of 161 days for Group A (n = 11) was longer than that of Group B (84 days, n = 9), but the difference was not statistically significant. The incidence of toxicities (leukopenia in particular) exceeding JCOG grade 3 was significantly higher for Group A, but no morbidity was observed. These results imply that patients with advanced or recurrent gastric carcinoma may benefit from a regimen of MTX, 5-FU and THP.

A second nationwide survey was conducted to determine the outcome of pregnancy in long-term survivors of acute leukemia and to clarify the influence of treatment on the offspring of long-term survivors. In July 1996, 336 survey responses were received from the 498 Japanese institutions surveyed. A total of 89 cases (39 spouses of male patients and 50 female patients) who had babies during their first remission were analyzed, including 43 patients from the first survey in 1991. Median age at the birth of first baby was 30.7 years for male patients and 28.6 years for female patients. A total of 109 of the 117 pregnancies resulted in live births and eight resulted in abortions. A total of 58 cases had single children and 23 cases had two or more, generally from separate pregnancies, but including two pairs of twins. The infant was male in 59 cases, female in 37 and gender was not reported in 13 cases. Ages of children ranged from 2 months to 20 years at the time of this study and all children were in good health. There were two minor anomalies, both of which were surgically corrected. Of the 81 parents bearing live infants, 75 remained in complete remission. Five fathers died (four of relapse and one of another disease). In conclusion, there was no apparent increase in pregnancy complications or congenital anomalies in the children of long-term survivors with acute leukemia.

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.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.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).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.

Serum pepsinogen I and II levels have recently become popular as indicators of atrophic gastritis in epidemiological studies. Previous studies show a significant association between serum pepsinogen levels and endoscopically diagnosed atrophic gastritis. This study assesses the level of agreement between the degree of atrophic gastritis as assessed by endoscopic examination and by serum pepsinogen assays. Study subjects were 200 outpatients at Aichi Cancer Center Hospital, Nagoya, Japan, who were endoscoped between February and August 1995. Agreement of the degree of atrophic gastritis was assessed by endoscopic examination and by serum pepsinogen levels. Agreement in assessing the extent of atrophic gastritis between the two methods was 57%, and the presence of atrophic gastritis was 79%. Serum pepsinogen assays identify the majority of patients with atrophic gastritis, although they are less useful in assessing the degree of atrophy in detail.

Although survival analysis dealing with right-censored data has enjoyed wide use, analysis of data with left-censored and interval censored cases is available only to a very limited number of clinical researchers because of the difficulty in understanding the concepts and performing the calculations. This paper applies Turnbull's self-consistency algorithm, which he applied in his paper on survival data with only left-censored cases, for nonparametric estimation of survival curve including both left and interval censored data. A difference in the estimates of survival rate among different modes of calculation was demonstrated using the data from the Hematopoietic Cell Transplantation Registry of the Japan Society for Hematopoietic Cell Transplantation, which illustrated the necessity of a correct analysis.

A case-control study of leukemia and diagnostic X-ray exposure was conducted by a multi-institution co-operative study group. The subjects were 134 patients with acute myelogenous leukemia, 57 with chronic myelogenous leukemia, 56 with acute lymphocytic leukemia and 50 with myelodysplasia syndrome, who were between 15 and 79 years old, and diagnosed at one of 27 hospitals between September 1993 and August 1995. The controls were 479 first-visit patients seen at eight of these 27 hospitals. History of diagnostic X-ray tests between 1982 and 1991 was determined by an anonymous self-administered questionnaire. The total relative dose of radiation exposure was calculated by summing the products of given weights and frequencies of each test. The relative risk was 0.83 (95% confidence interval (C.I.), 0.58-1.19) for relative dose of 10-30 (equivalent to 4-11 times of UGI series), 0.76 (0.48-1.20) for relative dose of 30 or more (more than 12 times of UGI series), when compared with relative dose of 0-10 (0-3 times of UGI series). Analysis according to type of leukemia revealed that only acute myelogenous leukemia had an estimated relative risk above unity (1.08, 95% C.I. 0.69-1.69, for relative dose 10-30). This study did not support the hypothesis that diagnostic X-ray tests increases leukemia risk.

The quality of clinical trials in Japan has been improving through clear protocol preparation, improvements in methodology, coordinating systems, and so forth. In order to further improvement, the following are discussed: 1) dilemmas regarding adherence of treatment determined by protocol, 2) hospital policy and physician's discretion, 3) systems to support randomized controlled trials in hospital, and 4) systems to help obtain informed consent from subjects.

We retrospectively analyzed the therapeutic prognosis of primary open-angle glaucoma by the life-table method and the proportional hazards model. One hundred and eight patients (202 eyes) were studied. The follow-up period ranged from 6 to 125 months (40 +/- 25 months: mean +/- SD). The Kaplan-Meier life-table method indicated that therapeutic prognosis was significantly related to pretreatment intraocular pressure (IOP) and visual field defect, and that more intensive treatment was needed for higher IOP and more deteriorated visual field defect. Analysis by the proportional hazards model showed that pretreatment IOP and mean deviation (MD) measured by static perimetry were significant prognostic factors for non-surgical treatment and that the hazard ratios were 1.29-1.31 for a 5 mmHg rise in IOP and 1.44-1.83 for a 10 dB fall in MD. We concluded that the therapeutic prognosis of primary open-angle glaucoma is highly related to the level of IOP and the severity of visual field defect at the time of diagnosis.

e19719 Background: How to administer cancer CTx safely is important. Occupational Safety and Health Management Systems (OSHMS) as proposed by the Ministry of Health, Labour and Welfare have spread to many companies in Japan. We therefore designed a CSMS based on OSHMS. Methods: We reached an agreement for the CSMS. Three main actions were taken: 1) we reduced risk through the positive use of risk assessment; 2) we continuously improved the system by using a plan-do-check-act cycle; and 3) we actively communicated with all staff members. We assessed risk according to a scale of 1 to 5 (with 5 indicating the highest risk) based on the degree and possibility of such risk. After scoring the risk, we estimated the degree of risk reduction, continuously assessed the results, and improved the system. Results: Between April 2009 and October 2010, a total of 4 risk assessments were performed. 1) Orders for the first course of CTx were checked by a medical oncologist, a pharmacist, and nurses (MOPN). The estimated ...

This paper discusses Zelen's method (a study design with pre-randomization) in randomized controlled trials from the following aspects: 1) compliance of patients with a randomly assigned treatment; 2) infringement of patients' right to choose treatments; and 3) unfairness that only patients assigned to a new treatment are allowed a choice of treatments. The reason Zelen's method is rarely used in the United States or European countries seems to be the lower compliance of treatments in Zelen's method than in the conventional design of randomized controlled trials. Considering the present study practice in Japan, where study subjects are not completely informed by randomized assignment of treatments, Zelen's method is thought to be more practical, and not inferior to the conventional design in terms of compliance.

This paper aims to introduce a measure for use by physicians for stating the degree of probable causal relationship for "Karoshi", ie, a sudden death from cerebrovascular diseases or ischemic heart diseases under occupational stresses, as well as to give a brief description for legal procedures associated with worker's compensation and civil trial in Japan. It is a well-used measure in epidemiology, "attributable risk percent (AR%)", which can be applied to describe the extent of contribution to "Karoshi" of the excess occupational burdens the deceased worker was forced to bear. Although several standards such as average occupational burdens for the worker, average occupational burdens for an ordinary worker, burdens in a nonoccupational life, and a complete rest, might be considered for the AR% estimation, the average occupational burdens for an ordinary worker should normally be utilized as a standard for worker's compensation. The adoption of AR% could be helpful for courts to make a consistent judgement whether "Karoshi" cases are compensatable or not.

Among civil trials there are cases which are influenced by evidence derived from epidemiologic studies. In such cases, causality of a factor (X) illegitimately introduced by defendants is considered to be measured with an epidemiologic measure, attributable risk percent (AR%) expressing the level of risk. This paper aims to discuss calculations and interpretations of AR% in complicated cases where plaintiffs themselves introduced an additional risk factor (Y) for the alleged health injury. When X is not an effect modifier, AR% of X adjusted for Y can be simply adopted for arriving at a judgement of causality. Where Y is an effect modifier, and is not an indispensable item in the plaintiffs' daily life (e.g., smoking), the AR% of X for those not exposed to Y and also the AR% for those exposed to Y may both need to exceed a legally determined threshold, in order for X to be legally acknowledged as being causal to the alleged injury. The role of epidemiologists for such trials is to determine the AR% of X for each level of Y, and to advise the court on a realistic range of the AR%s.

Helicobacter pylori IgG antibody test established in the United States showed a substantially lower sensitivity for Japanese population

The role epidemiology in courts has become increasingly important both in the United States and in Japan, especially in the field of product liability. In the United States, attributable risk percent (AR%) is used in civil trials as a measure to judge whether alleged factors caused health disturbances of plaintiffs. Most epidemiologists believe that an AR% of more than 50%, ie, relative risk more than 2, supports causality of alleged factors, because "preponderance of evidence" is regarded as a fundamental legal rule in the United States. In Japan, judges in courts require a more strict standard for proof of facts, which means that a much higher AR% may be needed to convince judges. The role of epidemiologists in courts may be to show a plausible range of AR%, based on design, execution, and analysis of quoted epidemiologic studies. Standards for accepting plaintiffs' allegation should be discussed in the legal framework of Japan.

To determine the clinical characteristics of grade 3 tumors with lamina propria invasion (pT1), we reviewed the data of 217 patients with superficial bladder cancer who had initially been treated by transurethral resection (193 patients) and fulguration (4), supravesical resection (13) or partial cystectomy (7). We classified the patients into four groups according to histological grade and stage of disease: group 1) grade 0 or 1, pTa tumors (n = 58); group 2) grade 2, pTa tumors (n = 106); group 3) grade 2, pT1 tumors (n = 30); and group 4a) grade 3, pT1 tumors (n = 23). Grade 3, pT1 tumors were significantly related to nonpapillary growth (p = 0.0002), multiple tumors (p = 0.005) and irritative bladder symptoms (p = 0.01). The 5-year progression rates were 0% for group 1, 5% for group 2, 8% for group 3, and 18% for group 4a. The respective 5-year survival rates were 97%, 91%, 83% and 79%. All five patients with grade 3, pT1 tumors who had originally undergone total cystectomy (group 4b) remained alive free of disease for a median follow-up 57 months, establishing a far better survival rate than that for group 4a. These findings show that patients with grade 3, pT1 tumors face a high probability of progression and poor chance of survival. Immediate radical treatment is indicated when tumors recur after initial transurethral resection.

In randomized controlled trials, it is likely that several subjects with atypical features are registered. In this paper, it was discussed from a statistical point of view how properly the subjects with the following atypical features could be dealt with; 1) subjects who were found to be not eligible for the trial after randomization, 2) subjects who did not receive the assigned regimen by the treatment protocol, 3) subjects whose outcome was ambiguous as the designated endpoint, and 4) subjects who were ambiguous whether to be regarded as censored cases. It was also emphasized that informations on equivocal subjects should be masked in the committee which is responsible for the statistical judgement. Plausible examples were added to assist the readers to understand the rules discussed here.

A total of 8,316 barbers were followed up from 1976 to 1987 to examine the relations between hair dye use and deaths from hematopoietic disorders. The follow-up rate was about 95%. Three leukemia deaths and two malignant lymphoma deaths were observed in this cohort. The observed deaths were less than the expected number calculated from age- and sex-specific mortality of the general population in Japan (3.8 and 3.0, respectively). No deaths from aplastic anemia or the other hematopoietic disorders were observed.

To clarify the clinical and pathological determinants affecting the sensitivity of urinary cytology, we reviewed cytological findings from 119 patients with bladder cancer who were initially treated between January 1982 and March 1988. Cytological specimens obtained from voided urine were stained by the Giemsa and Papanicolaou techniques, and were classified into three categories of malignant cells: positive, suspicious, and negative. Of 311 specimens examined, 114 (37%) were positive, 81 (26%) were suspicious, and the remaining 116 (37%) were negative. The overall positive rate, or sensitivity, was 50% (60 out of 119 patients). The sensitivities were 7% for patients with grade 1 tumors, 42% for grade 2 tumors, and 97% for grade 3 tumors. Univariate analysis by logistic regression analysis revealed that grade, stage, histological pattern of growth, size and number of tumors, and patient age were significantly related with the positivity of voided urinary cytology. The logistic regression model, as a multivariate analysis, demonstrated that grade was the most important determinant affecting the positive cytologic finding, followed by number of tumors with statistical significance. We conclude that the lower sensitivity in conventional urinary cytology for low-grade tumors necessitates new adjuncts, including immunocytochemistry and flow cytometry, to lower the false-negative rate.

7647 Background: This study evaluates the influence of gender on survival and tumor recurrence in patients with completely resected stage IA and IB adenocarcinoma of the lung based on the analysis of the Japan Lung Cancer Research Group trial, which was a randomized prospective study of adjuvant chemotherapy with uracil-tegaful for stage I pulmonary adenocarcinoma. Methods: Patients were randomized to receive either oral uracil-tegaful (250 mg of tegaful/m2/day) for 2 years postoperatively or no adjuvant treatment. Survival was calculated from randomization until death. Survival estimated using the Kaplan-Meier method, and difference in survival between two groups was compares with the log-rank test. Results: The 5-year survival rate was 88.9% for the 502 women and 84.3% for the 477 men (median follow-up 72 months, p=0.0066). The relative risk of death for men vs women was 0.658 (95% C.I., 0.476–0.910, p=0.011), although the mean age of men was significantly less than that of women (p=0.041). There was no interaction between the gender differences and the efficacy of uracil-tegaful (p=0.657). However men presented with significantly more preoperative complications, more T2 diseases (p=0.0006), less non-papillary growth for histology (p=0.0078), less well differentiated subtype (p No significant financial relationships to disclose.

7197 Background: To test the hypothesis that patients with completely resected p-stage I adenocarcinoma [Ad.] of the lung contain a favorable subgroup of patients with well differentiated histology and tumor 2.0 cm or less in greatest dimension, we analyzed the results of the JLCRG trial (a randomized prospective trial of adjuvant chemotherapy with Uracil-Tegaful for stage I adenocarcinoma of the lung) by tumor size, smoking history, degree of histological differentiation and more. Methods: Patients were randomized to receive either oral uracil-tegaful (250 mg of tegaful /m2/day) for 2 years postoperatively or no adjuvant treatment. Multivariate analyses and interactions with the Cox proportional-hazards model were used to estimate the simultaneous effects of prognostic factors on survival. Results: The 5-year survival rate of the 412 patients with tumor 2cm or less in size was 89.8% (95% confidence interval [CI]: 86.8 to 92.8) versus 84.4% (95% CI: 81.3–87.4) for the 569 patients with tumor more than 2cm in size (median follow-up 72 months, p = 0.002). Although univariate analysis demonstrated improved survival for the patients with no smoking history and female gender, the selected covariates by multivariate analysis were as follows: age (hazard ratio [HR] for patients aged 70 years or more, 2.25; 95% CI: 1.58 to 3.14, p < 0.0001), tumor size (HR for more than 2cm in size, 1.55; 95% CI: 1.10 to 2.21, p = 0.012), histological differentiation (HR for moderate and poor differentiation, 1.75, 95% CI: 1.25 to 2.47, p = 0.001), and treatment group (HR for the uracil-tegaful group, 0.68; 95% CI: 0.49 to 0.94, p = 0.02). For these prognostic factors, there was only one significant interaction between tumor size and the adjuvant treatment. Conclusions: 1) Patients with completely resected stage I Ad. of the lung contain a favorable subgroup of patients with aged less than 70 years, well differentiated histology, and a maximum tumor dimension of 2.0 cm or less. 2) Adjuvant chemotherapy with oral uracil-tegaful should also be considered for stage I Ad. patients more than 2 cm in tumor size. 3) 2cm in tumor size might be a good benchmark candidate of the description of T factor to facilitate treatment strategies and revisions of the TNM staging system. No significant financial relationships to disclose.