Critical review of 'Public domain application': a flexible drug approval system in Japan.

BACKGROUND: 'Public domain application' is a flexible drug approval system in Japan, similar to the fast track designation in the United States. METHODS: From 1999 to 2009, four drugs and three regimens received approval from `Public domain application'. The data from the review reports were extracted, and the reviewing process was critically re-evaluated. RESULTS: The study drugs were categorized into three groups according to the sizes of the studies and evidence levels in the original articles that were submitted. Carboplatin was categorized into the first group with a large number of study patients and a high evidence level; the review report had studies with more than 15 000 total patients and 8 phase III studies. The ifosfamide and vinblastine regimen was categorized into the second group, with a low number of study patients and a low evidence level; the review report had studies with less than 1000 total patients and 1 phase III study. Dacarbazine; cytarabine; methotrexate, vinblastine, doxorubicin, and cisplatin; bleomycin, etoposide, and cisplatin; and fludarabine were categorized into the remaining third group, with a moderate number of study patients and evidence level. CONCLUSIONS: Drugs with various backgrounds, including evidence levels and physicians' experiences, were approved via `Public domain application'. The approvals of most drugs were evaluated to be appropriate.

Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital.

BACKGROUND: Antimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan. METHODS: The infection control team was involved in the review of individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial-resistant bacteria and medical expenses. RESULTS: Prolonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second-generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin-resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram-negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship. CONCLUSION: Extensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay.

Adiposity, adult weight change and breast cancer risk in postmenopausal Japanese women: the Miyagi Cohort Study.

BACKGROUND: The role of adult weight change in breast cancer (BC) risk is unclear in Japanese women. METHODS: A total of 10,106 postmenopausal women aged 40-64 years (the Miyagi Cohort) were followed from 1990 to 2003, and 108 BC cases were identified. Hazard ratios (HRs) were estimated according to body mass index (BMI) at the current age and at the of age 20 years, and weight change since age 20 years. RESULTS: Higher current BMI was associated with an increased risk of BC (P for trend=0.02), whereas higher BMI at the age 20 years was inversely associated with this risk (P for trend=0.002). There was a significant association between weight change since age 20 years and BC risk (P for trend=0.0086). Compared with stable weight, HR was 0.35 for weight loss of 5 kg or more (P for weight loss trend=0.04) and 1.55 for weight gain of 12 kg or more (P for weight gain trend=0.05). CONCLUSION: Adiposity at younger and current age has differential effects on BC risk among postmenopausal women; weight gain in adulthood being associated with an increased, and weight loss with a decreased risk.

Passive smoking at home and cancer risk: a population-based prospective study in Japanese nonsmoking women.

OBJECTIVES: To investigate the relationship between passive smoking at home and the incidence of various cancers in a population-based prospective study. METHODS: The subjects were 9675 Japanese lifelong nonsmoking women aged over 40 years who lived in three municipalities of Miyagi Prefecture, and completed a self-administration questionnaire in 1984. During 9 years of follow-up, 426 cancers were identified by record linkage to the population-based cancer registry. The data were analyzed using the Cox proportional hazards model. RESULTS: The age-adjusted relative risks (RR) and 95% confidence intervals (CI) of smoking-related cancers and lung cancer for women who had smoking husbands, compared with women whose husbands did not smoke, were 1.7 (0.94 2.9, p = 0.079) and 1.9 (0.81-4.4, p = 0.14), respectively. In contrast, a significant inverse association was observed for breast cancer, the RR (95% CI) was 0.58 (0.34-0.99, p = 0.047). After multivariate adjustment for confounding factors, the risks of smoking-related cancers and breast cancer were materially unchanged. CONCLUSIONS: These results show that passive smoking may affect the risk of cancers other than lung cancer.

Green tea and the risk of gastric cancer in Japan.

BACKGROUND: Although laboratory experiments and case-control studies have suggested that the consumption of green tea provides protection against gastric cancer, few prospective studies have been performed. METHODS: In January 1984, a total of 26,311 residents in three municipalities of Miyagi Prefecture, in northern Japan (11,902 men and 14,409 women 40 years of age or older), completed a self-administered questionnaire that included questions about the frequency of consumption of green tea. During 199,748 person-years of follow-up, through December 1992, we identified 419 cases of gastric cancer (in 296 men and 123 women). We used Cox regression to estimate the relative risk of gastric cancer according to the consumption of green tea. RESULTS: Green-tea consumption was not associated with the risk of gastric cancer. After adjustment for sex, age, presence or absence of a history of peptic ulcer smoking status, alcohol consumption, other dietary elements, and type of health insurance, the relative risks associated with drinking one or two, three or four, and five or more cups of green tea per day, as compared with less than one cup per day, were 1.1 (95 percent confidence interval, 0.8 to 1.6), 1.0 (95 percent confidence interval, 0.7 to 1.4), and 1.2 (95 percent confidence interval, 0.9 to 1.6), respectively (P for trend=0.13). The results were similar after the 117 cases of gastric cancer that were diagnosed in the first three years of follow-up had been excluded, with respective relative risks of 1.2 (95 percent confidence interval, 0.8 to 1.8) 1.0 (95 percent confidence interval, 0.7 to 1.5), and 1.4 (95 percent confidence interval, 1.0 to 1.9) (P for trend=0.07). CONCLUSIONS: In a population-based, prospective cohort study in Japan, we found no association between green-tea consumption and the risk of gastric cancer.

Mortality and cancer incidence in patients with Parkinson's disease.

To investigate the risks of mortality and cancer incidence in Parkinson's disease (PD) we studied the prognosis of 246 PD patients in a community. The cohort of PD patients was identified in 1984, and survival, mortality, relocation, and cancer incidence during 1984-1992 were examined retrospectively in 1994. The risk was measured by a standard effect estimate, i.e., the standardized mortality ratio (SMR) or the standardized incidence ratio (SIR), compared with the rates in the general population. During the observation period 696 person-years in PD men and 1018 person-years in PD women were accumulated, and 49 PD men and 53 PD women died. The risk of mortality in PD was significantly increased in both sexes (SMR: men 1.74, women 1.97). In addition, the risk of cancer incidence was evaluated in 228 patients aged under 80 years; 8 PD men and 7 PD women developed cancer. The risk of overall cancer incidence in PD was less than 1 in either sex, but not significantly. The risk of breast cancer in PD women was significantly increased (SIR: 5.49), but the 95% confidence interval was wide (1.10-16.03). The results indicate that PD patients in a community have a twofold higher risk of mortality, and that PD may be associated with an increased risk of breast cancer in women.

Determinants of infant feeding method in relation to risk factors for breast cancer.

BACKGROUND: Breastfeeding is considered to be an important factor for maternal and children's health. However, the epidemiological findings related to the effect of breastfeeding on women's health, especially with respect to breast cancer development, are inconsistent. Determinants of infant feeding method may contribute to the inconsistency. METHODS: A total of 24,769 women aged 40-64 in Miyagi Prefecture, Japan, responded to a self-administered questionnaire survey in 1990. Using the data obtained from 22,085 parous women, we calculated odds ratios (ORs) for the choice of "breastfeeding only" during reproductive period. RESULTS: Late age at menarche (> or = 16 years, OR = 1.57) and high body mass index (BMI) at 20 years of age (> or = 24, OR = 1.31) were associated with the choice of breastfeeding only. Late age at birth of first child (> or = 28 years, OR = 0.29), history of breast cancer in mother (OR = 0.68), and high educational level (more than a high school education, OR = 0.53) reduced the possibility of choosing breastfeeding only. CONCLUSION: The results indicate that the choice of infant feeding method is associated with several breast cancer risk factors. Based on this finding, we should construct appropriate breast cancer risk models for parous women and investigate the changes in the effects of breastfeeding and other breast cancer risk factors among these risk models. Especially in a risk model controlling for breastfeeding, the effects of other breast cancer risk factors should be reevaluated. Through comparisons among different risk models, we may find the best-fitted risk model and identify the true effect of breastfeeding.

A reproductive health survey on unintended pregnancy in Yamagata, Japan: feasibility of the survey and test-retest reliability and validity of a questionnaire.

We have designed a survey to investigate factors related to unintended pregnancy using a newly devised questionnaire. This pilot study was conducted to examine the feasibility of the study and the test-retest reliability and the validity of the questionnaire. Samples were 107 cervical and breast cancer screening participants aged 35-49 year-old in 1999 in Yamagata, Japan. The same questionnaires were mailed twice to examine the test-retest reliability. Women's medical records for cancer screening were used to examine the validity of the questionnaire. Ninety-six women agreed to participate in the study and 89.6% of them responded to the first survey. The agreements between two surveys were substantial to perfect for the nominal and ordinal data, and for the continuous data, the standard deviations (SDs) were less than 1 and the correlation coefficients were over 0.6. The comparison between medical record and questionnaire derived data showed perfect agreements for reproductive items except age at last birth (SD: 0.71, correlation coefficient: 0.97), and fair agreements for drinking and smoking habits. Obtaining information on unintended pregnancy by questionnaire is feasible, and the test-retest reliability and the validity of the questionnaire are satisfactory. Currently we are conducting a survey with a larger sample.

Factors relating to place of death of Japanese people from a small town in a rural area.

The objective of our retrospective study was to clarify factors relating to place of death of Japanese people from a small town in a rural area who had been bedridden for at least one week before dying. The caregivers of subjects aged 40 and above who died during a three-year period were surveyed by trained interviewers. Of 352 subjects who died, 312 caregivers responded and agreed to a face-to-face interview. A total of 213 subjects were considered as an eligible sample. The main outcome measures were odds ratios for death at home in relation to age, pain, cause of death, and home visit service. One hundred and two people died at home, while 112 people died in a hospital. Multivariate logistic regression analysis showed that the probability of home death increased with age of the bedridden, lack of pain during the bedridden period, not having cancer as a cause of death, having senility as a cause of death, and receiving regular home visits by a Public Health Nurse. In conclusion, expansion of the home visit programs by Public Health Nurses may enable people to die at home as they so desire. Further prospective research is needed to explore the association between the attitude toward terminal care and the place of death.

Risk of breast cancer in Japanese women with benign breast disease.

To investigate the risk of breast cancer development in women with benign breast disease (BBD), 387 screen-detected BBD women and 1,489 normal women, taken from participants in the breast cancer screening program during 1978-1986, were followed through 1991. While 2,811 person-years in the BBD group and 11,018 person-years in the normal group were accumulated, 5 women in the BBD group and 6 women in the normal group developed breast cancer. Using the Mantel-Haenszel method, relative risks (RR) were estimated for all women with BBD and women in some BBD types. Significantly elevated risk of breast cancer was observed in all women with BBD (RR = 3.26, 95% confidence interval (CI) 1.08-9.83). Women with proliferative BBD were at high risk of breast cancer (RR = 8.48, 95% CI 2.99-24.10), but no increased risk was observed for women with non-proliferative BBD (RR = 0.93, 95% CI 0.11-7.66). These results are consistent with those in high-risk countries for breast cancer. In the management of women with BBD, histopathological diagnosis of the breast lesion is essential and women with proliferative BBD should be followed up carefully.

A case control study on the effectiveness of breast cancer screening by clinical breast examination in Japan.

A case-control study was conducted in Miyagi and Gunma prefectures, Japan, to evaluate the effectiveness of breast cancer screening by clinical breast examination (CBE) alone in reducing breast cancer mortality. Case subjects, who were female and had died of breast cancer, were collected from residential registry files and medical records. Control subjects matched in sex, age and residence were randomly selected from residential registry files. The screening histories during 5 years prior to the cases having been diagnosed as breast cancer were surveyed using the examinee files of the screening facilities. Finally, the data of 93 cases and 375 controls were analyzed. The odds ratio (OR) of breast cancer death for participating in screening at least once during 5 years was 0.93 (95% confidence interval (95% CI) 0.48-1.79). The cases were more symptomatic than the controls when screened. If the participants who had had symptoms in their breasts were classified as not screened, the OR decreased to 0.56 (95% CI 0.27-1.18). The case control study suggests that the current screening modality (CBE) lacks effectiveness (OR = 0.93), although it might be effective for an asymptomatic population (OR = 0.56). The number of cases was small, and a larger case-control study is desirable to define whether CBE is effective or not. However, it is necessary to consider the introduction of mammographic screening to reduce breast cancer mortality in Japan.

[Relation between passive smoking at home and dietary intake].

To investigate confounding factors in the relation of passive smoking to diseases, we compared the dietary intake of passive smokers, non-smokers without passive smoke exposure, and smokers. The subjects were female respondents to a baseline survey, which was conducted as part of a collaborative cohort study in a rural area. Of the subjects, 101 females were smokers. A total of 1978 female non-smokers answered the question about passive smoking exposure at home, including 1,392 (70.4%) passive smokers and 586 (29.6%) non-passive smokers. Among these three groups, the dietary intake of 36 foods (frequency and amount) was compared by odds ratios calculated with a logistic regression model. The percentages of subjects reporting frequent intake of milk or milk products, carrot or pumpkin, tomatoes, oranges, and fruits except oranges, were significantly lower in passive smokers than in non-passive smokers (OR = 0.80, 0.74, 0.80, 0.77, 0.79). On the other hand, more subjects in passive smokers reported frequent or large intake of pork, salt pickled vegetables, soy sauce pickled foods, soft drinks, coffee, and moso soup (OR = 1.38, 1.53, 1.32, 1.73, 1.30, 1.33). The dietary pattern of passive smokers was similar to that of smokers. In conclusion, in this study, passive smokers had different dietary patterns from non-passive smokers'. In future research regarding disease with passive smoking exposure, dietary factors should be considered as a confounder.

[Effectiveness and feasibility of a strategy for increasing participation in the Japanese Stomach Cancer Examination programs by incorporating serum pepsinogen tests].

The number of people examined in "the Japanese Stomach Cancer Examination" programs under "Health Services Law for the Aged" has not increased, and a strategy is needed to increase participation in the programs. We have thought out a plan to persuade people to the programs by using serum pepsinogen tests without changing the framework of the programs. The plan is as follows: The subjects are those who undergo phlebotomy in "the General Health Examination" programs and who do not undergo the Stomach Examination programs. Serum pepsinogen levels are measured using the sera and those with high risk for stomach cancer are persuaded to attend "the Stomach Examination" programs. To estimate the effect of the plan, we asked several local governments to complete a questionnaire on the numbers of subjects. The ratio of the number of the subjects in the plan to the number of screenees in recent Stomach Examination programs was 0.61. An increase of about 15% was expected in screenees of the Stomach Examination Programs, if 40% of the subjects in the plan were diagnosed as high risk and 60% of the high risk subjects attended the Stomach Examination programs. From the economical stand point, it was expected that detection rate would increase and that the plan did not raise the cost for detecting a patient with stomach cancer. We also conducted a questionnaire survey of those who would be the subjects of the plan. Eighty-two percent of the subjects answered that they would attend the Stomach Examination programs, if they were told that their risk of stomach cancer was high by the serum pepsinogen tests. These results seem to suggest that more people would participate in cancer examination programs when informed that their risk for cancer is high as determined by blood tests.

HPV, histologic grade and age. Risk factors for the progression of cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the clinical significance of human papillomavirus (HPV) type, grade of cervical intraepithelial neoplasia (CIN) and age on the progression of CIN. STUDY DESIGN: Clinical follow-up data, histopathologic diagnosis, polymerase chain reaction (PCR) and HPV DNA typing were available on 194 patients, 119 with CIN 2/moderate dysplasia and 75 with CIN 3/severe dysplasia. RESULTS: HPV 16 was observed most frequently (47.0%) in progressed CIN, while HPV-negative cases (57.7%) were most frequently regressed. HPV positivity (P = .0466), especially HPV 16 positivity (P = .0104), was significantly more frequent than HPV negativity in the progression group. The rate of CIN progression was higher with HPV (50.5%) than without HPV (35.4%). Of the CIN cases with HPV 16, 56.5% progressed, while 30.8% of the CIN cases with HPV 6 and/or 11 and 35.4% of the CIN cases without HPV progressed. The probability of progression was 1.87-fold higher in the HPV-positive group than that in the HPV-negative group (P = .03). Multiple logistic regression analysis revealed that HPV (odds ratio 2.23, P = .0103) and grade of the lesion (odds ratio 3.30, P = .0002) in the initial biopsy strongly and independently correlated with progression of CIN. CONCLUSION: HPV status and histologic grade are independent predictive risk factors for progression and may be useful in the management of CIN.

Risk factors for benign breast disease according to histopathological type: comparisons with risk factors for breast cancer.

We evaluated risk factors for benign breast disease by using a case-control study method. The series was taken from participants in breast cancer screening programs during 1978-1986 in Miyagi Prefecture, Japan. All benign breast lesions diagnosed during this period were reviewed and reclassified into proliferative and non-proliferative types based on the Dupont and Page classification. Data on 382 benign breast disease cases (130 proliferative-type cases and 252 non-proliferative-type cases) and 1,489 screening year-, age- and screening area-matched normal controls were used for analysis. Nulliparity or low parity and family history of breast cancer in mother or sisters were significantly associated with an increased risk of proliferative type. Premenopausal status was significantly associated with an increased risk of non-proliferative type. No significant association with history of lactation for the last child was observed in either type, but the risk of proliferative type increased with increasing duration of lactation (P=0.08). A comparison between the present findings and the risk factors for breast cancer indicated epidemiologic similarities between proliferative benign and malignant breast lesions in general. The associations of these two lesions with lactation patterns were, however, dissimilar.

A prospective cohort study on National Health Insurance beneficiaries in Ohsaki, Miyagi Prefecture, Japan: study design, profiles of the subjects and medical cost during the first year.

To examine the impact of health-related lifestyle upon medical care utilization and its costs, we conducted a cohort study among all National Health Insurance beneficiaries aged from 40 to 79 years living in the catchment area of Ohsaki Public Health Center, Miyagi, Japan. The baseline survey, using self-completed questionnaire regarding health-related lifestyle, was conducted between October and December 1994. Out of 54,996 eligible subjects, 52,029 (94.6%) responded and formed the cohort under study. Medical care utilization (number of outpatient visits and days of inpatient care) and the costs for each subject have been obtained from National Health Insurance Claim History files since January 1995. The baseline characteristics of health-related lifestyle and medical history at the study subjects were consistent with those at our another cohort subjects (so-called Miyagi cohort study; N = 47,605), which included all the residents aged from 40 to 64 years at 14 municipalities in Miyagi Prefecture, Japan conducted in 1990. The medical costs per capita in this cohort was quite compatible with the national average. This prospective cohort study would quantitatively demonstrate the economic impact of health-related lifestyle, thus would lead us to better provision of cost-effective preventive health services.

Cost-effective analysis of mass screening for cervical cancer in Japan.

Cost-effectiveness analysis for cervical cancer screening in Japan was performed to estimate the cost per life-year saved by the screening; cost-effectiveness ratio (CER). The analysis was made using a simulation model to estimate long-term cost and effectiveness of the screening programs. CER of cervical cancer screening was estimated to be US$ 40,604 which was 2.4 times more expensive than that for gastric cancer screening but was about the same as that for colorectal cancer screening. It was within the range of cost-effectiveness of other cancer screening programs financed under the Health and Medical Services Law for the Aged in Japan. We performed sensitivity analysis on the following seven estimates, the screening charge, the sensitivity and the specificity of the screening test, the frequency of carcinoma in situ (CIS) among cases detected in the screening program, the initial cost and the terminal cost for patients with invasive cancer, and the incidence rate of cervical cancer. The sensitivity analysis demonstrated that the screening charge was the most influential factor on CER. CER was fairly stable under various assumptions on the accuracy of the screening test, the frequency of carcinoma in situ (CIS), the treatment cost for patient, and the incidence of cervical cancer. CER was less sensitive to the changes in incidence, even to as low as a 50% decrease of the current figure. Then if the incidence rate becomes 85% of the current figure in 2015, CER would be US$ 48,176 and it was suggested that the cervical cancer screening would remain reasonably cost-effective until the year 2015.

Smoking behaviour and personality: a population-based study in Japan.

AIMS: The aim of our study was to determine whether the previously reported findings also apply to a general population in Japan and whether, among current smokers, such personality characteristics can be correlated with the age they started to smoke and their present daily consumption of cigarettes. DESIGN: Cross-sectional survey. SETTING: Miyagi prefecture, in northern Japan. PARTICIPANTS: 20,538 residents in Miyagi, aged 40-64 years. MEASUREMENT: A self-administered questionnaire involving smoking status (current, ex- and non-smokers) and patterns and the Japanese version of the short-form Eysenck Personality Questionnaire-Revised (EPQ-R). FINDINGS: (1) Current and ex-smokers were higher on Extraversion and Psychoticism than non-smokers for both genders. (2) Heavy smokers were higher on Psychoticism than light smokers and those who started to smoke prior to the legally permitted age were higher on Psychoticism than those who did not. CONCLUSIONS: (1) Our study confirmed that the findings which had been previously reported in selected samples in western countries also apply to a general population in Japan; (2) current smokers were found to be heterogeneous in terms of Psychoticism when the age they started to smoke and their present daily consumption of cigarettes were taken into account.

Cervical cancer screening in Japan. A case-control study.

OBJECTIVE: To prove the effectiveness of mass screening for cervical cancer with the cervical cytologic smear in Japan. STUDY DESIGN: The cases consisted of 109 patients with invasive carcinoma who were identified by mass screening for cervical cancer between 1984 and 1989. For each case, two age-matched controls were chosen from females who underwent mass screening in the same district during the same period. The odds ratio (OR) for invasive cervical cancer and that of each histologic type for the previously screened vs. unscreened females were calculated. In addition, the OR for invasive cervical cancer according to the screening interval was calculated. RESULTS: The OR of invasive cervical cancer for the previously screened vs. unscreened females was significant (P < .16). According to the histologic type, the OR of squamous cell carcinoma for the previously screened vs. unscreened females was significant (P < .14), while that for adenocarcinoma was not significant (P < .45). According to screening interval, the OR for screening at a one- or two-year interval was significant (P < .11 and .33, respectively). CONCLUSION: This case-control study statistically showed the usefulness of screening for cervical cancer in Japan.

Risk factors for breast cancer: a case-control study of screen-detected breast cancer in Miyagi Prefecture, Japan.

We examined the associations between reproductive factors and the risk of breast cancer on the basis of information from a total of 201,363 breast cancer screening program participants in Miyagi Prefecture, Japan, during 1987-1991. A case-control study method was applied on analysis. Data on 204 breast cancer cases identified and 810 screening year-, age- and screening area-matched normal controls were extracted. After adjustment for potential confounders, a trend of decreasing risk of breast cancer with increasing number of parity was observed (p for trend = 0.03). Among parous women, lactation for the last child decreased the risk of breast cancer (odds ratio (OR) = 0.61, 95% confidence interval (95% CI) 0.39-0.94). These findings were consistent with those in clinical breast cancer reported previously. When cases were divided into two age groups, younger (< or = 49 y.o.) and older (50 y.o. < or =), family history of breast cancer among mother and sisters (OR = 3.51, 95% CI 1.05-11.80), and lactation for the last child (OR = 0.46, 95% CI 0.25-0.84) were associated with younger age breast cancer, whereas number of parity was associated with older age breast cancer (p for trend = 0.03). The results by age group suggest that different mechanisms may exist in breast cancer developing at early and late onsets.