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Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

There are reasons to suspect that dietary changes through adult life may modify risk for some cancers. We examined the association of recent and past dietary habits and changes in dietary intake over time with ovarian cancer risk. Long-term nutritional assessment was performed retrospectively in 631 incident cases of invasive epithelial ovarian cancer and in 1174 matched controls (matched by age 6 2 y, country of origin, and period of immigration) as part of a nationwide casecontrol study of ovarian cancer conducted between the years of 1994 and 1996 in Israel. Using a 2-step quantified Food Frequency Questionnaire, participants were first asked about their consumption of food items 1 y prior to the interview, and then whether their consumption had changed over time. The time of the change and consumption level before the change were recorded, allowing reconstruction of daily intakes for several time points. The reported mean percentage of animal fat intake decreased by 1.3% in cases but by 1.9% in controls (P for difference ¼ 0.003). Conditional multivariate logistic regression was used to estimate odds ratios adjusted for total energy, parity, and oral contraceptive use. Substituting nonanimal fat in preference to animal fat over a relatively short term (between 2 and 7 y prior to interview) decreased the risk of ovarian cancer [OR ¼ 0.65/100 kcal (418.4 kJ), 95% CI ¼ 0.50 2 0.85]. Our results suggest that substitution of nonanimal for animal fat during adult life might reduce the risk of ovarian cancer, but this requires confirmation in prospective studies. J. Nutr. 136: 2362‐2367, 2006.

Objective. To assess the frequency of uterine involvement in primary peritoneal carcinoma (PPC) and to describe selected clinical characteristics in patients with and without hysterectomy. Methods. All incident cases of histologically confirmed cancer of the ovary or peritoneum, diagnosed in Israeli Jewish women between March 1 1994 and June 30, 1999, were identified within the framework of a nationwide epidemiological study of these neoplasms. The study population was accrued through an active search of all newly diagnosed patients in all the departments of gynecology in Israel. The data of 81 PPC patients included in the present study were abstracted from medical records. Results. Hysterectomy was performed in 48 patients. These patients had a lower mean age (62.4 ± 9.4 vs. 66.9 ± 10.4; P = 0.05) at diagnosis and a higher rate of ≤2 cm residual disease (54.2% vs.24.2%; P = 0.02). Of those with hysterectomy, microscopic involvement was verified in all those with macroscopic involvement. Overall microscopic involvement was present in 28 (58.3%) of the patients who underwent hysterectomy. In the majority of them, only the serosa was involved. Macroscopic uterine involvement was present in 27 (33.3%) patients but in only 12% it was >2cm. The median survival in patients with hysterectomy was 36 months and in those without hysterectomy 29 months, this difference was statistically not significant ( P = 0.2). Conclusions. Our study indicates that in an unselected group of PPC patients 33% have any macroscopic uterine involvement. The therapeutic value of routine hysterectomy at the initial operation for PPC should be further investigated.

Evaluation whether Jewish founder mutations in BRCA predispose to borderline tumors as they do to early invasive ovarian cancers.All Jewish women with borderline or invasive ovarian tumors, diagnosed over a 5-year period (1994-1999), were identified in the frame of a nationwide epidemiological study on ovarian cancer in Israel. Out of a total of 1489 patients, 1269 were interviewed; of them 256 (20.2%) patients were identified with stage I and II invasive epithelial ovarian tumors, and 233 (18.3%) patients were identified with borderline tumors. All patients underwent interviews, and blood or tissue samples from 117 borderline tumors and 161 early stage invasive tumors were analyzed for the presence of the 185delAG and 5382insC BRCA1, and the 6174delT BRCA2 Jewish founder mutations.Patients with borderline tumors were younger at diagnosis, and more frequently of the serous type (P0.001) as compared to patients with early stage ovarian cancer. Prevalence of Jewish founder mutations in BRCA1 and BRCA2 was only 4.3% of patients with borderline tumors as compared to 24.2% of patients with early stage ovarian cancer (P = 0.001).This nationwide study comparing patients with early stage borderline and invasive epithelial tumors of the ovary confirms our previous pilot study that showed a lower incidence of BRCA mutations in patients with borderline tumors. Our results suggest that the genetic predisposition and the molecular mechanisms underlying tumor initiation differ between invasive and borderline tumors of the ovary.

Ionizing radiation is an established risk factor for brain tumors, yet quantitative information on the long-term risk of different types of brain tumors is sparse. Our aims were to assess the risk of radiation-induced malignant brain tumors and benign meningiomas after childhood exposure and to investigate the role of potential modifiers of that risk. The study population included 10,834 individuals who were treated for tinea capitis with X rays in the 1950s and two matched nonirradiated groups, comprising population and sibling comparison groups. The mean estimated radiation dose to the brain was 1.5 Gy. Survival analysis using Poisson regression was performed to estimate the excess relative and absolute risks (ERR, EAR) for brain tumors. After a median follow-up of 40 years, an ERR/Gy of 4.63 and 1.98 (95% CI = 2.43-9.12 and 0.73-4.69) and an EAR/Gy per 10(4) PY of 0.48 and 0.31 (95% CI = 0.28-0.73 and 0.12-0.53) were observed for benign meningiomas and malignant brain tumors, respectively. The risk of both types of tumors was positively associated with dose. The estimated ERR/Gy for malignant brain tumors decreased with increasing age at irradiation from 3.56 to 0.47 (P = 0.037), while no trend with age was seen for benign meningiomas. The ERR for both types of tumor remains elevated at 30-plus years after exposure.

This study examines concomitants of volunteering in the context of other lifestyle activities. Investigating formal volunteering in old-old age, the authors analyzed data of 148 volunteers versus 1,195 nonvolunteers in a national sample of the Israeli Jewish population aged 75-94. As hypothesized, being a volunteer related (whether as a cause or effect) to more positive functioning on psychosocial markers and prospectively resulted in reduced mortality risk even when other activity outlets (physical activity, everyday activities, having a hobby) were controlled. These findings suggest that the benefits of volunteering in late life are not reducible to those of other activities.

Objective The objective was to evaluate the prevalence of BRCA1/2 mutations in selected categories of ovarian cancer patients in Israel. Methods Blood samples and specimens of ovarian tumors were obtained in the course of a national case control study of women with ovarian cancer in Israel. Eight hundred ninety-six patients with epithelial ovarian cancer, 40 cases with nonepithelial ovarian cancer, and 68 with primary peritoneal cancer were tested for the BRCA mutations. Analysis of the three common BRCA mutations in Israel (185delAG, 5382insC in BRCA1, and 6174delT in BRCA2) was done using a multiplex polymerase chain reaction assay. A multivariate logistic regression model was used to assess the association of mutation carrier status and other factors (age, origin, family history, and clinical variables). Results Of the 779 invasive epithelial ovarian cancer cases, 29.4% were mutation carriers. The prevalence of the mutations was higher among women below age 60 and in more advanced cases. The prevalence was low in mucinous tumors. There was almost a twofold excess of mutations among women with positive family history (45.7%), but still 26.5% of the family history negative cases were carriers. As expected, we found a higher rate of mutation carriers among the Ashkenazi group (34.2%) and 55% among Ashkenazi women with positive family history. No subjects born in North Africa were mutation positive. Conclusion BRCA mutations are strongly associated with ovarian cancer and they are present in variable rates in distinct age, ethnic, and histopathologic categories.

During the years 1994-1999, a nationwide ovarian cancer case-control study was conducted in Israel. The present analysis addresses the question: Is epithelial ovarian cancer associated with body mass index at age 18 years and/or with weight changes in body mass index between adolescence and adult life? The study is based on 1,269 women with epithelial ovarian cancer and 2,111 matched controls. A significant decrease in risk of ovarian cancer was observed with parity, oral contraceptive use, and postmenopausal status. A significant increase in risk with family history of ovarian/breast cancer was also found. No significant association with age at menarche or infertility was found. For body mass index at age 18 years, the odds ratio of the highest versus lowest body mass index quartile was 1.42 (95% confidence interval: 1.08, 1.85) and after adjusting for confounders was 1.54 (95% confidence interval: 1.17, 2.02). However, no statistically significant risk associated with change in weight from age 18 years to adult life was found. The authors conclude that, in their population, body mass index at age 18 years is an independent risk factor for ovarian cancer.

This study addressed long-term effects of extreme trauma among Holocaust survivors (N = 126) in an older (75-94 years) sample of the Israeli Jewish population. Survivors were compared with European-descent groups that had immigrated either before World War II (n = 206) or after (n = 145). Participants in the latter group had had Holocaust-related life histories but did not consider themselves survivors. Controlling for sociodemographics, the results indicated that survivors fared worse than prewar immigrants in certain psychosocial domains, mainly cumulative distress and activity, rather than in health-related ones. Survivors and postwar immigrant comparisons had almost no differences. The study highlights the need for a wide view of functioning facets and comparison groups in delineating late posttraumatic effects.

Objectives. Using a theoretical framework that divided social factors measures into structure, function, and social engagement, this study determined those aspects of social networks most significantly associated with 8-year, all-cause mortality among the old-old in Israel. Methods. Jews ( n � 1,340) aged 75–94 living in Israel on January 1, 1989, were randomly selected from the National Population Register; stratified by age, sex, and place of birth; and interviewed in person. Mortality was determined according to the National Death Registry (December 1997). Results. After controlling for sociodemographics and measures of health, cognitive status, depressive symptoms, and physical function, the measures of social engagement that explicitly involved others were associated with a lower risk of mortality. No measure of the function of the social network was associated with risk of mortality. Living in the community without a spouse and with a child and living in an institution were significantly associated with a higher risk of mortality. Discussion . The finding that participating in activities with people outside of the immediate family is associated with a lower risk of death has practical implications for helping the aging population and their families in their decisionmaking process. Lack of support for the hypothesis that those with more social support would show reduced risk of mortality may indicate that the positive effect of perceiving support and the negative effect of needing support may cancel each other out and result in no perceived effect. In this population, the association between socioeconomic status (SES) and the risk of mortality seems to be expressed through the living arrangements, with the sick and frail, both in institutions (higher SES) and in the community with a child or other (lower SES), having a higher risk of mortality. These findings are consistent with the use of children as a substitute for institutionalization, and imply that at least some cohabitation was the caretaking solution for the noninstitutionalized old-old who were of low SES, frail, and close to death.

The etiology of childhood brain tumors (CBTs) remains unknown. Tobacco smoke contains several known carcinogens and can induce DNA adducts in human placenta and hemoglobin adducts in fetuses. We present the results of an international case-control study to evaluate the association between CBTs and exposure of parents and children to cigarette smoke. The study was undertaken as part of the SEARCH program of the IARC. Nine centers in 7 countries were involved. The studies mainly covered the 1980s and early 1990s. Cases (1,218, ages 0-19 years) were children newly diagnosed with a primary brain tumor; there were 2,223 population-based controls. Most mothers who agreed to participate were interviewed in person at home. Odds ratios (ORs) were calculated by unconditional logistic regression, adjusted for age, sex and center, for all types of CBT combined, 4 CBT histotypes, 5 age groups and each center. There was no association between the risk of brain tumors in the child and parental smoking prior to pregnancy, maternal smoking or regular exposure to others' cigarette smoke during pregnancy at home or at work, or passive smoking by the child during the first year of life. These results did not change considering the child's age at diagnosis, the histologic type of tumor or center.

Objective: To assess whether ovarian hyperstimulation and IVF increase the risk for cancer. Design: Historical cohort analysis. Setting: IVF units of two medical centers in Israel. Patient(s): Five thousand twenty-six women who underwent IVF between 1981 and 1992. Intervention: Cancer incidence rates were determined through linkage to the National Cancer Registry and were compared with expected rates with respect to age, sex, and place of birth. Main Outcome Measure(s): Development of cancer. Result(s): Twenty-seven cases of cancer were observed, and 35.6 were expected (standardized incidence ratio, 0.76 [95% CI, 0.50–1.10]). Eleven cases of breast cancer were observed, whereas 15.86 were expected (standardized incidence ratio, 0.69 [95% CI, 0.46–1.66]). One case of ovarian cancer and 1 case of cervical cancer were observed, compared with 1.74 and 1.73 cases expected, respectively. The type of infertility, number of IVF cycles, and treatment outcome did not significantly affect risk for cancer. Conclusion(s): In a cohort of women treated with IVF, no excess risk for cancer was noted.

OBJECTIVES: The objective of this paper is to assess the risk factors for physician contact in the month before the interview (PM) and emergency room utilization (ERU) and overnight hospitalization (OH) in the year before the interview, through the use of the behavioral model as a conceptual framework. DESIGN: A random stratified sample of subjects age 75 to 94 was selected from the National Population Register (a complete listing of the Israeli population maintained by the Ministry of the Interior). The study sample consisted of Jews living in Israel on January 1, 1989, stratified by age (four 5-year age groups: 75–79, 80–84, 85–89, and 90–94), sex, and place of birth (Europe/America, Asia/Africa, and Israel). SETTING: Community-dwelling old-old Jewish Israelis. PARTICIPANTS: 1,487 people living in the community at the time of the baseline interview. MEASUREMENTS: The dependent variables were PM in the month before the interview and ERU and OH in the previous year. The independent variables were: predisposing variables (age, sex, place of birth, and education); enabling variables (income and the social network variables of marital status, living arrangements, and number of in-person contacts per week with any child); and need variables (number of self-reported chronic medical conditions, subjective health, depressive symptoms, number of difficulties with activities of daily living and instrumental activities of daily living, measures of physical robustness, and engaging in regular physical sportive activities). RESULTS: The predisposing and enabling factors were only minimally associated with utilization rates in the old old in Israel, with the exception of lower rates of ERU by those who were living alone. Age was not significantly associated with healthcare utilization in the old-old population studied. Healthcare utilization was found to be associated primarily with health and functional status. CONCLUSION: In a system of free and equal access to healthcare services, the demand for health services by a population with high levels of chronic disease and disability is driven primarily by health needs, rather than by extraneous factors such as income and education. The study indicates that equity in the provision of health services is attainable. Policy makers should provide for actual need, remove artificial barriers, and prepare accurate estimates of future needs.

Epidemiologic data have confirmed the high susceptibility of persons with Down syndrome (DS) to leukemia. The question of proneness to other kinds of cancer is still open. In this study we reassessed the incidence rates of leukemia and other malignancies in Israeli DS subjects, based on the total population. The target population consisted of all DS subjects in Israel in the period of 1948–1995. Due to incompleteness of data, the target population was not fully achieved, thus the study population was divided into 2 subgroups: subjects born in Israel between 1979 and 1995 (registry group) and currently or past-institutionalized subjects born before 1979 (institution group). The cohort was linked with the Cancer Registry, and cancer cases that had been diagnosed through December 1995 were subsequently identified. Observed incidence rates were compared with expected rates in the general population. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed for each disease category. Analyses were performed separately for each subgroup of the study population. In the registry group, 7 cancer cases were observed, compared with 1.5 expected (SIR = 4.67, 95% CI 1.9–9.6), all leukemia cases. For the institution group a total of 17 cancer cases were observed, compared with 12.8 expected. These included 4 cases of leukemia (SIR = 6.90, 95% CI 1.90–17.70). An excess of gastric cancer in male subjects (SIR = 11.9, 95% CI 1.3–42.9) was also observed. Significant excess of leukemia in DS population in Israel is in accordance with previously published data. An excess of gastric cancer in DS male subjects born before 1979, which has not been reported before, should be further explored. © 2001 Wiley-Liss, Inc.

Background: In Jewish individuals of Ashkenazi (East European) decent, three predominant mutations, 185 delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations in high-risk breast/ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG and the Tyr978X mutations, as well as several ‘private’ mutations have been reported within the BRCA1 gene. Objective: Assessing the occurrence rate of the Tyr978X BRCA1 germline mutation in Jewish non-Ashkenazi individuals: high-risk familial cases, unselected ovarian cancer patients and the general average risk Jewish Iraqi population. In addition, finding proof that this is a founder mutation. Methods: PCR amplification of the relevant fragment of the BRCA1 gene from constitutional DNA followed by restriction enzyme digest that differentiates the wild type from the mutant allele. In addition, BRCA1-linked markers were used for haplotype analysis. Results: The Tyr978X BRCA1 mutation was detected in 3/289 (1%) of the average-risk Jewish Iraqi population, in 7/408 (1.7%) high-risk Jewish non-Ashkenazi individuals (representing 332 unrelated families) and in 1/81 (1.2%) of unselected Jewish non-Ashkenazi ovarian cancer patients. Allelotyping using BRCA1-linked markers revealed an identical allelic pattern in all mutation carriers with the intragenic markers. Conclusions: Our findings suggest that this mutation is prevalent in Iraqi Jews, represents a founder mutation, and should be incorporated into the panel of mutations analyzed in high-risk families of the appropriate ethnic background.

Cancer of the bladder has long been associated with environmental risk factors, such as occupational hazards and smoking. The aim of the current study was to evaluate the contribution of known risk factors on a community basis in the 1990s, in view of the recent worldwide efforts to control environmental hazards. The study population included 140 male patients and 280 matched controls. Information on demographic data, occupational exposure, smoking habits and disease history was obtained by personal interviews. Our study confirmed the role of industrial occupation (OR=2.21; 95% Cl=1. 21-4.02) and exposure to 3 or more metals (OR=3.65; 95% Cl=1.21-11. 08) as risk factors. Prostate enlargement was also found significant, but probably not causal (OR=2.23; 95% Cl=1.29-3.87). Surprisingly, smoking showed only an inconsistent association with higher rates among those who started to smoke before 18 years of age (OR=2.64; 95% Cl=1.4-4.99) and those who smoked more than 30 cigarettes per day (OR=1.82; 95% Cl=0.95-3.49). The above data suggest that current efforts to reduce the load of bladder cancer in the population, via environmental measures, have not as yet yielded significant effects.

Our aim was to evaluate the role of maternal nutritional habits during the period of gestation and of children subsequent diet in the etiology of pediatric brain tumors. All cases of incident nervous system tumors under age 18, diagnosed between 1984 and 1993 (n = 300) in Israel were identified. Two matched population controls per case were selected (n = 574). Personal interviews, using a semi-quantified three-step food frequency questionnaire, were performed. Univariate analysis showed that increased child consumption of vegetable fat [p trend 0.01; 95% confidence interval (CI) 1.1–3.2], carbohydrates (p trend 0.05; CI 1.0–5.9), and vitamin E (p trend 0.05; CI 1.0–3.3), were significantly associated with brain tumor risk. No associations were found with nitrate, nitrite or vitamin C. A significant positive association with potassium consumption (p trend 0.01; CI 1.1–3.7) was noted during gestation. Results of multivariate analysis showed that the only persisting associations were with vegetable fat (OR = 1.36; CI 1.06–1.73) in the child diet and potassium intake during gestation (OR = 1.44; CI 1.04–1.99). In conclusion, nutritional associations with pediatric brain tumor etiology, remain unsubstantiated. Int. J. Cancer 86:139–143, 2000. © 2000 Wiley-Liss, Inc.

Head irradiation, the acceptable mode of treatment for tinea capitis in the past, is recognized today as a causative factor for meningioma. This treatment was applied en mass to immigrants coming to Israel from North Africa and the Middle East during the 1950s. In order to estimate the effect of the differential radiation treatment on the rates of meningioma in the total population, the authors assessed time trends of this disease in Israel over the past 40 years by main ethnic origin. Cohort analysis shows a marked incidence rise in the North African-born cohorts born in 1940-1954 starting from the 1980s. A similar pattern is seen in the Middle Eastern born, although the increase is not as sharp. In consequence, there is a crossover of the interethnic incidence curves in the 1940-1949 cohort. Comparison of the relative risk between 1940-1954 cohorts that comprised most of the irradiated with 1930-1939 cohorts, who were largely free of the radiation, shows that the North African born have the largest relative risk of 4.62, followed by the Middle Eastern born, with a relative risk of 1.95, while the European-American born have a relative risk close to 1. The differences between the three areas of birth are statistically significant. The data illustrate the potential risk of administering highly potent therapy for an essentially benign disease that led, in turn, to a drastic change in the national meningioma pattern.

A cohort of 968 Israeli women treated with radiotherapy for infertility was followed up for cancer incidence. The majority of the subjects were irradiated to both the ovaries and the pituitary gland. Mean doses to the brain, colon, ovary and bone marrow were 0. 8, 0.6, 1.0 and 0.4 Gy, respectively. More than 10 years after radiation treatment, 60 cancers were observed compared with 74.5 expected based on national cancer incidence rates (standardized incidence ratio 0.81, 95% confidence interval 0.61-1.04). No statistically significant excess or deficit was seen for any individual type of cancer; however, a non-significant 60% increased risk of colon cancer was observed. Risk of colon cancer was higher among women with 2 or more treatments and increased with length of follow-up. A decreased risk of breast cancer was suggested. Neither age at exposure nor attained age modified subsequent cancer risk. No clear excess of any cancer site was observed among women at organ doses above the median compared with subjects at doses below the median, except a slight increase in colon cancer. No significant excess incidence of cancer was demonstrated in this small cohort of patients treated with radiotherapy for infertility. Our results are consistent with those from an earlier study of cancer mortality among women receiving radiotherapy for infertility conducted in New York City. Int. J. Cancer 82:795-798, 1999. Published 1999 Wiley-Liss, Inc.

Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C → T, factor V (F V) nt 1691G → A (F V Leiden), and factor II (F II) nt 20210 G → A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9).The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women.

Background. The impact of chronic conditions on the development of disability has not yet been comprehensively studied among the elderly population living in Israel. This study evaluates the prevalence of disability and morbidity among the community-dwelling oldest-old population and examines the association between medical conditions, comorbidity, and disability in basic and instrumental activities of daily living (ADLs, IADLs). Method. The data are based on a national random stratified sample of 1,820 Israeli Jewish individuals 75-94 years old, of whom 1,487 lived in the community. Results. Nineteen percent of the population was disabled in ADLs and 36% in IADLs. Disability rose with age and was higher for women and among individuals of Middle Eastern and North African origin. Stepwise logistic regression indicates that the variables associated with disability in ADLs and IADLs were older age, Middle Eastern or North African origin, living with others, and the following conditions: stroke, hip fracture, diabetes, osteoporosis, anemia, and heart attack. In addition, lower education and suffering from urinary or kidney diseases, respiratory disease, and/or Parkinson's disease were related to disability in ADLs; being a woman and suffering from heart diseases other than heart attack were related to disability in IADLs. Comorbidity was related to increased disability only for individuals with three or more conditions. Conclusions. The identification of medical conditions and sociodemographic variables related to limitations in functioning may serve as a basis for health promotion and disease prevention in elders by attempting to reduce the incidence and disabling consequences of known disabling conditions.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976-1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and for 1919 controls in eight geographic areas of North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor [odds ratio (OR)=0.7; 95% confidence interval (CI)=0.5-0.9], with a trend toward less risk with longer duration of use (P trend= 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR=0.5; CI=0.3- 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the US, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously, from 3% in Israel and in France through 21% in Italy, 33% in Canada, 52% in Spain to 86-92% at the three US centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 up to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU and folate from 0 to 2000 mg. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.

Background: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients -i.e., Jewish patients of Eastern/ Northern European descent-with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors. Methods: Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer. Results: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations ; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (x 2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation. Conclusions: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.

Objective: To investigate the possible role of multifetal pregnancy reduction as a risk factor for the development of periventricular leukomalacia, which has been associated with prematurity and twin pregnancies. Design: A case-control study. Setting: In Vitro Fertilization Unit and Intensive Care Nursery of the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Patient(s): A total of 1,401 consecutive preterm infants who were born between January 1, 1994, and December 31, 1995. Intervention(s): Cranial ultrasonographic evaluation of each infant within 3 days of birth. Main Outcome Measure(s): Premature infants who developed periventricular leukomalacia (cases) were compared with premature infants who did not develop this disorder (controls) when multifetal pregnancy reduction was considered. Result(s): Fourteen premature infants developed periventricular leukomalacia. Of these, 28.6% (4 infants) were exposed to multifetal pregnancy reduction, compared with 1.9% of the controls, giving an odds ratio (OR) of 20.9 (95% confidence interval [CI] 5.5–79.4). Adjustment of this OR for IVF treatment (OR, 18.6; 95% CI, 1.8–140.3), twinning (OR, 6.3; 95% CI, 1.3–30.3), and for both IVF treatment and twinning simultaneously (OR, 8.5; 95% CI, 1.7–42.2) did not explain all the observed associations between periventricular leukomalacia and multifetal pregnancy reduction. Conclusion(s): Our data suggest that multifetal pregnancy reduction may be an additional risk factor for periventricular leukomalacia among premature infants, regardless of twinning.

The 185delAG mutation in BRCA1 is detected in Ashkenazi Jews both in familial breast and ovarian cancer and in the general population. All tested Ashkenazi mutation carriers share the same allelic pattern at the BRCA1 locus. Our previous study showed that this 'Ashkenazi' mutation also occurs in Iraqi Jews with a similar allelic pattern. We extended our analysis to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites and 150 Iranian Jews. Heteroduplex analysis complemented by direct DNA sequencing of abnormally migrating bands were employed. Four of Moroccan origin (1. 1%) and none of the Yemenites or Iranians was a carrier of the 185delAG mutation. BRCA1 allelic patterns were determined for four of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. Six non-Ashkenazi individuals shared the common 'Ashkenazi haplotype', four had a closely related pattern, and the rest ( n = 6) displayed a distinct BRCA1 allelic pattern. We conclude that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have a common allelic pattern, supporting the founder effect notion, but dating the mutation's origin to an earlier date than currently estimated. However, the different allelic pattern at the BRCA1 locus even in some Jewish mutation carriers, might suggest that the mutation arose independently.

BACKGROUND The study of cancer in spouses may play an important role in the assessment of cancer etiology. METHODS Patterns of occurrence of cancer in 195 couples related by marriage only and treated in a regional hospital are reported. The distribution of tumors by site was compared with national data. RESULTS Seven sites of cancer were found to be more frequent in married couples than in the general population, in particular carcinoma of the colon (37 observed vs. 19.5 expected in husbands [relative risk (RR) = 1.89 (95% confidence intervals [CI], 1.5-2.4); P < 0.001] and 32 vs. 16.7 in wives [RR = 1.92 (95% CI, 1.4-2.5); P < 0.001]), carcinoma of the prostate (32 vs. 20 in husbands [RR = 1.6 (95% CI, 1.19-2.09); P < 0.01]), and carcinoma of the female breast (84 vs. 55 in wives [RR = 1.53 (95% CI, 1.3-1.8); P < 0.001]). Same site tumors were observed in 13 couples versus 6.21 expected in the general population (RR = 2.09 [95% CI, 1.25-3.26]; P < 0.01). A combination of carcinoma of the prostate and female breast sites was found in 18 couples versus 5.4 expected in the general population (RR = 3.34 [95% CI, 2.19-4.84]; P < 0.001). CONCLUSIONS The distribution of cancer sites among spouses in those families in which both spouses have developed a cancer differs from that of the general population. These differences may be caused by shared risk factors. Increased awareness can explain only part of the excess. Cancer 1998;82:180-5. ©; 1998 American Cancer Society.

Several possible risk factors for brain tumors have been suggested in the past, including N-nitroso compounds, but with the exception of ionizing radiation, none has been consistently confirmed. The present study was aimed at assessing the influence of nutritional factors, including N-nitroso compounds, in the etiology of brain tumors, specifically gliomas and meningiomas. One hundred and thirty-nine cases with confirmed brain tumors diagnosed between 1987 and 1991 in central Israel and 278 controls matched according to age, sex, and ethnic origin were interviewed. Nutritional data were obtained using a semiquantitative food frequency approach. A significant positive association for both types of brain tumors was found with high protein intake (odds ratio (OR) = 1.94, 95% confidence interval (CI) 1.03-3.63), while intake of sodium was inversely related to both types of brain tumors (OR = 0.52, 95% CI 0.31-0.87). Increased consumption of total fat and cholesterol was inversely related to gliomas (high intake of fat: OR = 0.45, 95% CI 0.20-1.07; high intake of cholesterol: OR = 0.38, 95% CI 0.14-1.01). However, neither fat intake nor cholesterol intake was significantly related to the risk of meningiomas. Although N-nitroso compounds were not found to be directly associated with brain tumors, the data suggested the presence of an interaction between the effects of N-nitroso compounds and protein intake and between N-nitroso compounds and cholesterol intake. The data suggest that dietary factors may play an important, though yet undefined, role in the development of brain tumors.

To assess the possibility of reducing the risk of unwanted pregnancy through a controlled intervention program that was based on a sex education workshop.Educational intervention study.Newly drafted women in a central absorption army base in Israel.One thousand seven hundred ninety-three female draftees in the Israeli Defence Force.A 2-day workshop on sex education at the beginning of army service.Rate of unwanted pregnancy.After 2 years of follow-up, there were approximately 40% fewer unwanted pregnancies among women with a lower socioeconomic and intellectual profile.Structured intervention programs may reduce significantly the rate of unwanted pregnancy in young women.This study evaluates the success of sex education workshops in preventing unwanted pregnancy among 1793 newly drafted women in 1987 in the central absorption army base in Israel. The sex education workshops were held over a 2-day period at the beginning of army service. The study sample included 968 women in the intervention group and 825 controls. The sex education program included information on sexuality, the anatomy and physiology of the reproductive system, contraceptive methods, pregnancy and childbirth, decision making processes, interpersonal relations, pregnancy prevention, sexually transmitted diseases, and personal hygiene. Each of the 4 daily sessions aimed to involve young women in verbal participation on sex-related topics and to correct myths and prejudices. Questionnaires were administered pre and post army service among cases and controls. The extent of unwanted pregnancy was assessed at a point 2 years after induction. During the 2-year study period, 58 women became pregnant. 2.6% in the intervention group and 4% in the control group had unwanted pregnancies. Unwanted pregnancy was significantly higher among controls and among lower socioeconomic groups. The rates of contraceptive use at first intercourse and visiting a gynecologist were higher in the case group than in the control group after the workshops. Logistic models confirmed the statistical significance of the relationship between unwanted pregnancy and the low Caba subscale (education, Hebrew language proficiency, and language and scholastic fluency), low level of language skill, and controls.

The potential use of the ferritin bearing lymphocytes (FBL) blood test which enumerates oncofetal FBL as a biomarker for early breast cancer was explored. Analysis of the FBL positive test results carried out on high risk women who underwent biopsy in 1983-84 was found to be a significant predictor for early breast cancer (relative risk (RR) = 2.9, 95% confidence interval (CI) 1.4-5.8). A group of 635 women from the above study diagnosed in 1983-84 as having no evidence of breast cancer was further traced 8 years later with the aid of the National Cancer Registry. We identified 35 malignancies, including 19 cases of breast cancer. The RR of breast cancer for the FBL positive group was 2.51; 95% CI = 1.04-6.07 while for the other malignancies it was 0.93, 95% CI = 0.30-2.84. All the breast cancer cases in the FBL positive group were of the infiltrative duct carcinoma category and 71% were in early stage. In contrast, in the FBL negative group, 60% of the cases were infiltrative ductal carcinoma and most of them were at stage III. Positive FBL is associated with early manifestation of breast cancer and may be considered as a tool for the screening of breast cancer in high risk women.

The authors examined the rate and correlates of depressive symptoms among community-dwelling oldest-old citizens in Israel with a sample of about 1,200 Jewish Israelis age 75-94. The estimated national rate of depressive symptoms was 43.5%. Significantly higher rates of depressive symptoms were found in women (52%, vs. 29.5% for men) and those of low educational level, low income, and Middle Eastern or North African origin. Having more depressive symptoms was associated with 1) all measures of impaired health status; 2) the psychosocial factors of living alone or with a nonspouse, having no available caretaker, and social and physical inactivity; 3) the following health behavior and habits: poor sleep, skipping meals, sexual inactivity, and drinking no alcohol; and 4) traumatic life events and immigration after age 20. The rate of depressive symptoms is relatively high among oldest-old citizens in Israel, possibly because of the immigrant nature of this population.

Second cancer in a women with a primary gynecological malignancy could reflect a common etiology or sequealae of a potentially carcinogenic treatment. The aim of the present study was to determine the incidence rate of second primary cancer in a cohort of women with primary gynecological cancer and patient characteristics, namely age, diagnosis, type of treatment, and duration of follow-up. The study cohort comprised 925 Israeli Jewish women with histologically confirmed gynecologic malignancies. The file was linked by computer matching to the Israel Cancer Registry for identification of second primary cancers. Standardized incidence rates (SIRs) for site-specific as well as for all cancer were computed. A significant excess for subsequent leukemia among ovarian (SIR 10; 95% CI 1.1–36.1) and uterine corporal cancer patients (SIR 10.0; 95% CI 2.7–25.6) was found. The significant increase in leukemia was treatment-related and limited to patients treated with radiotherapy. Age older than 60 years constituted a significantly unfavorable factor. The estimated probability of developing a subsequent cancer at 175 months is 6.1%. Physicians should be aware of the possibility of a second primary malignancy when prescribing treatment and during follow-up.

Background. Inappropriate use of hospital services, in the form of unjustified hospital stay days (HSD), constitutes a major burden on a health budget. Reduction of unjustified HSD was achieved in a medical ward in a previous intervention study. Methods. A controlled intervention aimed at reducing unjustified hospital stay was performed on 155 paediatric inpatients and 248 controls, by applying pre-set criteria for hospitalization and comparing to results in previous studies. Results. Unjustified stay was decreased from 32.6% to 14.8% on the study ward, and from 25.7% to 19.3% on the control ward. The children on both wards did not differ significantly in rates of subsequent out of hospital mortality, re-admission, and the subjective evaluation of health by their parents one month following discharge. Conclusions. This study demonstrates that despite the fact that the per cent of unjustified HSD on a paediatric ward is much lower than on medicine or surgery, a significant reduction in unjustified stay can be achieved by intervention programme.

The aim of our study was to compare the outcome of patients with a first acute myocardial infarction (AMI) among three large cohorts of patients hospitalized between 1966 and 1992 in Israel, in view of changes in treatment facilities and investigation methods. Patients with a first AMI constituted 71% of all myocardial infarctions in 1966, 74% in 1981–1983, and 71% in 1992. The male—female ratio and the distribution of the site of infarction also remained stable from 1966 to 1992. The mean age of patients increased over time. Thrombolytic therapy was not available in 1966 and 1981–1983, whereas 53% of patients were treated with a thrombolytic agent and 22% examined with coronary angiography in 1992. The 21-day mortality rate decreased markedly, from 22% in 1966 to 14% in 1981–1983 and to 8% in 1992. The decrease was similar in both genders and among 10-year age groups. The 1-year postdischarge mortality rate (not evaluated in 1966) decreased from 7% in 1981–1983 to 6% in 1992. We conclude that a significant reduction in mortality rate after a first AMI took place over the 25-year period. Changes in treatment modality and management of the acute phase may explain this decrease in mortality rate over time.

Israel, located in a region endemic for hepatitis A virus (HAV), recently absorbed a large population of immigrants who came from the former USSR. To assess the risk of high morbidity in this population a serosurvey of HAV antibodies was undertaken. Serum samples were collected from 965 new immigrants, of whom 664 came from the European, non-endemic region, and 301 from the Asian and Caucasian endemic regions of the former Soviet Union. They were compared to 240 Israelis. Each population was divided into six age groups: 1-9, 10-19, 20-29, 30-39, 40-49, and 50 years of age and older. The Asian/Caucasian immigrants and the Israeli population were found to share similar characteristics. In both groups, antibodies to HAV (anti-HAV) were present in the 1-9-year-old age group and reached maximum prevalence (90% and 86.7%, respectively) in the 20-29-year-old age group. In contrast, among the European immigrants anti-HAV was first found in the 10-19-year-olds and peaked (93%) in the age group of 50 years and older. It is concluded that immigrants originating from the European part of the former USSR may require vaccination against hepatitis A.

von Willebrand factor (vWF) is synthesized almost exclusively by endothelial cells and is stored there as ultra-high-molecular-weight multimers. The vWF multimers that are detected in the plasma are smaller than those stored within the endothelium. In two previous studies, comprising small series of cases with classic Kaposi's sarcoma (KS), an endothelium-derived tumor, increased levels of plasma von Willebrand factor antigen (VWF:Ag, the antigenic structure) were reported, suggesting that vWF:Ag may be a marker of endothelium proliferation.Our purpose was to investigate the quantitative as well as qualitative alterations of plasma vWF in a large series of patients with classic KS at various stages of the disease.Levels of plasma vWF:Ag were studied in 38 patients with classic KS confined to the skin at various stages of the disease and compared with a control group. Thirty-three patients had active KS (i.e., with skin lesions) and five were in remission. In five patients with active KS multimeric analysis of plasma vWF was also performed.The levels of vWF:Ag were significantly higher among KS patients than in the control group (n = 29, p0.01). Levels of vWF:Ag were also significantly higher in patients with active disease as compared with those in remission (p0.05). No correlation was found between vWF:Ag levels and the extent of KS. Analysis of the multimeric pattern of plasma vWF showed enhanced staining of all bands, particularly the intermediate and high molecular weight forms, which resemble the endothelial forms as opposed to normal circulating vWF multimers.Quantitative as well as qualitative alterations in plasma vWF were found in patients with KS, which may reflect the destruction or activation of endothelial cells within the lesions. vWF:Ag may serve as a marker of disease activity in classic KS; however, it is not a good marker for the extent of the disease.

This study was designed to investigate concurrently the psychological and hormonal changes at three critical points during in vitro fertilization (IVF) treatment. One hundred thirteen couples suffering from mechanical and unexplained infertility participated in the study and 23 of them conceived. Psychological evaluation included background questionnaires, Lubin's Depression Adjective Check List, and Spielberger's State Trait Anxiety inventory. Cortisol and prolactin levels were estimated by radioimmunoassay. The results showed that patients' anxiety and depression scores were significantly higher than the population norm. Psychological test scores and hormonal levels showed a similar pattern of change, increasing on oocyte retrieval day, decreasing on embryo transfer day, and rising again on pregnancy test day. Differences between these phases were generally significant. Differences in parameters' means between conceiving (C) and nonconceiving (NC) women were generally not significant. However, correlations between psychological measures and hormonal levels showed a clear disparity between C and NC women in the last phase. Whereas significant negative correlations were found in C patients, no relationship was found in NC patients. The findings suggest that success in IVF treatment may depend, in part, on differential modes of coping with anxiety and depression, involving hormonal or endorphin mediation.

BACKGROUND The possible association between ovarian carcinoma and ovulation-inducing drugs has led to renewed interest in the potential carcinogenic risks of these drugs. In vitro fertilization (IVF) has been linked to multiple pregnancies and possibly congenital malformations. However, to the authors' knowledge the association between IVF and pediatric cancer has been described only in sporadic case reports. The aim of this study was to assess the incidence rate of pediatric cancer among a cohort of children born after IVF. METHODS A historic prospective study based on a cohort of 332 children from 1254 women who underwent IVF treatment between 1981–1994 was performed. Medical files were reviewed and names were linked to the National Population and Cancer Registries. Pediatric cancer incidence rates were compared with the expected age-adjusted rates of the general population during the respective time period. RESULTS No cancer cases were observed among the study cohort with respect to 1.7 cases that were expected. CONCLUSIONS Because the small cohort analysis in the current study lacked the necessary power to reach definite conclusions, larger prospective studies are needed to assess the potential carcinogenic effect on children born after ovulation induction and IVF.

Fifty-four per cent of hospital stay days on the medical wards in a large teaching hospital, 40% on surgery and 26% on pediatrics, were found to be unjustified, using an assessment method based on explicit criteria. Despite the observed differences between the various specialities, the frequency distribution of the reasons for unjustified hospital stay days was essentially similar. Most of the unjustified hospital stay days were attributed to diagnostic evaluation, non-emergency treatment and immediate follow-up, which were carried out within the hospital rather than on an ambulatory basis. The major factors for unjustified hospital stay days were age, ethnic group, ward of admission and diagnostic category. These findings may contribute to the implementation of hospital utilization management programs aimed at cost containment.

A community outbreak of hepatitis A is described, involving 23 persons in a small town in central Israel. Seventy-four percent of the cases were related to a contact with toddlers in one nursery class in a day care center. There were no overt cases in that class itself. The mode of transmission exemplified in this community underlines the difficulties in identifying a common source of hepatitis A infection, which is necessary for the elimination of a further spread of the disease.

A number of issues inherent in the selection of friends as controls in case-control studies are illustrated in the light of a recent dietary study, based on hospital and friend controls. Preselection of certain characteristics of the controls by the interviewee is almost unavoidable. The choice of controls to be used in a case-control study must reflect the nature and type of hypothesis which is being tested. Advantages and drawbacks of potential control groups must be weighted against each other. Case-control studies, controls, friends, N-nitroso compounds, brain tumours 28 November 1997 Choosing appropriate controls is certainly the most critical issue in the design of case-control studies. Probably the major assumption underlying the validity of studies is that controls represent the study population in terms of probability of exposure to risk factors that are not under investigation, and that they should have had a similar opportunity for exposure to the risk factor under consideration.12 Theoretically, controls may be selected from a variety of sources, yet each of the choices, such as the general population, hospital patients, peer workers, neighbours, relatives and friends1-3"8 is susceptible to bias. One common option is to use controls suffering from another disease from the same hospital in which the cases were diagnosed, assuming that the risk factor under study is unrelated or, rather, less related, to the condition of the case subject. Many selective parameters, such as financial status, residence, ethnicity, and occasionally, degree of religious observance, will be commonly shared by such controls. On the other hand, hospital controls are often selected on the basis of factors associated with their underlying disease.19 In contrast, friends of cases are rarely used as matched controls4"7''° even though they tend to be of the same age and sex, and usually share a common and similar socioeconomic status and may therefore effectively account for potential confounders. Considerable time and financial effort may be saved due to their easy accessibility.1' Yet, certain potential disadvantages of selecting friends as controls, particularly overmatching, have discouraged many investigators from choosing this option.3-8'11-12 We wish to underline a few issues inherent in the selection of friends as controls, in the light of a recent dietary case-control

OBJECTIVE: To assess the risk of neoplastic development among persons exposed to scalp irradiation. STUDY DESIGN: Historical cohort study initially; prospective follow-up subsequently. METHOD: Two control groups--population and siblings--matched for age, sex, ethnic origin, and year of immigration. Follow-up from time of irradiation (1950s) until the end of 1991. Linkage with nationwide cancer registry. RESULTS: A 4.5-fold incidence of cancer (P < .01) and a 2.6-fold increase of benign tumors were noted. The mean length of latency period until tumor development was 11 years for malignant tumors and 21.5 years for benign. A clear dose response effect for both cancer and benign tumors was demonstrated. CONCLUSIONS: The study confirms the role of radiation in salivary gland carcinogenesis. It indicates a need for better awareness, a comprehensive examination, and long-term follow-up of patients who have been subjected to head and neck radiation.

Priority setting in radiation policy is complex because it depends to a large extent on risk perception. It has been shown repeatedly that the public is much more sensitive to potential harmful sequelae of radiation than to those of other environmental pollutants. Thus, cancer risk, particularly at low doses, has become a sociopolitical issue. The principle that radiation causes cancer, is life shortening, and causes an array of other pathologic disorders, is well accepted yet the quantification of sequelae at the lower end point of the dose-response curve is still controversial. The presence of a significant carcinogenic effect at very low doses has strong financial implications. Sociopolitical and economic values play a major role in the interpretation of available data. Thus, the use of nuclear energy is a function of risk/benefit, pressures, available alternatives, and cost. Three case studies--nuclear plant workers, children irradiated for an essentially benign condition, and food safety--are used to illustrate polar policy decisions.

Ionizing radiation is the strongest risk factor known for the development of thyroid neoplasia. Although ret/PTC rearrangements have been identified in both spontaneous and radiation-induced papillary thyroid cancer, they seem more frequent among radiation-associated tumors. We studied the frequency of ret/PTC activation in a group of sporadic and radiation-induced thyroid carcinomas (n = 49) and adenomas (n = 13) among 44 individuals treated for Tinea Capitis with low-dose external irradiation as well as in 18 nonirradiated subjects. Total RNA recovered from paraffin-embedded thyroid cancer surgical specimens was analyzed for ret/PTC 1, 2, and 3 mutations using RT-PCR with Southern blotting to maximize detection sensitivity. Ret/PTC rearrangements were identified in 42.9% of thyroid carcinoma and 46.2% of adenoma subjects. Among the positive carcinoma specimens, three were follicular carcinomas. Ret/PTC 1, the predominant rearrangement, was more prevalent in nonirradiated compared with irradiated carcinomas (66.7 vs. 27.0%; P = 0.04). Ret/PTC activation was associated with male gender. The strengths of this study included analysis of age-, gender-, and ethnicity-matched groups; molecular analysis using two techniques; and a complete blinding of laboratory analysis from clinical features. The differences seen between these and other published results may be related to differences in radiation doses to the thyroid, latency period between time of radiation exposure and development of clinically apparent thyroid cancer, and ethnic background of the study populations.

Objective This study was undertaken to characterize primary peritoneal carcinoma (PPC) compared with ovarian carcinoma (OvC). Study design Within the framework of a nationwide epidemiologic Israeli study, 95 PPC patients were identified and compared with 117 FIGO stage III-IV epithelial OvC patients matched by age and continent of birth. Data were abstracted from medical records and personal interviews. Results Our data confirm the similarities between PPC and OvC. A higher rate of abdominal distention, volume of ascites, and malignant cells in ascitic fluid and lower rate of pelvic palpable mass and personal breast cancer history were found in the PPC compared with the OvC group. The overall survival was similar in both groups (30-33 months). In optimally cytoreduced patients, survival was better in the OvC group. Diameter of residual disease was associated with better survival only in the OvC group. Conclusion The clinical differences do not enable a preoperative distinction between the neoplasms.

ObjectiveTo analyze the somatic pattern of p53 expression and BRCA germline mutation status in Israeli patients with both ovarian (OvCa) and breast cancer (BrCa).MethodsThe study group comprised 43 Israeli patients with OvCa, all of whom had previous primary BrCa. p53 immunohistochemistry (IHC) on all available archival tissues and genotyping for the three predominant Jewish germline BRCA1–2 mutations were carried out. Samples from 64 patients with solitary OvCa and 61 with solitary BrCa were similarly analyzed as controls.Resultsp53 expression pattern and the immunopositivity rate were similar in the ovarian and breast tumors within the study group and in the two control groups: positive p53 staining was detected in 68% of ovarian tumors in the study group compared with 71.9% in the controls, and in 19.4% of the BrCa tissues versus 21.3% in the controls. Within the study group, advanced stage OvCa had a higher rate of p53 expression (84%) compared to early stage disease (38.5%) (P = 0.006). This difference was not apparent in the solitary OvCa control group. OvCa in BRCA1–2 mutation carriers from the study group were more likely to display positive p53 staining (79%), especially in tumors diagnosed before the age of 60 (90%) compared with the OvCa of noncarriers (60%), but this difference was statistically insignificant. The p53 expression rate in BrCa samples from the study group was not associated with BRCA1–2 mutation status.ConclusionsPositive p53 expression, detected by IHC, in OvCa patients with previous primary BrCa is significantly higher in advanced stage disease in BRCA1–2 mutation carriers. There is a higher positive p53 expression somatically in OvCa in BRCA1–2 carriers in whom OvCa was diagnosed before the age of 60 years, although this trend is not statistically significant. These observations suggest that somatic p53 inactivation may be an important event in ovarian tumorigenesis in this subset of patients.