Benign and malignant thyroid neoplasms after childhood irradiation for tinea capitis.

The incidence of all thyroid surgery was studied among 10,842 persons whose thyroid glands had been exposed in childhood to an average dose of 9 rads of X-radiation during treatment for tinea capitis and among 2 matched control groups. A statistically significant increased risk for both benign and malignant neoplasms was found in the exposed group. The excess risk was 8.3 cases/year/rad/million population. There were no differences in other surgical conditions between the irradiated and nonirradiated groups. Persons irradiated under age 6 years had the highest excess risk for developing carcinomas. The incidence of thyroid neoplasms was approximately threefold higher in women than in men among the irradiated persons and among the controls, but the relative risk for the irradiated group of women was greater than the addition of the relative risks of the other groups. Low-dose radiation is instrumental in the development of both benign and malignant thyroid neoplasms.

Role of fat, animal protein, and dietary fiber in breast cancer etiology: a case-control study.

A case-control study of 818 breast cancer (BC) patients and 2 matched control groups, surgical controls (SCs) and neighborhood controls (NCs), was undertaken in Israel between 1975 and 1978. The interview schedule included a detailed dietary history based on the frequency of consumption of 250 food items, which were grouped according to their principal nutrient component. The average frequency of consumption of each food item in each nutrient group was computed. Medical, demographic, hormonal, and parity histories were also obtained. Risks associated with fat, animal protein, and fiber consumption were evaluated. Two types of analysis were performed [in 2 age groups (less than 50 yr and greater than or equal to 50 yr)], using the conditional logistic method: evaluating the risk attributable to nutrition only and controlling for nondietary confounding factors as well. When no adjustment for nondietary confounding factors was made, the risk increased with fat intake in both age groups [one-tailed P-value for linear trend = .08 and .07 in age less than 50 and .01 and .10 for the greater than or equal to 50 age category for the BC case (BCC)-SC and BCC-NC comparisons, respectively]. Increased fiber intake decreased the risk in the younger age group (one-tailed P-value for linear trend = .06 and .07 for the BCC-SC and BCC-NC comparisons, respectively), while in the 50-or-over age category the trend was inconsistent. The risk associated with animal protein was much less clear. For women in the highest quartiles of fat and animal protein intake and the lowest quartiles of fiber intake, risk was about twice as high as that for women in the lowest quartiles of fat and animal protein intake and in the highest quartile of fiber intake (one-tailed P-value for linear trend = .04 and .08 for age less than 50 and .08 and .09 for the age category greater than or equal to 50 BCC-SC and BCC-NC comparisons, respectively). When hormonal and demographic confounding factors were controlled for, this pattern persisted but it remained significant for 1 control only. Power increased when cases were analyzed against both controls simultaneously (one-tailed P-value for linear trend = .10 for age less than 50 and .02 for age greater than or equal to 50). Thus a higher fat-animal protein and lower fiber diet is associated with increased cancer risk, but this relationship needs to be studied further.

Coffee and methylxanthines and breast cancer: a case-control study.

A dietary case-control study based on 818 newly diagnosed breast cancer (BC) patients was conducted in Israel between 1975 and 1978. The role of coffee and total methylxanthine intake from coffee, tea, cola, chocolate, and cocoa drinks was evaluated in the BC patients as compared to that in two matched control populations [surgical controls (SC) and neighborhood controls (NC)]. Because it has been suggested that caffeine enhances mammary carcinogenesis in rats fed high polyunsaturated fat diets, analysis was done also in relation to fat consumption. When comparison was done to both matched control groups, a nonsignificant negative association was found between consumption of cups of coffee and BC (odds ratios of greater than or equal to 4 cups of coffee/day vs. less than or equal to 1 per week = 0.6 for BC/NC and 0.7 for BC/SC). This association was observed in all 3 ethnic subgroups studied. The pattern was stronger among the high-fat consumers after controlling for several hormonal confounding factors (two-tailed P-value for linear trend = 0.06 for SC and P = 0.05 for NC). In addition, when the consumption of methylxanthine of BC patients was compared to that of benign breast patients, adjusted by age and ethnic group, a diminished risk was found (odds ratio for BC of the highest level of methylxanthine vs. lowest level = 0.59).

Relationship between steroid excretion patterns and breast cancer incidence in Israeli women of various origins.

A nationwide study of the steroid excretion patterns in postmenopausal Israeli migrant women demonstrated differences between high- and low-risk groups for breast cancer in the following variables: age at first parturition, number of pregnancies, number of live births, height, and weight. The direction of the differnces was in line with those observed for breast cancer patients. The groups also differed in the exretion of estriol, 17-ketosteroids, and allotetrahydrocortisol. Multiple regression analysis revealed that the exretion of estriol was significantly lower in population groups in whom breast cancer incidence was high. Possibly this trend--which has also been observed in adolescent and premenopausal women--reflected environmental influences on peripheral estrogen metabolism.

Low-fiber intake as an etiologic factor in cancer of the colon.

A case-control dietary study of 198 patients with cancer of the colon and two matched control groups demonstrated a significantly lower fiber consumption frequency among the cancer patients. This difference was not confined to a few items. Of the 73 items on the fiber list, 61 were eaten less often by the cancer patient than by a neighborhood control, and 57 were consumed less frequently than by a surgical control. These findings support the hypothesis that low-residue foods play an etiologic role in colon carcinogenesis. A mechanism related to the possible potential carcinogenic properties of degraded biliary compounds may be implicated.

Rates of Jewish ancestral mutations in BRCA1 and BRCA2 in borderline ovarian tumors.

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 (chi2 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.

Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies.

We conducted a combined analysis of the original data to evaluate the consistency of 12 case-control studies of diet and breast cancer. Our analysis shows a consistent, statistically significant, positive association between breast cancer risk and saturated fat intake in postmenopausal women (relative risk for highest vs. lowest quintile, 1.46; P less than .0001). A consistent protective effect for a number of markers of fruit and vegetable intake was demonstrated; vitamin C intake had the most consistent and statistically significant inverse association with breast cancer risk (relative risk for highest vs. lowest quintile, 0.69; P less than .0001). If these dietary associations represent causality, the attributable risk (i.e., the percentage of breast cancers that might be prevented by dietary modification) in the North American population is estimated to be 24% for postmenopausal women and 16% for premenopausal women.

Seasonality in the occurrence of breast cancer.

A nationwide study of all 3183 female patients with breast cancer in Israel diagnosed over a 7-year period (1960 to 1966) was conducted. Monthly series analysis showed a clear seasonal pattern in the symptomatology of the disease most pronounced in patients younger than 55 years, in all ethnic groups, mainly confined to cases with a nonlocalized tumor at diagnosis. Peaks occurred during spring, and troughs appeared during autumn. It is suggested that the pattern is of endogenous, probably hormonal nature, although environmental factors cannot be excluded.

Dietary factors and cancer in Israel.

The risk of developing cancer is relatively higher in the European-born Israeli population than in those originating from the Middle Eastern or North African countries. The majority of cancer sites with a higher risk in the European groups involve the gastrointestinal and reproductive systems. Certain leads suggest that at least some of these differences may be attributed to diet. Data based on case-control studies are provided; they indicate a high consomption of starches among gastric cancer patients and a lower fiber consumption in patients with cancer of the colon. The latter observations may be extended to cancer of the breast, ovary, and corpus uteri, assuming an interplay between the concentration of bile degradation products and hormone metabolism. Although a low fiber consumption seems a more likely mechanism, a higher fat consumption is also compatible with this model. However, due to the complexity of human nutrition, it seems unwarranted to incriminate any single dietary factor in carcinogenesis. A better understanding of the metabolic pathways, coupled with consistent observations from distinct populations, should be looked for.

Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

Evaluation of an intervention aimed at reducing inappropriate use of preoperative blood coagulation tests.

A multiphase intervention trial based on education, implementation of criteria, and restriction, aimed at modifying the established clinical policy of mandatory preoperative screening for coagulation abnormalities, was carried out on five surgical wards of a general hospital. The education period did not influence the ordering of partial thromboplastin time tests, despite a significant posteducational change in surgeons' attitudes. In contrast, administrative restriction of coagulation test orders led to a 50% decline on four of the five study wards. We conclude that an educational intervention followed by administrative restriction may be considered an acceptable means of overcoming clinician reluctance to change well-established but redundant clinical policy.

Could the 185delAG BRCA1 mutation be an ancient Jewish mutation?

A predominant mutation within the BRCA1 predisposition gene, 185delAG, has been detected in about 1% of the Ashkenazi population, considered a high-risk group for breast and ovarian cancers. We examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group, for the existence of this mutation. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers revealed that 2 of the Iraqis shared a common haplotype with 6 Ashkenazi mutation carriers, and 1 had a haplotype which differed by a single marker. This study suggests that the BRCA1 185delAG mutation also occurs in populations considered at low-risk for breast and ovarian cancers, and that it might have occurred prior to the dispersion of the Jewish people in the Diaspora, at least at the time of Christ.

Nutritional factors associated with benign breast disease etiology: a case-control study.

Between 1977 and 1980, 854 biopsied cases of benign breast disease (BBD) and 755 matched surgical and 723 matched neighborhood controls subjects were interviewed in Israel by using a detailed food frequency questionnaire. Cases were classified according to degree of ductal atypia (Black-Chablon grading system). Women with atypic lesions (grades greater than or equal to 3) reported a higher intake of all types of foods compared with both control series. Further analyses indicated that the increased consumption was due primarily to foods containing greater than or equal to 10% fat. Odds ratios associated with the highest fat consumption quartile were close to 3.0. There was a trend for increasing saturated fatty acid consumption with increasing ductal atypica. After adjusting for hormonal and demographic confounders, the association with fat intake was strengthened. Because atypic BBD has been reported to be a precursor of breast cancer, our findings lend support to the hypothesis that dietary fat is a risk factor for breast cancer.

In vitro radiosensitivity of fibroblasts from thyroid and skin cancer patients treated with X-rays for tinea capitis.

To investigate the hypothesis that persons who developed thyroid or skin cancer subsequent to scalp irradiation for tinea capitis are particularly sensitive to radiation, possibly because of a high frequency of ataxia-telangiectasia, we used an in vitro cell survival assay to evaluate radiosensitivity of their fibroblast cell strains. Study subjects were selected from a cohort of 10,834 Israelis irradiated during childhood for tinea capitis. Skin fibroblasts were obtained from thyroid and skin cancer patients (cases) as well as a sample of subjects who did not have cancer (controls). Fibroblasts were cultured and then loss of colony-forming ability as a result of acute X-irradiation was evaluated. Comparison of survival curve parameters (mean inverse of the slope and the dose needed to reduce colony survival to 10%) between 12 thyroid cancer and 12 control strains showed no differences (P > 0.5). A slightly increased radiation sensitivity of the skin cancer cases compared with their controls was observed. Although based on few subjects (14 cases and 11 controls), the findings were similar whether the mean inverse of the slope (P = 0.06) or the dose needed to reduce colony survival to 10% (P = 0.05) was evaluated. However, because of the small size of the study and potential errors inherent in survival assays, our finding that cell strains derived from patients who developed skin cancer exhibit enhanced radiosensitivity should be viewed as preliminary and interpreted cautiously.

A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.

Screening for cervical cancer--should the routine be challenged?

Despite the extensiveness of cervical cancer screening programs, certain major issues are still at stake: (a) substantial false negative rates are common, mostly due to impaired test quality, (b) the optimal length of interval between screenings is uncertain, being a function of available resources and the physicians' attitude, (c) the postmenopausal population, in which incidence is highest, is inadequately tapped. Efforts must be made to optimise the process through more stringent control measures, and a more comprehensive cover of the target population.

Selectively increased risk of cancer in men with coronary heart disease.

Cancer incidence was assessed among a cohort of 10,923 male coronary patients in Israel screened for participation in a secondary prevention trial and compared with national cancer incidence rates. Higher total and age-specific incidence rates of cancer were observed among male coronary patients than among the Israeli male population, but this excess was limited to cancers of the lung, bladder, and colon.

Increased cardiovascular disease mortality rates in traumatic lower limb amputees.

We evaluated the 24-year mortality rates of male traumatic lower limb amputees (n = 201) of the Israeli army, wounded between 1948 and 1974 compared with a cohort sample representing the general population (n = 1,832). Mortality rates were significantly higher (21.9% vs 12.1%, p <0.001) in amputees than in controls. Cardiovascular disease (CVD) mortality was the main cause for this difference. The prevalence of selected risk factors for CVD was determined in 101 surviving amputees (aged 50 to 65 years) and a sample of the controls (n = 96) matched by age and ethnic origin. Amputees had higher plasma insulin levels (during fasting and in response to oral glucose loading) and increased blood coagulation activity. No differences were found in rates of current symptoms of ischemic heart disease or of cerebrovascular disease, obesity, hypertension, altered plasma lipoprotein profile, impaired physical activity, smoking, or nutritional habits. Traumatic lower limb amputees had increased mortality rates due to CVD. Surviving amputees had hyperinsulinemia, increased coagulability, and increased sympathetic and parasympathetic responses (described previously). These established CVD risk factors may explain the excess mortality due to CVD in traumatic amputees.

Radiation policy: a decision-making model.

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.

Results from an international case-control study of childhood brain tumors: the role of prenatal vitamin supplementation.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and 1919 controls from eight geographic areas in North America, Europe, and Israel. Although 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 of 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 United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously: from 3% in Israel and France, 21% in Italy, 33% in Canada, 52% in Spain and 86 to 92% at the three U.S. centers. The composition of the various multivitamin compounds taken also varied: the daily dose of vitamin C ranged from 0 to 600 mg, vitamin E ranged from 0 to 70 mg, vitamin A ranged from 0 to 30,000 IU, and folate ranged from 0 to 2000 micrograms. 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.