Genetic polymorphisms in fatty acid metabolism genes and colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels.

Serum 25(OH)D concentrations in sunny Israel.

SUMMARY: This study assesses vitamin D status in Israel. Serum 25(OH)D levels <25 and <50 nmol/L are common in Israel with noted differences between Arabs and Jews, Arab females were particularly at high risk. These findings may require public health intervention at the population level. INTRODUCTION: Small studies from Israel have suggested a high prevalence of hypovitaminosis D. The objective of this study was to evaluate the extent of hypovitaminosis D among demographic subgroups in Israel. METHODS: The data of this study are from the Clalit Health Services (CHS) which is a non-for-profit health maintenance organization (HMO) covering more than half of the Israeli population. We included all CHS members for whom a 25(OH)D test result in 2009 was available and who were not taking vitamin D supplements in 2008-2009 before that 25(OH)D result. Complete data were available for 198,834 members. RESULTS: The mean level of 25(OH)D was 51.9 ± 24.5 nmol/L and was higher in summer compared to winter (P < 0.0001). Level <25, <37.5, and <50 nmol/L were detected in 14.4%, 30.7%, and 49.9% of tests; 16.4% had levels >75 nmol/L. Females had higher prevalence of 25(OH)D levels < 50 nmol/L which were found in 51.8% of females versus 45.0% in males (P < 0.0001); 76.7% of the Arabs had levels <50 nmol/L versus 46.5% in Jews (P < 0.0001). Arabs females were particularly at high risk for 25(OH)D <50 nmol/L; 84.8% of them had levels <50 nmol/L versus 48.1% of Jewish females (P < 0.0001). The relation of 25(OH)D levels with age had a sinusoidal shape among Jews, a U-shape in Arab females, and inverse linear pattern in Arab males. CONCLUSIONS: 25(OH)D levels <25 and <50 nmol/L are common in Israel. Public health measures are needed for values lesser than about 30 nmol/L and further monitoring of concentrations between about 30 and 50 nmol/L to determine if there are adverse health effects.

Smoking attenuates the negative association between carotenoids consumption and colorectal cancer risk.

OBJECTIVES: Consumption of vegetables and fruits, physical activity, obesity and caloric intake are all strongly related to the risk of colorectal cancer (CRC). The association between dietary intake of carotenoids from vegetables/fruits and risk of CRC in the context of cigarette smoking was studied in a nutritionally diverse population. METHODS: The study included 1,817 age sex residence-matched case-control pairs from a population-based study in Northern Israel. Data were acquired by food-frequency questionnaire. Individual intake of carotenoid isomers was calculated using an Israeli food content database. Odds ratios (ORs) were calculated using conditional logistic regression models adjusted for known risk factors. RESULTS: Strong inverse associations were found with consumption of 9-cis-beta-carotene (OR = 0.35, 0.26-0.47), all-trans-beta-carotene (OR = 0.58, 0.44-0.76), cis-beta-cryptoxanthin (OR = 0.67, 0.50-0.90), all-trans-zeaxanthin (OR = 0.64, 0.48-0.86), and lutein (OR = 0.74, 0.57-0.96). Lycopene (OR = 2.22, 1.71-2.89) and all-trans-beta-cryptoxanthin (OR = 2.01, 1.48-2.73) were associated with increased risk of CRC. Inverse associations of most carotenoids with CRC, demonstrated in non-smokers, were much attenuated or reversed in past or current smokers with a highly significant interaction term. CONCLUSIONS: Consumption of most dietary carotenoids was found to be strongly associated with reduced risk of CRC. However, smoking significantly attenuated or reversed this observed protective effect on CRC occurrence. Smokers should be advised that smoking also hampers the potential health promoting effects of high fruit and vegetable consumption.

Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel.

Three specific mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes have been reported to be of high prevalence in the Jewish Ashkenazi population. We studied the differences in phenotype of families carrying these mutations. All consecutive families found by the CHS Familial Cancer Service to carry one of the three 'Jewish' mutations of the BRCA1/BRCA2 genes were evaluated for phenotypic characteristics. Chi-squared and Student's t-test statistics were employed to study differences in a variety of clinical and demographic parameters. A total of 111 families with 1499 family members were included. Among them 454 cases of cancer (297 in breast/ovary) were reported. Ovarian cancer, but not breast cancer, was detected at a significantly younger age among carriers of 185delT compared with other mutation carriers. In families with 185delAG, 5382insC and 6174delT mutations, breast cancer was found in 20.2, 39.4 and 24.1% of all identified women (born between 1900 and 1975), correspondingly. The corresponding figures for ovarian cancer were 13.9, 6.8 and 4.9%. Families carrying the 5382insC mutation had the highest probability of expressing bilateral breast cancer (38.9% of families, 15.4% of women with cancer, 6.1% of all women in family) and metachronous breast and ovary tumours (22.2, 9.8 and 4.5% correspondingly). Other tumours were reported in 7.9, 9.1 and 12.0% of women and 9.5, 12.9 and 15.8% of men in families with 185delAG, 5382insC, 6174delT, correspondingly. Marked phenotypic differences were found between families carrying different BRCA mutations warranting mutation-specific counselling to families seeking risk-reduction advice. 5382insC emerged as a most aggressive mutation.

Population colorectal cancer screening with fecal occult blood test.

Screening for early detection of colorectal cancer using fecal occult blood testing has been shown to be effective in reducing mortality from this disease. The largest Health Maintenance Organization in Israel initiated the use of Hemoccult Sensa in 1992 to evaluate the field performance of this test. All primary care physicians were invited to order home-based tests for their asymptomatic patients 50-74 years of age. This report summarizes the results of 45,166 tests performed, 22,193 in the prevalence round. Seventy-eight cancers, 60 patients with adenomas, and 163 patients with polyps were detected, yielding a cancer detection rate of 2.61/1,000 screened in the prevalence round. Of these, 21.6% were in the right colon. Of screen-detected cancers, 44.5% and 58.9% were detected in Dukes' A and in situ stages in the prevalence and incidence rounds, correspondingly. The overall estimated sensitivity of the test (median follow-up, 35 months) was 85.3% for the prevalence round with a specificity of 95.5%. The sensitivity for left-side tumors (87.9%) was higher than for right-side or rectal tumors (78.6%). The positive predictive value for cancer increased with increasing number of positive fields. Four or more positive fields had a positive predictive value for cancer of 16-26% and a positive predictive value of 46-71% for all tumors combined. Population screening with a sensitive fecal occult blood test performs well outside a trial setting, detecting a high proportion of expected tumors with favorable stage distribution. Given its proven power to significantly reduce mortality, use of this test is strongly advised to both medical organizations and the healthy population at average risk.

Calcium intake and bone mass development among Israeli adolescent girls.

OBJECTIVE: To determine the possible relationship between food and life style habits and bone health in adolescent Israeli females. METHODS: 2,000 adolescent Israeli Jewish and Arab high-school girls (mean age 14.5) completed a semi-quantitative food frequency questionnaire and a personal history questionnaire. 27 food components were calculated for each subject. Bone mineral content and density were determined for 112 subjects with calcium intake below 800 mg/day. RESULTS: Average calcium intake was found to be 1,260 mg/day, but 20% of all girls had a calcium intake below 800 mg/day. All low-energy diets were very low in calcium, as mean calcium intake per 1,000 calories was 411 128 grams. A large percentage of diets with less than 800 mg calcium were also deficient in phosphorus (95.2%), magnesium (84.8%). iron (90.5%) and zinc (100%). Due to differences in food sources. Jewish girls had more phosphorus in their diet, but less magnesium and iron compared to Arab girls. Calcium and zinc deficiencies in Jewish and Arab diets were similar. A negative correlation was found between body mass index (BMI) and age at menarche for all girls in the study. Bone mineral density (BMD) measured for girls with calcium intake below 800 mg/day distributed normally around the average when compared to age matched controls despite their low calcium intake. There was a strong positive correlation between BMD and bone mineral content (BMC) at all sites and body weights. CONCLUSIONS: Low calcium intake, other nutritional deficiencies and delayed menarche due to low-energy diet in the growing period and in adolescence may prevent the formation of healthy bones. There is no evidence of lower bone mass among the low calcium intake group in the study population at this stage. It remains to be documented if the window of opportunity for optimal bone accretion for this group will be missed in the future. possibly leading to increased risk of osteoporosis.

Similar late revascularization rates 10 to 12 years after angioplasty or bypass surgery for multivessel coronary artery disease: a report from the Lady Davis Carmel Medical Center (LDCMC) Registry.

We compared completed long-term outcome and late repeat revascularization rates in 272 consecutive patients with multivessel coronary disease who underwent revascularization (95 angioplasty cohort, 177 surgical cohort) between 1984 and 1986. Long-term survival was similar at 12 years in the angioplasty (70%) and surgical (74%) cohorts (p = NS), and repeat revascularization, although more frequent in the angioplasty patients during the first 5 years of follow-up, was performed equally in the 2 patient cohorts after 10 to 12 years of follow-up.

Late-onset heart failure as a mechanism for adverse long-term outcome in diabetic patients undergoing revascularization (a 13-year report from the Lady Davis Carmel Medical Center registry).

The adverse long-term prognosis following myocardial revascularization in diabetic patients has been ascribed to accelerated coronary disease, a higher incidence of late coronary restenosis after revascularization, and myocardial dysfunction. To examine the development of heart failure and its prognostic implications in diabetic patients, we analyzed the long-term (13-year) follow-up data of 363 patients-193 percutaneous transluminal coronary angioplasties and 170 coronary artery bypass operations-revascularized in a single cardiovascular center from 1984 to 1986. Baseline characteristics (age, previous infarction, baseline ventricular function) were similar in the 80 diabetic and 283 nondiabetic patients; multivessel disease and hypertension were marginally more common in diabetics (p = NS). Cumulative incidence of hospitalization for heart failure was high in the diabetic cohort (25% vs 11%, p = 0.001), with a rapidly increasing incidence after 5 years. Survival after first hospitalization for heart failure was markedly reduced in diabetics (11 of 20 [55%] vs 25 of 31 [81%] at 3 years; p = 0.04), as was survival free of further hospitalization for heart failure (5 of 20 [25%] vs 20 of 30 [63%]; p <0.005). Long-term 13-year survival (43% vs 78%, p <0.0001) and survival free of heart failure (33% vs 71%, p <0.0001) were decreased in diabetics, especially those with reduced ventricular function at baseline (17% vs 42%, p = 0.07). Multivariate analysis showed diabetes to be the strongest independent predictor of decreased survival (odds ratio 3. 6, 95% confidence interval 2.0 to 6.2; p <0.0001) and survival free of heart failure (odds ratio 4.0, 95% confidence interval 2.2 to 7. 1; p <0.0001) in patients undergoing revascularization. In summary, late-onset heart failure was frequent in diabetic patients after percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, and once present heralded an unrelenting progressive downhill clinical course.

Epidemiology of candidemia--a nationwide survey in Israel.

Bloodstream infections with Candida are often lethal and have been reported to be increasing in frequency. The current retrospective study describes the magnitude and epidemiological characteristics of candidemia in all western-type hospital facilities in Israel in 1994. Comprehensiveness of the data from the reporting hospitals was checked by cross-study of the data from the infectious diseases records and from the hospitalization records. Vital status of all reported cases was evaluated 1 year after the diagnosis. Data on 298 newly diagnosed cases of candidemia were received from 14 of the 18 general hospitals in Israel. The proportion of candidemia in the Israeli hospitals ranged from 0.1 to 0.01% of all admissions, with a mean of 0.05%. The incidence of candidemia differed significantly between the wards from 4-5/10,000 in general surgery and internal medicine wards to about 60/10,000 and 80/10,000 in intensive care and preterm units, respectively. Of all detected cases 53.6% were Candida albicans. Another nine specific species of Candida (mainly Candida parapsilosis, Candida tropicalis and Candida glabrata) were detected, with major differences between the various hospitals. The species of Candida differed significantly by sex and age. Of the cases of candidemia 21.5% died within 30 days of the isolation of the pathogen. The one-year mortality rate was 31.9%. Species-specific 30-day mortality rate was highest for C. glabrata. Throughout the analysis, C. glabrata emerged as a unique cause of candidemia, producing higher mortality, appearing at a younger age and predominating among females.

Pooled analysis of p53 mutations in hematological malignancies.

A computerized database is described that contains information about 507 mutations in the p53 gene of hematologic tumors and corresponding cell lines. Analysis of these mutations indicated the following findings: First, mutational spectrum analysis in these tumors was found to be similar to the pattern found for other solid tumors. However, when the patterns of base substitutions were examined separately according to the types of hematologic malignancies, followed by subgroup analysis, notable differences (in some cases of statistical significance) emerged. Second, mutational pattern analysis indicates that about 48% of base substitutions in hematologic tumors are suspected to be associated with carcinogen exposure. Third, deletions and insertions are localized mainly to exons 5-8 and repeated DNA sequences. However, the unusual profile of variations in frequency within each type of tumor suggests that, in addition to endogenous damage to template DNA, there is the factor of exposure to environmental physical and chemical carcinogens/mutagens. Fourth, p53 protein alterations analysis indicate that most of the changes in the amino acids are "semiconservative," presumably in order to avoid disrupting the structure of the p53 monomer. Consistent with this notion, structural mutations are more conservative than the binding mutations. Finally, molecular mechanisms that lead to p53 mutations, etiological factors that play a role in their formation, and the pathophysiological significance of consequent p53 protein alterations are discussed.

A community hospital experience with colonoscopic polypectomies.

This study analyzed 432 consecutive polypectomies performed in 279 patients in the gastroenterology unit of a community hospital. The patients were separated into 2 groups; group I--symptomatic patients considered suitable for colonoscopic examination, and group II--asymptomatic high-risk patients. The mean number of detected polyps was similar in both groups, the vast majority of the polyps in both groups were small (< 5 mm), and were mainly of tubular histology. Polyps in the rectosigmoid area were more common (56.6%) in the symptomatic patients than in the asymptomatic patients (44.1%). Fourteen percent of patients in group I and 33% in group II had no polyps within 60 cm from the anal verge. Carcinoma in situ was found in large polyps mainly in group I. Flat adenomas were not found in the studied population. The incidence of hyperplastic polyps was similar in both groups and did not predict the concomitant existence of adenomatous polyps. The male:female ratio was the same in both groups. The percent of detected polyps increased with age. A strong right shift in the location of the polyps was evident with increasing age. Multiple polyps were a common event in this Israeli population of symptomatic and high-risk asymptomatic patients. More than 30% of the polyps were found outside the reach of the sigmoidoscope, with this proportion increasing with age. These data provide further support to the claim that colonoscopy should therefore serve as the choice diagnostic tool in these high-risk populations.

Hypotensive reactions on passive head-up tilt testing of hypertensive patients.

With the aid of a protracted passive postural test, the rate of occurrence and the variants of orthostatic hypotensive reactions in hypertensive patients were studied. Three hundred and eighty-two consecutive tilt tests in 161 hypertensive patients, 89.4% of whom were taking antihypertensive medications, were reviewed. Orthostatic hypotensive reactions were recognized in 33.8% of examinations. Thirty-one hypotensive episodes (8.1%) were associated with symptoms of cerebral ischemia, resulting in termination of the tilt test at a median of 5 min from onset (range 1-30 min). A survey of possible risk markers of symptomatic hypotensive reactions during tilt showed that increasing age was associated with significantly increased risk (P < 0.001), while gender, office blood pressure (BP), diabetes mellitus, ischemic heart disease, anxiety, history of syncope, and treatment with antihypertensive drugs were not. Asymptomatic orthostatic hypotension early in the course of the tilt test was a weak predictor of symptomatic hypotensive reactions later during the test (positive predictive value 17.4-33.3%). Among the 31 symptomatic hypotensive reactions, 10 were typical cases of orthostatic hypotension, four were typical vasovagal reactions, and 17 episodes were difficult to classify. The implications of symptomatic hypotensive reactions triggered by protracted head-up tilt in hypertensive patients are unknown and can only be elucidated in longitudinal studies.

Clinical characteristics of metachronous colorectal tumors.

A cancer-registry-based study was conducted to investigate the survival patterns associated with metachronous colorectal tumors and to compare the survival of patients with single and metachronous colorectal tumors. The study included all 1,396 White patients with metachronous colorectal tumors diagnosed among 143,283 patients with primary colorectal tumors reported between 1973-1986 to the SEER program. The influence on survival of age at diagnosis, site of tumor and stage was evaluated by means of multivariate survival analysis, using Cox Proportional Hazards Models. Metachronous tumors developed more often following left-colon tumors. Stage distribution of the second tumors was better than that of single 47% of the second tumors were discovered in regionally-advanced or distant-metastatic stages. Survival from the second tumor diagnosed in the rectum was worse than that of a single tumor in the same stage and site. Only the stage of the second tumor was found to influence survival from metachronous tumors. The relatively high rate of diagnosis of advanced second colorectal tumors may reflect either improper follow-up after the diagnosis of the first tumor, or more aggressive biological characteristics of the second tumors.

Survival of first and second primary breast cancer.

BACKGROUND: A second primary tumor (SPT) in the breast is the most common one seen in clinical practice. There are conflicting reports regarding the incidence and survival of patients with SPT in the breast. METHODS: To elucidate this, data on 139,932 patients with primary breast cancer, reported to the Surveillance, Epidemiology, and End Results Program between 1973 and 1986, were analyzed. Of these, 3431 patients had a contralateral metachronous breast cancer (interval, > 6 months). RESULTS: Survival from the date of diagnosis of the metachronous breast tumors was compared with that of patients with single breast tumors, controlling for age at diagnosis, stage, race, and treatment. In the multivariate analysis, age and stage at diagnosis of first and second tumors were the only variables that significantly influenced survival. The survival of patients with localized SPT was similar to that of patients with a localized single breast tumor. Patients with regionally advanced SPT lived for a shorter time than did corresponding patients with only one tumor. CONCLUSIONS: Patients with single breast cancer were at increased risk of having a SPT in the breast. As a result, efforts for early detection by physical examination and mammography of survivors of single breast cancer are advocated because the survival of patients with a localized SPT in the breast is as good as that of those with a single localized tumor.

Lung cancer histology in Jews and Arabs in Israel, 1962-1982.

Lung cancer rates in Israel are lower than in Western countries, not explainable by smoking habits. Because of the different relations of squamous cell carcinoma and adenocarcinoma to smoking it was of interest to study the histologic distribution in Israel. A total of 7,871 histologically confirmed lung cancer cases were studied in the period 1962-1982. Squamous cell carcinoma was the leading tumor type in Jewish men and adenocarcinoma in Jewish women. Rates of both adenocarcinoma and squamous cell carcinoma increased throughout the period in both Jewish men and women, but the increase in adenocarcinoma was more pronounced in the last study period than that in squamous cell carcinoma. In 1977-1982 the rate ratio of squamous cell carcinoma to adenocarcinoma among Jewish men was 1.7. In Arab men it was 2.9, and in Jewish women 0.57. The Kreyberg I/II ratio among Jewish men was about 2.7 with no clear trend throughout the study period, and among Arab men this gradually decreased from 8.1 to 3.5. Jewish women had a constant Kreyberg I/II ratio of about 1 through the whole study period, but the ratio in Arab women was significantly higher than 1, with a mean overall ratio of 3.2. Jews and Arabs in Israel are different from each other in their patterns of lung cancer histology and are different to some extent from other populations in the Western world.

Lung cancer histology in major ethnic groups among the Jews. Israel, 1962-1982.

Lung cancer rates in Israel are lower than in other Western countries, not explainable by smoking habits. Due to the different relation of Squamous cell carcinoma (SqCC) and Adenocarcinoma (AC) with smoking it was of interest to study the histologic distribution in Israel. A total of 7508 histologically confirmed lung cancer cases among Jews were studied in the period 1962-82. SqCC was the leading tumor-type in Jewish men and AC in Jewish women. European-American born males in the last study period showed a decrease in SqCC rate while Asian-African born males showed a steep increase in SqCC rate, most prominent among the younger age-groups. Rates of AC increased in both, European-American and Asian-African males, but more steeply in the latter in most age-groups. Only for Large cell carcinoma were the overall rates higher in Asian-African than in European-American born males. SqCC increased in European-American born females and also steeply increased in the over 55 years old Asian-African born females. AC increased in European-American born females (both young and old), but only in the young Asian-African born females (decreasing in the older). European-American born Jews still have higher rates of both, more and less smoking related lung cancer histological types, than Asian-African born Jews. The steep increase in rates of some of the histological types in the latter with the pronounced increased in the younger age-groups is expected to cause a change in the ethnic rate-ratio which has already been demonstrated for the overall lung cancer rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung cancer histology and smoking--relationship and time trends among Jewish males in Israel.

Due to the recent reported increase in incidence rates of adenocarcinoma and the weaker relationship of this histological type to smoking, a study was undertaken to investigate changes over time in smoking and lung cancer histology. Medical records of 428 Jewish male lung cancer patients from 1957 to 1985 were studied for smoking history and histological diagnosis. No time trend was found in the smoking-histology relationship, although in this study adenocarcinoma was found to be strongly related to smoking in all periods. Thus, the increase in adenocarcinoma reported in Israel is not the reflection of less smoking or a change in the smoking-adenocarcinoma relationship. It is postulated that changes in the type of cigarettes smoked might be responsible for the change in the incidence of histological types.

Lung cancer in Israel, 1962-1982. II. Ethnic differences among Jews.

Lung cancer incidence rates among Jews in Israel are significantly lower than in most developed countries in the world. A more detailed analysis of the rates among different Jewish ethnic groups also showed low rates. While Jewish males born in Europe-America (EA) had an 11% increase in rates between 1962-66 and 1977-82, Jewish males from Asian-African (AA) origin had a 45% increase resulting in current higher rates among North African than among East European Jews (the two dominant ethnic groups in Israel). In Jewish females, rates have been relatively stable from 1972 to 1982 and were almost twice as high for females born in EA than females born in AA with less prominent differences between countries. While smoking patterns probably explain the increase in rates among Asian-African Jewish males, other possible risk factors as well as the overall smoking prevalence cannot explain the low incidence in the major ethnic Jewish groups. The possibility of differed susceptibility is raised.