Biomedical subjects
Publications and source records attributed to E Ron.
A 5-fold excess risk of nonmedullary thyroid cancer among close relatives of affected patients was detected in a population-based case-control study of thyroid cancer in Connecticut. The 2 familial cases with early onset and multiple foci suggest genetic susceptibility, whereas the 2 cases with late onset may be related to a common environmental exposure.
Radiation exposures to the scalp during childhood for tinea capitis were associated with a fourfold increase in skin cancer, primarily basal cell carcinomas, and a threefold increase in benign skin tumors. Malignant melanoma, however, was not significantly elevated. Overall, 80 neoplasms were identified from an extensive search of the pathology logs of all major hospitals in Israel and computer linkage with the national cancer registry. Radiation dose to the scalp was computed for over 10,000 persons irradiated for ringworm (mean 7 Gy), and incidence rates were contrasted with those observed in 16,000 matched comparison subjects. The relative risk of radiogenic skin cancer did not differ significantly between men or women or by time since exposure; however, risk was greatest following exposures in early childhood. After adjusting for sex, ethnic origin, and attained age, the estimated excess relative risk was 0.7 per Gy and the average excess risk over the current follow-up was 0.31/10(4) PY-Gy. The risk per Gy of radiation-induced skin cancer was intermediate between the high risk found among whites and no risk found among blacks in a similar study conducted in New York City (Shore et al., Radiat. Res. 100, 192-204, 1984). This finding suggests the role that subsequent exposure to uv radiation likely plays in the expression of a potential radiation-induced skin malignancy.
Of 6,426 colonoscopies performed in 1978-1987, 66 invasive colorectal adenomatous polyps were removed in 58 examinations. The study group included 36 (62%) men and 22 (38%) women with an age range of 42-96 years. Forty-three patients had invasive pedunculated polyps and 15 had invasive sessile polyps. Following the colonoscopic polypectomy, secondary surgical resection was done in 19 patients with pedunculated polyps and in 13 patients with sessile polyps. The operative specimens showed that the colonoscopic polypectomy removed the entire cancerous focus in all patients with pedunculated polyps, including those with stalk invasion. In contrast, most cases with sessile polyps turned out on operation to be Dukes' B or C carcinoma. Follow-up (mean 4.4 years) was available for 53 (93%) patients: none of 24 unoperated patients with pedunculated polyps suffered from local recurrence. We conclude that colonoscopic polypectomy is sufficient for invasive pedunculated polyps, provided that histology shows that the resection margins are free of tumoral cells. Surgery is recommended for all invasive sessile polyps.
The idea that caffeine might be involved in the etiology of breast disease was first proposed by Minton et al. in 1979. Since that time, numerous experimental and epidemiologic studies evaluating the relationship between methylxanthines and breast disease have been conducted. Results from studies on benign breast disease have been inconsistent, with some investigators observing a positive association and others no association. However, all but one of the studies which have examined methylxanthine intake and malignant breast disease have concluded that methylxanthines do not play a role in the development of this cancer. Although various methodologies were employed and different populations were evaluated, results were consistently negative. Thus, there appears to be no evidence of an association between coffee and other methylxanthine-containing beverages and breast cancer.
The potential of using a blood test enumerating oncofetal ferritin-bearing lymphocytes (FBL) as a biomarker for early breast cancer was further explored. Nine hundred women attending a high-risk breast cancer clinic and 2500 normal-risk women were physically examined and their blood drawn for FBL determination using a newly developed radioimmunoassay. The FBL test results were compared to clinically or histopathologically diagnosed breast disease and to known breast cancer risk factors. A gradual increase in the mean FBL ratio was seen from normal risk disease-free women to those with in situ or early stage breast cancer. The percentage of women with positive FBL was 13.6% for the normal risk group, 19% and 25.7% for clinically and histopathologically diagnosed benign breast disease, respectively, and 100, 77.8, and 66.7% for in situ, Stage I, and Stage II breast cancer, respectively. In locally advanced disease (Stage III) the percentage of positive women was only 17.2%. It was further found that a negative FBL result in known breast cancer patients at Stage I, II of the disease was a bad prognostic marker indicating a shorter disease-free survival. The follow-up of patients after surgery by periodical clinical examination and the FBL test revealed that the positive FBL was declining after removal of the precancerous or malignant tumor and that it was highly sensitive (100%) in predicting tumor development and recurrence. Using a logistic regression analysis, an FBL-positive test indicated a significant association with risk of early breast cancer (odds ratio = 2.9; 95% confidence interval = 1.4-5.8). Being a measure of the immune response the positive FBL was associated with early breast cancer and good prognosis. Since patients with locally advanced cancer and poor prognosis were FBL negative but such patients were shown to have increased serum ferritin levels. It is suggested to use the FBL and serum ferritin assays for screening and diagnosis of breast cancer.
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.
Dietary calcium may inhibit colonic carcinogenesis promoted by high fat, phosphate, and low fibre diets. In persons at risk for colon cancer oral calcium supplements significantly suppress increased rectal epithelial proliferation. This was studied in a cohort of 35 volunteers: 26 first degree relatives of colorectal cancer patients and nine who had had colonic adenomas (mean age 51.6 years, 17 (49%) men, all negative for large bowel neoplasia). 1.25-1.5 g elemental calcium was given in divided daily doses for three months. Rectal pinch biopsies were taken without bowel preparation, before and mean 8.4 weeks during and 7.2 weeks after treatment and incubated with tritiated thymidine. The mean number of labelled cells, as a ratio of the total number of crypt cells (labelling index-LI), and their crypt position, were determined. The mean number of labelled cells decreased during treatment by 29%, especially in the basal three-fifths of crypts. There was also a significant 10% increase in mean number of crypt cells during treatment. [Mean LI decreased by 36% (p less than 0.001) during calcium treatment and almost returned to basal values after cessation.] If a raised LI is a marker of potential malignancy and a randomised clinical trial confirms that calcium suppresses it, dietary intervention studies in high risk persons are indicated.
First-degree relatives of colorectal cancer patients are at increased risk for this malignancy which, in certain families, has right-sided predilection. For both these reasons, some clinicians recommend colonoscopy as the initial screening examination for these relatives. We used the results of a screening program of families of colon cancer patients to determine whether the tumor yield and costs justified this recommendation. Our study included 468 asymptomatic, first-degree relatives of large bowel neoplasia patients. Of these, 429 had only one relative with colorectal neoplasia and 39 had two or more such relatives. Persons with one affected relative were screened by fecal occult blood and flexible sigmoidoscopy, followed by colonoscopy if either test was positive, whereas colonoscopy was used as the primary screening test for those with two or more relatives with colorectal neoplasia. The comparison group included 452 persons without this family history of large bowel neoplasia. They were screened with fecal occult blood tests and flexible sigmoidoscopy. Based on a range of costs in the United States, and taking into account the hypothetical increased yield of screenees with neoplasia detected if colonoscopy was used as the primary screening examination, calculations of costs indicate that screening asymptomatic adults by colonoscopy is markedly (4-fold) more cost-effective if they have two or more first-degree colon cancer relatives. Otherwise, screening families with only 1 affected relative by flexible sigmoidoscopy, together with fecal occult blood, would seem the most economic method.
The thyroid gland is highly sensitive to the carcinogenic effects of ionizing radiation. Previously, we reported a significant increase of thyroid cancer and adenomas among 10,834 persons in Israel who received radiotherapy to the scalp for ringworm. These findings have now been extended with further follow-up and revised dosimetry. Overall, 98 thyroid tumors were identified among the exposed and 57 among 10,834 nonexposed matched population and 5392 sibling comparison subjects. An estimated thyroid dose of 9 cGy was linked to a fourfold (95% Cl = 2.3-7.9) increase of malignant tumors and a twofold (95% Cl = 1.3-3.0) increase of benign tumors. The dose-response relationship was consistent with linearity. Age was an important modifier of risk with those exposed under 5 years being significantly more prone to develop thyroid tumors than older children. The pattern of radiation risk over time could be described on the basis of a constant multiplication of the background rate, and an absolute risk model was not compatible with the observed data. Overall, the excess relative risk per cGy for thyroid cancer development after childhood exposure is estimated as 0.3, and the absolute excess risk as 13 per 10(6) PY-cGy. For benign tumors the estimated excess relative risk was 0.1 per cGy and the absolute risk was 15 per 10(6) PY-cGy.
We investigated the relation between radiotherapy in childhood for tinea capitis and the later development of tumors of the brain and nervous system among 10,834 patients treated between 1948 and 1960 in Israel. Benign and malignant tumors were identified from the pathology records of all Israeli hospitals and from Israeli national cancer and death registries. Doses of radiation to the neural tissue were retrospectively estimated for each patient (mean, 1.5 Gy). Sixty neural tumors developed in the patients exposed as children, and the 30-year cumulative risk (+/- SE) was 0.8 +/- 0.2 percent. The incidence of tumors was 1.8 per 10,000 persons per year. The estimated relative risk as compared with that for 10,834 matched general-population controls and 5392 siblings who had not been irradiated was 6.9 (95 percent confidence interval, 4.1 to 11.6) for all tumors and 8.4 (confidence interval, 4.8 to 14.8) when the analysis was restricted to neural tumors of the head and neck. Increased risks were apparent for meningiomas (relative risk, 9.5; n = 19), gliomas (relative risk, 2.6; n = 7), nerve-sheath tumors (relative risk, 18.8; n = 25), and other neural tumors (relative risk, 3.4; n = 9). A strong dose--response relation was found, with the relative risk approaching 20 after estimated doses of approximately 2.5 Gy. Our study confirms that radiation doses on the order of 1 to 2 Gy can significantly increase the risk of neural tumors.
The incidence of colorectal cancer was studied in an unselected group of 1035 patients (total group) with ulcerative colitis and in a subgroup of 822 who resided, at the time of diagnosis, within a defined area in central Israel (regional group). The operation rate was 5.2% and the follow-up period (mean +/- SD) was 11.5 +/- 8.3 yr, range 1-52 yr. The cumulative incidence of colorectal cancer in all patients was 0.2% at 10 yr, 2.8% at 15 yr, 5.5% at 20 yr, and 13.5% at 30 yr. The ratio of observed to expected cancer was 0.9 at 10 yr, 5.0 at 20 yr, and 6.4 at 30 yr. The cancer incidence was 1 case per 3895 patient-years in the first decade of disease, 1 case per 198 patient-years in the second decade, and 1 case per 100 patient-years in the third decade. All these figures were higher in patients with total colonic involvement. There were no significant differences between the total and regional patient groups. Onset of ulcerative colitis in the first and second decade of life was not associated with a higher cancer incidence when standardized for extent and duration of disease. The risk of colorectal cancer in patients with ulcerative colitis was more strongly expressed in population groups with a lower incidence of this cancer. The cumulative incidence of colorectal cancer in ulcerative colitis is much lower in population-based studies than that reported from major medical centers. Worldwide this incidence may also vary among different populations.
The mortality experience of 10,834 children treated with x-rays for ringworm of the scalp between 1948 and 1960, 10,834 matched comparison subjects, and 5,392 siblings was evaluated over an average follow-up period of 26 years. Mortality was ascertained by linking unique personal identification numbers of study subjects with the national death registry. Radiotherapy in childhood was associated with an increased risk of death due to tumors of the head and neck (relative risk (RR) = 3) and leukemia (RR = 2.3). No other causes of death were significantly elevated after irradiation. The excess of brain tumors (average intracranial dose = 150 rads) confirms that the central nervous system of the child is sensitive to the induction of cancers by radiation. The bone marrow dose averaged over the entire body was approximately 30 rad, and the estimated risk coefficient of 0.9 excess leukemias per million per year per rad is consistent with other studies of whole-body exposure. A significant excess of bone and soft tissue sarcomas (RR = 9) was also observed. The pattern of cancer risk over time was bimodal; an early peak due to excess leukemias occurred within a few years of exposure, whereas excesses of solid tumors were most apparent after about 15 years. Despite the excess of cancers among exposed persons, over 50% of the deaths in the entire study population were from external events, mainly accidents or events related to military service. An estimate of the total impact of radiogenic cancer after childhood irradiation will require additional years of observation since the population irradiated is just now entering the age ranges normally associated with high cancer risk.
The secondary prevention of colorectal cancer is based on the early detection of noninvasive cancer and removal of adenomatous polyps. The two commonly used screening tests are flexible sigmoidoscopy and guaiac fecal occult blood testing. Both were performed simultaneously and independently on 1176 asymptomatic volunteers followed by colonoscopic examination if either occult blood or a neoplasm was detected. Neoplasia (adenomatous polyps or cancer) were found in 48 screenees. Only ten had positive stool occult blood while 45 were detected by sigmoidoscopy. Analysis of sensitivity for neoplasia was 93.8% for sigmoidoscopy but only 20.8% for the occult blood tests, while the positive predictive values for neoplasia were 100% and 23.8% respectively. The fecal occult blood test detected only 18% of screenees with adenomas and 60% with invasive cancer. Flexible sigmoidoscopy detected 95% and 80% respectively. Analysis (kappa statistic) demonstrated little agreement between the two tests (P greater than 0.05), indicating that they are diagnosing different neoplasia. Evaluation of expected gain in diagnosing neoplasia, by combining both tests, gave 18% for the fecal blood test and 94% for the endoscopic test. These results confirm the complementary value of performing both tests, but especially the high sensitivity and predictive value positive of flexible sigmoidoscopy for adenomas, including those with severe dysplasia, and the converse for the fecal occult blood test. This latter test must be recommended and used within a screening program with caution and full understanding of its limitations.
Epidemiologic studies have shown that asymptomatic adult relatives of colorectal cancer patients are at increased risk for developing this tumor. A prospective, published pilot study confirmed this added risk and demonstrated the importance of the family history of cancer as a marker of potential malignancy. The study group was enlarged to include 471 asymptomatic adult, first degree relatives of patients having large bowel neoplasia (cancer or adenomatous polyps) but without polyposis syndromes. These first degree relatives were screened by fecal occult blood examinations and flexible sigmoidoscopy, followed by colonoscopy when indicated. Adenomatous polyps or cancer were found in 8.1% of the study group as compared with 3.7% in a comparison group of screens, not having the same family history of neoplasia and undergoing similar screening tests. Of the study group the age-adjusted rate for colorectal adenomas or cancer increased threefold (P less than 0.001) for subjects older than 40 years and an even higher fivefold relative risk was found for large bowel cancer only (P = 0.01). This was true even if there was only one relative with colorectal neoplasia (P less than 0.01) but was even more pronounced among those having more than one affected relative. The results confirm the usefulness of the family history, of even one member with large bowel neoplasia, in isolating a group at high risk for these lesions. This group would most likely benefit from regular cancer and adenomatous polyp screening particularly when older than 40 years.
The incidence of colorectal cancer in Israel is highest in European- and American-born immigrants. This is believed to be related mainly to their dietary habits. To investigate this issue further, we compared the diets of a sample of members of a well-established kibbutz (BA), which was settled by immigrants of European origin, with the diets of an age- and sex-matched sample of European-born residents of Tel-Aviv and of a previously studied kibbutz (GB). The diet of the people of kibbutz BA compared with those in Tel-Aviv was significantly lower in poultry and significantly higher in polyunsaturated fats; it also had a higher polyunsaturated/saturated fats ratio. Compared with both the Tel-Aviv residents and the kibbutz GB members, the kibbutz BA members had a significantly lower intake of saturated fats; they also had a higher intake of dietary fiber, available carbohydrates, calories, and many minerals and vitamins. However, the incidence of colorectal cancers in the kibbutz BA population was slightly, but non-significantly, higher than expected, based on age, ethnic group, sex, and calendar year-specific national incidence rates. These results are in contrast to our earlier study in which we found that kibbutz GB had less colorectal cancer than expected; thus, the results of the current study are presently unexplained.
To explore further the relation between infertility and breast and female reproductive cancers, cancer incidence among 2,632 Israeli women treated for infertility between 1964 and 1974 was evaluated. Cancer incidence through December 1981 was determined by matching the study cohort to the Israel Cancer Registry. The observed number of cancers was compared with sex-age-ethnic and calendar-year, site-specific national cancer rates. There were 42 cancers observed compared with 37.4 expected, yielding a standardized incidence ratio of 1.1 (95% confidence interval (CI) = 0.8-1.5). Analysis by infertility diagnosis demonstrated no significant excess of total cancer incidence; the standardized incidence ratio was 1.3 (95% CI = 0.8-1.8) for infertility due to hormonal deficiency, 0.7 (95% CI = 0.3-1.4) for mechanical infertility, 1.6 (95% CI = 0.6-3.6) for infertility of the male partner, and 1.1 (95% CI = 0.5-2.2) for unclassified diagnosis. Site-specific analyses revealed a significantly increased risk (8.0; 95% CI = 2.5-19.3; four cases observed, 0.50 expected) of endometrial cancer for the hormonal group and a nonsignificant excess of breast cancer and melanoma. Although numbers were small, women with disorders causing unopposed estrogen production had a risk of 1.4 (95% CI = 0.8-2.2) for all cancer sites, which reached 10.3 (95% CI = 2.6-28.2; three cases observed, 0.29 expected) for endometrial cancer and 1.8 (95% CI = 0.8-3.4; eight cases observed, 4.43 expected) for breast cancer. Among women with nonhormonal infertility, there was a suggestion of increased risks of carcinoma of the ovary (3.2; 95% CI = 0.3-32.9; two cases observed, 0.63 expected) and thyroid (3.0; 95% CI = 0.3-24.6; two cases observed; 0.67 expected). No evidence of an association between ovulation-inducing drugs and cancer was found. This study supports the hypothesis that infertility caused by hormone deficiency is a risk factor for uterine cancer, but is inconclusive regarding breast cancer.
The relationship between chronic lymphocytic leukaemia (CLL) and primary malignant neoplasms was evaluated using data from the Hematology Division in Beilinson Medical Center and the Israel Cancer Registry. The study population consisted of 81 patients diagnosed between 1962 and 1984. A total of 16 patients were found to have 21 malignant neoplasms in addition to their CLL. Excluding patients with nonmelanoma skin tumours, a 1.7 increased risk (statistically not significant) for developing second malignant neoplasms in CLL patients was detected. The only tumour which occurred significantly more than expected subsequent to CLL diagnosis was brain cancer. The coexistence of multiple cancers in the same patient was diagnosed in four of the patients. The results of this study further support the hypothesis that patients with CLL are prone to develop second neoplasms.
A population-based case-control interview study of thyroid cancer (159 cases and 285 controls) was conducted in Connecticut. Prior radiotherapy to the head or neck was reported by 12% of the cases and 4% of the controls [odds ratio (OR) = 2.8; 95% confidence interval = 1.2-6.9]. Risk was inversely related to age at irradiation and was highest among children exposed under age 10. Few persons born after 1945 received prior radiotherapy, consistent with the declining use of radiation to treat benign conditions in the 1950's. Among females the radiogenic risk appeared to be potentiated by the number of subsequent live-births. Other significant risk factors included a history of benign thyroid nodules (OR = 33) or goiter (OR = 5.6). Miscarriage and multiparity increased risk but only among women who developed thyroid cancer before age 35 years. Consumption of shellfish (a rich source of iodine) seemed to increase the risk of follicular thyroid cancer, whereas consumption of goitrogen-containing vegetables appeared to reduce risk of total thyroid cancer, possibly because of their cruciferous nature. A significantly low risk was observed among persons of English descent, whereas Italian ancestry appeared to increase risk. No significant associations were found with a number of suspected risk factors: diagnostic x-rays, radioactive isotope scans, occupational radiation exposure, tonsillectomy, Jewish ethnicity, alcohol intake, cigarette smoking, oral contraceptives, lactation suppressants, menopausal estrogens, most other common medications, and water source. New associations were suggested for obesity among females (OR = 1.5), surgically treated benign breast disease (OR = 1.6), use of spironolactone (OR = 4.3) or vitamin D supplements (OR = 1.8), and a family history of thyroid cancer (OR = 5.2). About 9% of the incident thyroid cancers could be attributed to prior head and neck irradiation, 4% to goiter, and 17% to thyroid nodular disease, leaving the etiology of most thyroid cancers yet to be explained.