Angela Chetrit

Tumors of the brain and nervous system after radiotherapy in childhood.

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.

Parity, Oral Contraceptives, and the Risk of Ovarian Cancer among Carriers and Noncarriers of a BRCA1 or BRCA2 Mutation

BACKGROUND Multiparity and the use of oral contraceptives reduce the risk of ovarian cancer, but their effects on this risk in women with a BRCA1 or BRCA2 mutation are unclear. METHODS We conducted a population-based case-control study of ovarian cancer among Jewish women in Israel. Women were tested for the two founder mutations in BRCA1 and the one founder mutation in BRCA2 that are known to be common among Jews. We estimated the effects of parity and oral-contraceptive use on the risk of ovarian cancer in carriers and noncarriers in separate analyses that included all control women, who did not have ovarian cancer. RESULTS Of 751 controls who underwent mutation analysis, 13 (1.7 percent) had a BRCA1 or BRCA2 mutation, whereas 244 of 840 women with ovarian cancer (29.0 percent) had a BRCA1 or BRCA2 mutation. Overall, each additional birth and each additional year of use of oral contraceptives were found to lower the risk of ovarian cancer, as expected. Additional births were protective in separate analyses of carriers and noncarriers, but oral-contraceptive use appeared to reduce the risk only in noncarriers; among carriers, the reduction in the odds of ovarian cancer was 12 percent per birth (95 percent confidence interval, 2.3 to 21 percent) and 0.2 percent per year of oral-contraceptive use (-4.9 to 5.0 percent). CONCLUSIONS The risk of ovarian cancer among carriers of a BRCA1 or BRCA2 mutation decreases with each birth but not with increased duration of use of oral contraceptives. These data suggest that it is premature to use oral contraceptives for the chemoprevention of ovarian cancer in carriers of such mutations.

The INTERPHONE study: design, epidemiological methods, and description of the study population

The very rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. A multinational case–control study, INTERPHONE, was set-up to investigate whether mobile phone use increases the risk of cancer and, more specifically, whether the RF fields emitted by mobile phones are carcinogenic. The study focused on tumours arising in the tissues most exposed to RF fields from mobile phones: glioma, meningioma, acoustic neurinoma and parotid gland tumours. In addition to a detailed history of mobile phone use, information was collected on a number of known and potential risk factors for these tumours. The study was conducted in 13 countries. Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the UK using a common core protocol. This paper describes the study design and methods and the main characteristics of the study population. INTERPHONE is the largest case–control study to date investigating risks related to mobile phone use and to other potential risk factors for the tumours of interest and includes 2,765 glioma, 2,425 meningioma, 1,121 acoustic neurinoma, 109 malignant parotid gland tumour cases and 7,658 controls. Particular attention was paid to estimating the amount and direction of potential recall and participation biases and their impact on the study results.

Long-Term Follow-up for Brain Tumor Development after Childhood Exposure to Ionizing Radiation for Tinea Capitis

Abstract Sadetzki, S., Chetrit, A., Freedman, L., Stovall, M., Modan, B. and Novikov, I. Long-Term Follow-up for Brain Tumor Development after Childhood Exposure to Ionizing Radiation for Tinea Capitis. Radiat. Res. 163, 424–432 (2005). 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 104 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.

Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study

OBJECTIVE To investigate a possible linkage between the use of fertility drugs for infertility and the risk of breast and ovarian cancers. DESIGN Long-term, historic-prospective study. SETTING Fertility clinic in a university hospital. PATIENT(S) Files of 1,197 infertile women with a mean (+/- SD) follow-up of 17.9+/-5 years (21,407 person-years) were reviewed. Diagnoses, number of courses, and dosage of fertility drugs were extracted from the files. INTERVENTION(S) Cancers were identified by record linkage to the National Cancer Registry. Histopathologic reports and data on estrogen and progesterone receptors in breast cancer tissue were also reviewed. MAIN OUTCOME MEASURE(S) Standardized incidence ratio with 95% confidence interval (CI) were used for risk assessment. RESULT(S) Of 20 breast cancers (standardized incidence ratio, 1.40 [95% CI, 0.83-2.10]), 16 were detected among 780 women who had been exposed to 3,978 cycles of clomiphene citrate (CC) and/or hMG (standardized incidence ratio, 1.65 [95% CI, 0.94-2.68]). The standardized incidence ratio for this cancer was significantly increased only in patients with one or two CC treatments and a dose of < or =1,000 mg (2.6 [1.19-5.0] and 2.52 [1.21-4.64], respectively). Two cases of ovarian cancer (1 patient unexposed) were observed with no evidence of excessive risk. Six of the eight patients with data on estrogen and progesterone receptors were exposed to CC, and all tested positive for these receptors. CONCLUSION(S) An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed.

Validation of short term recall of mobile phone use for the Interphone study

Aim: To validate short term recall of mobile phone use within Interphone, an international collaborative case control study of tumours of the brain, acoustic nerve, and salivary glands related to mobile telephone use. Methods: Mobile phone use of 672 volunteers in 11 countries was recorded by operators or through the use of software modified phones, and compared to use recalled six months later using the Interphone study questionnaire. Agreement between recalled and actual phone use was analysed using both categorical and continuous measures of number and duration of phone calls. Results: Correlations between recalled and actual phone use were moderate to high (ranging from 0.5 to 0.8 across countries) and of the same order for number and duration of calls. The kappa statistic demonstrated fair to moderate agreement for both number and duration of calls (weighted kappa ranging from 0.20 to 0.60 across countries). On average, subjects underestimated the number of calls per month (geometric mean ratio of recalled to actual = 0.92, 95% CI 0.85 to 0.99), whereas duration of calls was overestimated (geometric mean ratio = 1.42, 95% CI 1.29 to 1.56). The ratio of recalled to actual use increased with level of use, showing underestimation in light users and overestimation in heavy users. There was substantial heterogeneity in this ratio between countries. Inter-individual variation was also large, and increased with level of use. Conclusions: Volunteer subjects recalled their recent phone use with moderate systematic error and substantial random error. This large random error can be expected to reduce the power of the Interphone study to detect an increase in risk of brain, acoustic nerve, and parotid gland tumours with increasing mobile phone use, if one exists.

Effect of very advanced maternal age on pregnancy outcome and rate of cesarean delivery

Objective To determine outcomes of pregnancies in women at least 44 years of age and to determine factors predicting cesarean delivery in these patients. Methods Between January 1988 and December 1995, 109 women at least 44 years old delivered in our medical center. These women were matched to a group of 309 women 20–29 years of age. Multiple logistic regression analysis was used to evaluate the association between maternal age and outcome variables, controlling for possible confounding factors. Based on the logistic regression, a predictive model was calculated for cesarean delivery and validated prospectively in a separate group of 30 consecutive women at least 44 years old, who delivered during the first 8 months of 1996. Results Very advanced maternal age, compared with younger age, was associated with a significantly higher rate of medical complications (hypertensive disorder and diabetes) (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5, 4.1; P < .001), instrument-assisted vaginal delivery (OR 7.5; 95% CI 2.2, 25.0; P < .004), and cesarean delivery (OR 7.3; 95% CI 2.2, 16.7; P < .001). The incidences of preterm labor, premature rupture of membranes, emergency cesarean delivery, meconium-stained amniotic fluid, small for gestational age newborns, and 5-minute Apgar scores of 7 or lower were not influenced by maternal age. The regression model showed an increased risk for cesarean delivery associated with age of at least 44 years (OR 7.3; 95% CI 2.2, 16.7), primiparity (OR 3.5; 95% CI 1.3, 9.8), infertility treatment (OR 3.6; 95% CI 1.5, 8.8), and egg donation (OR 19.5; 95% CI 6.1, 62.2), with positive and negative predictive values of 94 and 86%, respectively. Conclusion Maternal age of at least 44 years is associated with medical complications in pregnancy and more interventions during labor. However, overall pregnancy outcomes are favorable. Cesarean delivery can be predicted accurately based on maternal age, parity, and infertility treatment.

Cancer incidence in a cohort of infertile women who underwent in vitro fertilization

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(S); 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.

Colchicine nonresponsiveness in familial mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization

OBJECTIVES To identify the ethnic, clinical, genetic, and pharmacokinetic correlates of colchicine treatment failure in patients with familial Mediterranean fever (FMF). METHODS Fifty-nine FMF patients, unresponsive to a daily dose of > or =2 mg colchicine, were compared with 51 colchicine-responsive patients by clinical, demographic, and socioeconomic assessment, FMF gene (MEditerranean FeVer [MEFV]) mutation and serum amyloid A1 (SAA1) gene polymorphism analysis, and plasma and white blood cell colchicine level determination. RESULTS Colchicine responders and nonresponders were comparable with respect to gender, age, duration and onset of the disease, and various demographic parameters. The 2 cohorts were found to carry mainly the M694V MEFV mutation and had a similar number of homozygotes or compound heterozygotes. Predominance of the alpha/beta alleles of SAA1 and comparable plasma and polymorphonuclear colchicine concentrations characterized both groups. Nonresponders were from lower socioeconomic backgrounds, had less education, and a more severe form of disease. A statistically significant 2-fold elevation of colchicine concentration in the mononuclear cells (MNC) of responders was found. CONCLUSIONS Colchicine treatment failure in FMF is associated with inadequate colchicine MNC concentration, probably resulting from a genetic defect unrelated to the underlying FMF.

Prognostic significance of the admission electrocardiogram in acute myocardial infarction

OBJECTIONS We sought to access the ST segment and the terminal portion of the QRS complex in the initial electrocardiogram (ECG) as tools to predict outcome in patients with acute myocardial infarction given thrombolytic therapy. BACKGROUND Previous studies assessing early risk stratification of patients with acute myocardial infarction by ECG criteria have focused on the number of leads with ST segment elevation or the absolute magnitude of ST deviation. A new classification independent of the absolute values of ST deviation was pursued. METHODS Patients with ST elevation and positive T waves in at least two adjacent leads who received thrombolytic therapy were classified into two groups based on the absence (1,232 patients) or presence (1,371 patients) of distortion of the terminal portion of the QRS complex on the admission ECG. RESULTS There were no differences between groups in the prevalence of previous angina, hypertension, current smoking, anterior infarction, time from onset of symptoms to therapy of type of thrombolytic regimen. Patients with QRS distortion were less likely to have had a previous infarction (12.0% vs. 18.4%, p = 0.02) or diabetes mellitus (16.9% vs. 21.4%, p = 0.003). They had higher peak creatine kinase levels (1,617 +/- 1,670 vs. 1,080 +/- 1,343 IU, p = 0.00001). Hospital mortality for those with and without QRS distortion was 6.8% and 3.8%, respectively (p = 0.0008). Multivariable logistic regression analysis confirmed that hospital mortality was independently associated with distortion of terminal portion of the QRS complex (odds ratio 1.78, 95% confidence interval 1.19 to 2.68, p = 0.004). CONCLUSIONS Distortion of the terminal portion of the QRS complex on the admission ECG is independently associated with a higher hospital mortality rate in patients with acute myocardial infarction given thrombolytic therapy.