Contribution of muscle MRI for diagnosis of myopathy.

Inherited myopathies are a group of disease, which, although distinct from a genetic and prognostic point of view, can lead to non-specific clinical pictures due to phenotypic overlap. Acquired immuno-mediated myopathies may also pose the problem of clinically accurate etiological orientation. The assessment of fatty infiltration and pathological increase in water volume of the muscle contingent on whole-body muscle MRI is becoming increasingly important in aiding the initial diagnosis of inherited and acquired myopathies. MRI helps orientating the clinical diagnostic hypotheses thanks to the patterns of muscle involved (more or less specific according to the entities), which led to the development of decision-making algorithms proposed in the literature. The aim of this article is to specify the proper MRI protocol for the evaluation of myopathies and the basis of the interpretation and to provide a summary of the most frequently inherited and acquired myopathies described in the literature.

Wireless phone use in childhood and adolescence and neuroepithelial brain tumours: Results from the international MOBI-Kids study.

In recent decades, the possibility that use of mobile communicating devices, particularly wireless (mobile and cordless) phones, may increase brain tumour risk, has been a concern, particularly given the considerable increase in their use by young people. MOBI-Kids, a 14-country (Australia, Austria, Canada, France, Germany, Greece, India, Israel, Italy, Japan, Korea, the Netherlands, New Zealand, Spain) case-control study, was conducted to evaluate whether wireless phone use (and particularly resulting exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF)) increases risk of brain tumours in young people. Between 2010 and 2015, the study recruited 899 people with brain tumours aged 10 to 24 years old and 1,910 controls (operated for appendicitis) matched to the cases on date of diagnosis, study region and age. Participation rates were 72% for cases and 54% for controls. The mean ages of cases and controls were 16.5 and 16.6 years, respectively; 57% were males. The vast majority of study participants were wireless phones users, even in the youngest age group, and the study included substantial numbers of long-term (over 10 years) users: 22% overall, 51% in the 20-24-year-olds. Most tumours were of the neuroepithelial type (NBT; n = 671), mainly glioma. The odds ratios (OR) of NBT appeared to decrease with increasing time since start of use of wireless phones, cumulative number of calls and cumulative call time, particularly in the 15-19 years old age group. A decreasing trend in ORs was also observed with increasing estimated cumulative RF specific energy and ELF induced current density at the location of the tumour. Further analyses suggest that the large number of ORs below 1 in this study is unlikely to represent an unknown causal preventive effect of mobile phone exposure: they can be at least partially explained by differential recall by proxies and prodromal symptoms affecting phone use before diagnosis of the cases. We cannot rule out, however, residual confounding from sources we did not measure. Overall, our study provides no evidence of a causal association between wireless phone use and brain tumours in young people. However, the sources of bias summarised above prevent us from ruling out a small increased risk.

Application of the DAWN clinical imaging mismatch and DEFUSE 3 selection criteria: benefit seems similar but restrictive volume cut-offs might omit potential responders.

BACKGROUND AND PURPOSE: An external validation of the selection criteria of diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake-up and late-presenting strokes undergoing the Neurointervention with Trevo (DAWN) and the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE3) trials was conducted in a cohort of unknown onset stroke (UOS) patients treated with thrombectomy. METHODS: A validation cohort of UOS patients was selected from a prospectively collected thrombectomy database to match the inclusion criteria of DAWN and DEFUSE 3. Patients with an initial National Institutes of Health Stroke Scale (NIHSS) ≥10 were stratified according to the DAWN selection criteria. Patients ≤90 years old with an initial NIHSS ≥6 were stratified according to the DEFUSE 3 selection criteria. The proportions of patients with a modified Rankin Scale (mRS) ≤2 at 3 months follow-up were compared between DAWN-eligible patients and the DAWN trial thrombectomy group, and between DEFUSE 3-eligible patients and the DEFUSE 3 trial thrombectomy group. RESULTS: Of the 60/102 (59%) DAWN-eligible patients, 26 patients (43%) reached a mRS ≤2 at 3 months follow-up [versus 52/107 patients (49%) in the DAWN trial thrombectomy group; P = 0.52]. Of the 100/117 (85%) DEFUSE 3-eligible patients, 48 patients (48%) reached a mRS ≤2 at 3 months follow-up [versus 41/92 patients (45%) in the DEFUSE 3 trial thrombectomy group; P = 0.67]. Of the DAWN-ineligible and DEFUSE 3-ineligible patients who underwent thrombectomy, 38% (16/42) and 41% (7/17) of patients reached a mRS ≤2, respectively. CONCLUSION: The results of the DAWN and DEFUSE 3 trials were externally validated in a UOS cohort where the trials' selection criteria identified a similar proportion of responders to thrombectomy.

The joint association of self-rated health and diabetes status on 14-year mortality in elderly men and women.

PURPOSE: Low self-rated health (SRH) has been found to be associated with increased risk of type 2 diabetes (T2D) and with mortality. We examined the possible interaction between SRH and diabetic state on all-cause mortality in a large cohort of elderly subjects, followed for 14 years. METHODS: During the years 2000-2004, survivors of the nationwide longitudinal Israel Study of Glucose Intolerance, Obesity and Hypertension were interviewed and examined for the third follow-up. The 1037 participants (mean age 72.4 ± 7.2 years) were asked to rate their health as: excellent, good, fair, poor, or very poor. Glucose categories were as follows: Normoglycemic, Prediabetes, T2D and Undiagnosed diabetes. Survival time was defined as the time from interview to date of death or date of last vital status follow-up (August 1, 2013). Multivariate Cox proportional hazards models were performed in order to assess whether SRH interacts with glycemic state in the association with mortality. RESULTS: A better SRH was reported by those with undiagnosed than known diabetes, and best for normoglycemic and prediabetic individuals. While all individuals with fair or poor/very poor SRH were at increased risk of mortality compared to those with excellent/good SRH, in the known diabetic individuals a greater hazard was observed in the excellent/good SRH (HR 3.32, 95 % CI 1.71-6.47) than in those with fair or poor/very poor SRH (HR 2.19, 95 % CI 1.25-3.86), after adjusting for age, sex, ethnic origin, marital status, education, BMI, physical activity, CVD, tumors, and creatinine level (p for interaction = 0.01). CONCLUSIONS: Self-rated health is not a sensitive tool for predicting mortality in elderly men and women with known T2D.

One-hour post-load plasma glucose level during the OGTT predicts mortality: observations from the Israel Study of Glucose Intolerance, Obesity and Hypertension.

AIMS: The relationship between 1- and 2-h glucose levels following an oral glucose tolerance test (OGTT) and long-term mortality was evaluated. METHODS: Over a 33-year period, 2138 individuals were followed for all-cause mortality. Fasting and post-OGTT glucose parameters categorized the cohort according to baseline glycaemic status. Four categories were established according to 1- and 2-h glucose levels (in mmol/l): group A = 1 h ≤ 8.8 and 2 h < 7.8; group B = 1 h > 8.6 and 2 h < 7.8; group C = 1 h ≤ 8.6 and 2 h = 7.8-11.1 (impaired glucose tolerance); group D = 1 h > 8.6 and 2 h = 7.8-11.1 (impaired glucose tolerance). Individuals with diabetes at baseline were excluded from the cohort. RESULTS: By August 2013, 51% of the study cohort had died. The worst prognosis occurred in group D (73.8% mortality), followed by groups C (67.5%), B and A (57.9% and 41.6%, respectively). When the 2-h glucose value is 'normal' (< 7.8 mmol/l), the 1-h glucose value > 8.6 mmol/l is an important predictor of mortality (28% increased risk) compared with group A, controlling for sex, age, smoking, BMI, systolic and diastolic blood pressures. A gradual increased hazard for mortality was seen by study group (hazard ratio = 1.28, 1.60 and 1.76, for groups B, C and D, respectively; group A = reference). CONCLUSIONS: A 1-h glucose value > 8.6 mmol/l predicts mortality even when the 2-h level is < 7.8 mmol/l. However, when the 2-h level is in the impaired glucose tolerance range, the hazard for mortality rises significantly independent of the 1-h value. Individuals at risk for developing diabetes could be identified earlier using the 1-h threshold value of 8.6 mmol/l, which could avert progression to diabetes and increased mortality.‬.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up.

BACKGROUND: In a preliminary report, we found an association between hyperinsulinemia in the basal (fasting) state and the development of diabetes. OBJECTIVES: The current analysis further explored the long term link between basal hyperinsulinemia and conversion to dysglycemia. METHODS: This is a prospective study with up to 24 years of follow-up of 515 normoglycemic individuals (mean age at follow up = 70.3 ± 7.0; range 58-94) of an Israeli cohort. Fasting glucose and insulin were measured, and dysglycemia was defined as fasting glucose > 100 mg/dL. RESULTS: At the end of the follow-up period, almost half had progressed to dysglycemia. Male sex and elevated baseline levels of basal insulin, body mass index, blood glucose and blood pressure each favoured progression to dysglycemia over the subsequent two decades. A multivariate logistic regression model identified basal hyperinsulinemia as the strongest predictor for progression to dysglycemia (odds ratio = 1.79; 95% confidence interval 1.12-2.88), while controlling for ethnicity, blood pressure, fasting glucose, male sex, body mass index and age. CONCLUSIONS: Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for metabolic deterioration to dysglycemia over adulthood, and may help to identify apparently healthy subjects at increased risk for diabetes.

Adult-onset diabetes among Arabs and Jews in Israel: a population-based study.

AIMS: To study the age at presentation and factors associated with adult-onset diabetes (≥ 20 years) among Arabs and Jews in Israel. METHODS: Participants (n = 1100) were randomly selected from the urban population of the Hadera District in Israel. The study sample was stratified into equal groups according to sex, ethnicity (Arabs and Jews) and age. Information on age at diabetes presentation, family history of diabetes, history of gestational diabetes, socio-demographic and lifestyle characteristics was obtained through personal interviews. Self reports of diabetes were compared with medical records and were found reliable (κ = 0.87). The risk for diabetes was calculated using Kaplan-Meier survival analysis. Factors associated with diabetes in both ethnic groups were studied using Cox proportional hazard model. RESULTS: The prevalence of adult-onset diabetes was 21% among Arabs and 12% among Jews. Arab participants were younger than Jews at diabetes presentation. By the age of 57 years, 25% of Arabs had diagnosed diabetes; the corresponding age among Jews was 68 years, a difference of 11 years (P < 0.001). The greater risk for diabetes among Arabs was independent of lifestyle factors, family history of diabetes and, among women, history of gestational diabetes; adjusted hazard ratio 1.70; 95% confidence interval 1.19-2.43. CONCLUSIONS: Arabs in Israel are at greater risk for adult-onset diabetes than Jews and are younger at diabetes presentation. Culturally sensitive interventions aimed at maintaining normal body weight and active lifestyle should be targeted at this population. Possible genetic factors and gene-environmental interactions underlying the high risk for diabetes among Arabs should be investigated.

Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries.

OBJECTIVES: The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. METHODS: Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. RESULTS: ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. CONCLUSIONS: There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made.

Ovarian carcinoma apparently confined to the ovaries--the accuracy of surgical staging in Israel.

BACKGROUND: In order to allot an ovarian malignancy to FIGO Stage I, in addition to abdominal exploration and the basic operation, it is also necessary to do peritoneal washings for cytological examination, random peritoneal biopsies (including diaphragmatic assessment) and omental and retroperitoneal lymph node assessment. OBJECTIVE: The aim of the study was to assess the accuracy of surgical staging of ovarian carcinoma classified as Stage I in Israel. METHODS: Included were all patients with histologically confirmed epithelial ovarian carcinoma (EOC) classified as Stage I in a data base of a nationwide incidence case control epidemiological study of ovarian carcinoma conducted in Israeli Jewish women during the period 1994-1999. Surgical staging data of these patients were retrieved from pathological reports, and from clinical records when available. RESULTS: A total of 182 EOC patients were classified as Stage I. About 86% of the patients underwent hysterectomy and bilateral salpingo-oophorectomy. The most commonly performed staging procedure was omental assessment (85.2%) while peritoneal biopsy was the least common one (34.1%). In 17 (9.3%) of the patients none of the staging procedures were done and only 34 (18.7%) had optimal staging. CONCLUSION: Although the data are from a decade ago, they seem to indicate the need for an increased awareness of the necessity for accurate surgical staging of tumors apparently confined to the ovaries since it can identify a group of patients who require surgical therapy alone and who can be spared the complications, inconvenience and cost of adjuvant chemotherapy.

Determinants of mobile phone output power in a multinational study: implications for exposure assessment.

OBJECTIVES: The output power of a mobile phone is directly related to its radiofrequency (RF) electromagnetic field strength, and may theoretically vary substantially in different networks and phone use circumstances due to power control technologies. To improve indices of RF exposure for epidemiological studies, we assessed determinants of mobile phone output power in a multinational study. METHODS: More than 500 volunteers in 12 countries used Global System for Mobile communications software-modified phones (GSM SMPs) for approximately 1 month each. The SMPs recorded date, time, and duration of each call, and the frequency band and output power at fixed sampling intervals throughout each call. Questionnaires provided information on the typical circumstances of an individual's phone use. Linear regression models were used to analyse the influence of possible explanatory variables on the average output power and the percentage call time at maximum power for each call. RESULTS: Measurements of over 60,000 phone calls showed that the average output power was approximately 50% of the maximum, and that output power varied by a factor of up to 2 to 3 between study centres and network operators. Maximum power was used during a considerable proportion of call time (39% on average). Output power decreased with increasing call duration, but showed little variation in relation to reported frequency of use while in a moving vehicle or inside buildings. Higher output powers for rural compared with urban use of the SMP were observed principally in Sweden where the study covered very sparsely populated areas. CONCLUSIONS: Average power levels are substantially higher than the minimum levels theoretically achievable in GSM networks. Exposure indices could be improved by accounting for average power levels of different telecommunications systems. There appears to be little value in gathering information on circumstances of phone use other than use in very sparsely populated regions.

Effects of a copper-medicated intrauterine device on ovarian artery, uterine artery, and intrauterine blood flow.

AIM: To determine the effect of a copper-medicated intrauterine device (IUD) on ovarian, uterine, arcuate, radial and subendometrial Doppler-derived indices of blood flow. METHOD: 23 regularly menstruating patients requested insertion of an IUD. All patients had a copper T (Nova T) IUD inserted between days 8 and 11 of the menstrual cycle. Ovarian, uterine, arcuate, radial and subendometrial artery pulsatility indices (PIs) were assessed by transvaginal color Doppler prior to insertion between days 8 and 11 of the menstrual cycle, and after 2 months in the same period of the cycle. Ovarian, uterine, arcuate, radial and subendometrial artery PIs were considered prior to and following IUD insertion. RESULTS: No differences were recorded in any of the blood vessels sampled between pre- and post-insertion PIs. CONCLUSION: No significant change in ovarian or in uterine system vascular impedance is associated with the presence of a copper-medicated IUD.

Successful polar body-based preimplantation genetic diagnosis for achondroplasia.

Achondroplasia, the most common form of dwarfism, is a candidate for preimplantation genetic diagnosis (PGD) because a single mutation accounts for almost all cases. Multiplex fluorescent assay including the common G380R mutation in the FGFR3 gene and eight close polymorphic markers was developed. First and second polar bodies (PB) were used for PGD analysis. An affected woman was treated with routine long-protocol ovarian stimulation and puncture. In the first PGD cycle, out of four fertilized oocytes, PB analysis revealed two mutant oocytes, one with total amplification failure of the maternal allele and one with inconclusive results. In the second PGD cycle, 14 oocytes were retrieved following a higher FSH dose and by performing oocyte retrieval and by placing the patient in the anti-Trendelenburg position using abdominal pressure to allow all follicles to be drained. Following PB analysis, two embryos containing the wild-type FGFR3 allele were transferred. This led to an uncomplicated pregnancy and delivery by Caesarean section at week 38 of a healthy boy, carrying the FGFR3 wild-type maternal allele. In conclusion, oocyte retrieval, while difficult in patients with achondroplasia, can be successfully performed. PB analysis is a reliable and sensitive method for PGD for maternal achondroplasia.

A statistical comparison of different family history scores.

Family history (FH) scores are used for estimating the familial risk (FR), i.e. the level of risk for a particular disease among members of that family. An FH score is created from reports about the disease status of the relatives in each family. The most commonly used score is the dichotomous score (positive when at least one relative is affected), which does not consider the family size, number of affected relatives nor each relative's risk factor profile. Authors have proposed many other FH scores that overcome these deficiencies by using external expected risks adjusted for important risk factors. We consider the use of FH scores in studies, which investigate risk factors for a disease and where family risk is considered as a confounder, and examine through simulations the performance of a variety of FH scores in controlling the FR status. We also examine performance in predicting true FR status. For both criteria, only small differences were found between most of the FH scores, although the dichotomous score performed the poorest. Since the proportion score (the proportion of first-degree relatives of the index who have the disease) is the simplest to calculate, use of this score seems to be justified.

Investigation and treatment of repeated implantation failure following IVF-ET.

Pregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, some couples fail repeatedly. The causes for repeated implantation failure (RIF) may be because of reduced endometrial receptivity, embryonic defects or multifactorial causes. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules and immunological factors, may decrease endometrial receptivity, whereas genetic abnormalities of the male or female, sperm defects, embryonic aneuploidy or zona hardening are among the embryonic reasons for failure of implantation. Endometriosis and hydrosalpinges may adversely influence both. In this mini review, we discuss the suggested methods for evaluation and treatment of RIF: repeated hysteroscopy, myomectomy, endometrial stimulation, immunotherapy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation protocols and salpingectomy for hydrosalpinges.

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.

Diagnosis delay in familial Mediterranean fever (FMF): social and gender gaps disclosed.

OBJECTIVE: To characterize the factors contributing to a greater than 10 year delay in the diagnosis of familial Mediterranean fever (FMF). METHODS: 50 patients, in whom diagnosis of FMF was delayed by more than 10 years, comprised the study population. The clinical, demographic and molecular genetic characteristics were compared to a control group of 50 FMF patients, in whom the diagnosis was made within a reasonable time period (less than 5 years from onset). Additional factors contributing to a delayed diagnosis in the study group, including physician-related factors, patient-related factors, disease-factors and other factors, were studied as well. RESULTS: Overall, attack sites, duration and severity were comparable among study and control groups. No differences in ethnic origin or family history of FMF were noted between the groups. There were significantly more females (p = 0.009), newly-arrived immigrants (p = 0.005) and carriers of unidentified MEFV mutations (p = 0.04) in the study group. Delayed diagnosis of FMF stemmed from misdiagnosis and physician negligence (70%), as well as from patient negligence (70%). The diagnosis was ultimately made mainly due to a change in disease pattern and other causes, such as diagnosis of FMF in a relative. CONCLUSION: The study unveils unexpected causes behind a prolonged delay in the diagnosis of FMF such as social status (immigrant), female gender, physician negligence and lack of patient awareness. The possibility that the delay stems from a milder disease pattern was dismissed.

Analyses of p53 expression pattern and BRCA mutations in patients with double primary breast and ovarian cancer.

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

A possible genetic factor in the pathogenesis of ovarian dermoid cysts.

This study was undertaken in order to evaluate a possible genetic influence on the pathogenesis of ovarian dermoid cysts. We have performed a case-control study comparing the prevalence of a history of dermoid cysts in first-degree relatives of women with dermoid cysts and among first-degree relatives of women without dermoid cysts. The study group included 285 women with an established diagnosis of ovarian dermoid cysts. The control group included 378 women with sonographically normal ovaries. To assess the relationship between a first-degree family history of dermoid cysts and the diagnosis of ovarian dermoid cysts, a multivariate stepwise logistic regression model was applied. In 28 families of the study group (9.8%), a dermoid cyst was found in at least 1 first-degree relative as compared with only eight families (2%) among the controls (adjusted odds ratio -5.60; 95% CI 2.24-14.2). The data suggest a genetic predisposition towards dermoid cysts which merits further exploration.

Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in israel.

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