Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

Miconazole buccal gel and risk for systemic bleeding: how certain topical formula can interfere with anticoagulants.

The association of miconazole and oral anticoagulants should be carried out with great caution because of potentially serious side effects. This phenomenon is well known in the case of systemic administration of miconazole, but there is limited awareness that also topical oral administration of miconazole can provoke these effects. In this paper we describe four patients followed at the Cardiology Department of the Ghent University Hospital, who used an oral mucosal miconazole preparation, and who developed an increased international normalized ratio.

French professionals in genetic counselor careers.

The profession of genetic counseling in France was recognized in 2004, based on the recommendations of a mandate commissioned by the Health Minister to explore the medical demographics of France. The report predicted a shortage of health professionals in the field of genetics, particularly in light of the rapid development of molecular testing. Development of the profession was supported by a legal framework, and today 107 genetic counselors have graduated from the specific educational program which awards the Professional Master's Degree of Human Pathology, entitled Master in Genetic Counseling and Predictive Medicine. Here we will trace the development of the profession in France and review the demographic characteristics of the students and genetic counselors practicing the profession today.

Contribution of CDKN2A/P16 ( INK4A ), P14 (ARF), CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma.

Uveal melanoma arises from melanocytes of the uveal tract (iris, ciliary body and choroid) and represents the most common intraocular malignancy in adults. Some rare clinical situations (young age at diagnosis, bilateral or multifocal forms, association with cutaneous malignant melanoma and/or familial aggregations of melanomas) are suggestive of genetic susceptibility. The aim of this study was to evaluate the contribution of CDKN2A/P16INK4A, P14ARF and CDK4 gene germline mutations in a series of patients with uveal melanoma recruited in a single institution with a clinical presentation indicative of genetic predisposition. Molecular analyses were proposed to 36 patients and were performed in 25 cases. The contribution of BRCA1/2 gene germline mutations in patients with uveal melanoma and a personal and/or family history of breast/ovarian cancers was also evaluated. Molecular analysis of BRCA1/2 genes was proposed to 35 patients and was performed in 25 patients. No deleterious germline mutation was identified in either group of patients. These results indicate that the CDKN2A/P16INK4A, P14ARF, CDK4 genes are not responsible for the vast majority of genetic susceptibility to uveal melanoma. They also suggest that one case of uveal melanoma in a family with a history of breast cancer is not sufficient to justify BRCA1/2 genetic testing when the classical criteria for molecular analysis are not present. International studies are ongoing in melanoma-prone families in an attempt to identify uveal melanoma susceptibility loci and genes.

[Estimation of individual breast cancer risk: relevance and limits of risk estimation models]. / Estimation du risque individuel de cancer du sein: intérêt et limites des modèles de calcul de risque.

Several risk estimation models for breast or ovarian cancers have been developed these last decades. All these models take into account the family history, with different levels of sophistication. Gail model was developed in 1989 taking into account the family history (0, 1 or > or = 2 affected relatives) and several environmental factors. In 1990, Claus model was the first to integrate explicit assumptions about genetic effects, assuming a single gene dominantly inherited occurring with a low frequency in the population. BRCAPRO model, posterior to the identification of BRCA1 and BRCA2, assumes a restricted transmission with only these two dominantly inherited genes. BOADICEA model adds the effect of a polygenic component to the effect of BRCA1 and BRCA2 to explain the residual clustering of breast cancer. At last, IBIS model assumes a third dominantly inherited gene to explain this residual clustering. Moreover, this model incorporates environmental factors. We applied the Claus, BRCAPRO, BOADICEA and IBIS models to four clinical situations, corresponding to more or less heavy family histories, in order to study the consistency of the risk estimates. The three more recent models (BRCAPRO, BOADICEA and IBIS) gave the closer estimations. These estimates could be useful in clinical practice in front of complex analysis of breast and/or ovarian cancers family history.

Gemcitabine combined with cisplatin as first-line treatment in patients with epithelial ovarian cancer: a phase II study.

OBJECTIVE: This phase II study was performed to evaluate the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of advanced epithelial ovarian cancer. METHODS: Chemonaive patients with histologically or cytologically confirmed FIGO stage III or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg/m(2) on Day 1 and gemcitabine 1250 mg/m(2) on Days 1 (after cisplatin) and 8 of a 21-day cycle. RESULTS: Of the 42 female patients (median age 60 years) enrolled, 81% had a Zubrod performance status of 0 or 1. Among the 37 response-evaluable patients, there were 5 (13.5%) pathological complete responses (CRs), 16 (43.2%) pathological partial responses (PRs), and 3 (8.1%) clinical PRs, for an overall response rate of 64.9% (95% CI: 47.4-79.8%) and a pathological response rate of 56.8%. Per an intent-to-treat analysis, the overall response rate was 57.1% (95% CI: 41.0-72.3%). After a median follow-up time of 15.8 months, the median survival was 24.0 months and median progression-free survival was 13.4 months. Grade 3/4 neutropenia and thrombocytopenia occurred in 69.0 and 33.3% of patients, respectively, with no febrile neutropenia or hemorrhage. Grade 3/4 nausea and vomiting occurred in 35.7% and grade 3 alopecia in 21.4% of the patients. One patient died due to a toxicity-related death (dyspnea). CONCLUSIONS: Gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials adding gemcitabine to first-line treatment seem warranted.

Dysphagia in multiple sclerosis.

OBJECTIVES: (1) To determine the prevalence of swallowing problems in MS patients and its relation to the overall disability. (2) To define the most frequent symptoms suggestive of dysphagia. (3) To describe the abnormalities on manofluoroscopy (MFS). METHODS: Three hundred and eight consecutive MS patients were asked whether they ever had swallowing problems. If so the questionnaire of the Johns Hopkins Swallowing Centre was applied to qualify the dysphagia. A MFS was performed in 30 patients with dysphagia covering the entire spectrum of MS. Overall disability was assessed using the Expanded Disability Status Scale (EDSS). RESULTS: Seventy-three of our 309 patients had permanent dysphagia (24%). Another 5% had a history of transitory swallowing problems only. Permanent dysphagia started to be a problem in mildly impaired patients (EDSS 2-3). Prevalence increased together with rising disability to reach 65% in the most severely disabled subjects (EDSS 8-9). Two alarming symptoms of patients with swallowing problems, coughing or choking during the meal and a history of pneumonia were present in 59%, respectively, 12% of these patients. MFS showed deficiency of the oral phase in all patients, while only the patients with an EDSS higher than 7.5 showed abnormalities of the pharyngeal phase. CONCLUSIONS: Permanent dysphagia may already develop in mildly impaired MS patients but becomes a rather frequent finding in MS patients with moderate or severe disability. MFS is a sensitive and useful ancillary examination. Important qualitative changes of the pharyngeal phase on MFS are seen in patients with an EDSS higher than 7.5.

Plasma D-dimer concentrations in different clinical conditions.

D-dimers (DD), specific degradation products of crosslinked fibrin, are markers for activation of plasma coagulation and/or fibrinolysis. DD results below the cut-off level are proven to be useful to rule out the probable diagnosis of deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Our objective was to demonstrate that positive DD occur in many diseases and certain physiological conditions as high age and pregnancy and to look for gradations in positivity between different pathological conditions. We wanted to investigate the request attitude of our clinicians concerning DD. Positive DD results still confuse some physicians. Retrospectively, we examined medical records of 574 consecutive patients, in whom plasma DD were measured in daily routine. Both outpatients (n = 423) and inpatients (n = 151) were included. We noted their clinically predominant disease. Measurement of DD concentration is too often requested by clinicians, in any medical condition, and is not always clinically relevant. The relation of a positive result and the clinical problem is sometimes not understood. Overall, we found 64% DD positivity with a median concentration of 775 micrograms/L. We found elevated DD concentrations in various clinical conditions.

Adenoid cystic carcinoma arising in an adenomyoepithelioma of the breast.

Adenomyoepithelioma is a mixed epithelial and myoepithelial tumour. In rare cases adenomyoepitheliomas give rise to carcinomas with epithelial, myoepithelial, or mixed epithelial and myoepithelial differentiation. Carcinomas arising in adenomyoepithelioma range from low grade to high grade, and 15 cases have been reported in the literature. We describe a 36-year-old woman with a very rare adenoid cystic carcinoma arising in a tubular adenomyoepithelioma. The histogenesis of carcinoma arising in an adenomyoepithelioma is discussed.

CT demonstration of perirenal lymphatic cysts.

A case of perirenal lymphatic cysts demonstrated by computed tomography is reported. These lymphatic cysts, a histological subtype of lymphangiomata, are clearly visible as collections with clear fluid-type density surrounding both kidneys. The retroperitoneal localization of this rarity has been reported in the radiological literature, whereas, to our knowledge, the radiological demonstration of the perirenal localization has not. CT provides a unique method for direct radiological visualization of the cyst.

Leiomyosarcoma of the inferior vena cava.

The thirty-second case of leiomyosarcoma of the inferior vena cava and the twelfth resectable patient in the series is presented. A review of the literature demonstrates a marked female preponderance (5 to 1). The most common presenting symptom is right abdominal pain and a palpable mass. The different surgical problems generated by the involved segment of the cava are discussed. Noteworthy is the high incidence of Budd-Chiari syndrome owing to hepatic vein obstruction with involvement of the upper third of the cava in the postmortem cases. An argument is developed for debulking the tumor for palliation when it is not completely removable.

Echinococcal disease of the kidney.

A case of hydatid disease of the kidney is presented. The parasitology, diagnostic evaluation and surgical treatment for the entity are discussed.