[Uterine fibroids]. / Fibromes utérins.

UTERINE FIBROIDS. Uterine fibroids are the most common tumors of the female genital tract. They can be asymptomatic or associated with various symptoms like abnormal uterine bleeding, pelvic pain, pelvic or extra pelvic compressive signs, or anaemia. They can also be associated with infertility. The main further examination for fibroids diagnosis is pelvic ultrasound. Pelvic MRI (Magnetic Resonance Imaging) is also useful before surgery or interventional radiology for fibroid mapping. All fibroids must be located according to the FIGO classification. No treatment is necessary in the absence of clinical symptoms. The management of uterine fibroids depends on the clinical signs, the mapping, and the preservation of the uterus as well as fertility. Medical treatment is the first-line option. In case of failure, therapeutic options include surgery or uterine artery embolization.

FIBROMES UTÉRINS. Les fibromes utérins sont les tumeurs les plus fréquentes de l'appareil génital féminin. Ils peuvent être asymptomatiques ou associés à des saignements utérins anormaux, des douleurs pelviennes, des signes compressifs pelviens ou extrapelviens ou à une anémie. Ils peuvent parfois jouer un rôle délétère sur la fertilité. Le premier examen diagnostique à proposer est une échographie pelvienne. L'imagerie par résonance magnétique (IRM) pelvienne est prescrite en deuxième intention, avant chirurgie ou radiologie interventionnelle, pour préciser une cartographie des fibromes. Cette cartographie est établie selon la classification de la Fédération internationale de gynécologie et d'obstétrique (Figo). En l'absence de symptomatologie clinique, il n'y a pas d'indication thérapeutique. Aucun traitement médical ne peut faire disparaître les myomes. La prise en charge dépend des signes cliniques, de la localisation des myomes, du désir ou non de conserver l'utérus et du projet parental. Le traitement médical des symptômes est à privilégier en première intention. En cas d'échec, une chirurgie ou une embolisation par radiologie interventionnelle peuvent être envisagées.

APC germline pathogenic variants and epithelial ovarian cancer: causal or coincidental findings?

APC germline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours. APC inactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification of APC germline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a second hit of APC inactivation nor ß-catenin activation. Both tumours did not have a homologous recombination (HR) deficiency, pointing towards the implication of other genes than those involved in HR. APC may contribute to the carcinogenesis of EOC in a multifactorial context. Further studies are required to clarify the role of APC in predisposition to EOC.

Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

Blood transcriptomic biomarkers of Alzheimer's disease patients treated with EHT 0202.

Monitoring the genomic expression of patients in clinical trials for Alzheimer's disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease.

Toward an Alzheimer's disease diagnosis via high-resolution blood gene expression.

BACKGROUND: There is a significant need for reliable molecular biomarkers to aid in Alzheimer's disease (AD) clinical diagnosis. METHODS: We performed a genome-wide investigation of the human transcriptome, taking into account the discriminatory power of splice variations from the blood of 80 AD patients and 70 nondemented control (NDC) individuals. RESULTS: We characterized a blood RNA signature composed of 170 oligonucleotide probe sets associated with 133 genes that can correctly distinguish AD patients from NDC with a sensitivity of 100% and specificity of 96%. Functionally, this signature highlights genes involved in pathways that were associated with macrophages and lymphocytes within AD patients: Transforming growth factor (TGF-beta) signaling, oxidative stress, innate immunity and inflammation, cholesterol homeostasis, and lipid-raft perturbation, whereas other genes may also provide new insights in the biology of AD. CONCLUSIONS: This study provides proof-of-concept that whole-blood profiling can generate an AD-associated classification signature via the specific relative expression of biologically relevant RNAs. Such a signature will need to be validated with extended patient cohorts, and evaluated to learn whether it can differentiate AD from others types of dementia.

Circadian pharmacology of L-alanosine (SDX-102) in mice.

L-alanosine (SDX-102) exerts its cytotoxicity through inhibition of de novo purine biosynthesis, an effect potentiated by methylthioadenosine phosphorylase (MTAP) deficiency. The relevance of circadian dosing time was investigated for chronotherapeutic optimization of SDX-102. Toxicity was assessed in healthy mice following single (1,150, 1,650, or 1,850 mg/kg/d) or multiple doses (250 or 270 mg/kg/d). Efficacy was tested in mice with P388 leukemia receiving multiple doses (225 or 250 mg/kg/d). SDX-102 was administered at six circadian times 4 hours apart in mice synchronized with 12 hours of light alternating with 12 hours of darkness. MTAP expression was determined in liver, bone marrow, small intestinal mucosa, and P388 cells. Dosing at 19 hours after light onset reduced lethality 5-fold after single administration and 3-fold after multiple doses as compared with worst time [P < 0.001 and P < 0.01, respectively (chi2 test)]. Neutropenia, lymphopenia, and bone marrow hemorrhagic lesions were significantly less in mice dosed at 19 hours after light onset as compared with 7 hours after light onset. SDX-102 at 7 hours after light onset transiently ablated the 24-hour patterns in body temperature and activity. A circadian rhythm characterized small intestinal MTAP expression with a maximum at 6:30 hours after light onset (P = 0.04). A minor survival improvement was found in MTAP-deficient P388 mice receiving SDX-102 at 7 or 23 hours after light onset as compared with other times (P = 0.03, log-rank test). In conclusion, the therapeutic index of SDX-102 was improved by the delivery of SDX-102 in the mid to late activity span. These results support the concept of chronomodulated infusion of SDX-102 in cancer patients.