Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Otological Manifestations in Adults with Primary Ciliary Dyskinesia: A Controlled Radio-Clinical Study.

Primary ciliary dyskinesia (PCD) is a rare genetical disease characterized by an abnormal structure or function of the cilia, causing sinusitis, otitis, and bronchiectasis. Hearing loss affects 60% of PCD patients, but data are lacking concerning hearing and temporal bone imaging in adults. Our aim was to describe clinical and radiological ear disease in adults with genetically confirmed PCD. Data were recorded from January 2018 to December 2019. PCD patients were compared with controls with bronchiectasis without PCD. Clinical examination included otomicroscopy and auditory tests. A temporal bone CT scan (TBCT) was systematically performed. Seventeen patients (34 ears) were included in each group. The eardrums were abnormal in 25 (74%) PCD ears versus 8 (24%) ears in the controls (p < 0.05). Conductive hearing loss was more frequent in the PCD group (24% vs. 12% in controls). TBCT were abnormal in 94% PCD patients vs. 32% in the controls (p < 0.05). The Main CT-scan images in PCD were middle ear inflammation (65%), mastoid condensation (62%), or ossicular anomalies (35%). With its excellent sensitivity, TBCT gives typical arguments for PCD diagnosis, adding otological signs to the usual sinus CT signs (hypoplasia, aplasia). Systematic TBCT could be useful in the initial evaluation of patients with suspicion of PCD.

Impact of the new molecular classification of endometrial cancer: A French cohort study.

OBJECTIVE: To evaluate the potential impact of the latest ESGO guidelines for endometrial cancer with molecular classification on the management strategy in a French cohort. METHODS: All patients treated between January 1st, 2014 and December 31, 2020 for an endometrial cancer at the Centre Hospitalier Intercommunal de Créteil (CHIC, FRANCE) were selected from our prospectively maintained database. All postoperative samples were reviewed to confirm histological subtype, myometrial infiltration, cytonuclear grade and presence of lymphovascular emboli. Analysis of p53, MLH1, MSH2, MSH6, PMS2 genes was performed by immunohistochemistry first then a systematic POLE sequencing was performed to identify gene mutation. The impact of the latest ESGO 2020 guidelines was assessed regarding adjuvant therapy, surgical strategy, and survival. RESULTS: Eighty patients were analyzed, including 70% NSMP (n = 56), 13.75% MSI (n = 11), 10% p53 mutated (n = 8) and 6.25% POLEmut (n = 5). A total of 21 patients (26.3%) were reclassified using the latest ESGO classification. Patients classified at low risk or with advanced / metastatic disease were not reclassified using molecular analysis. Molecular analysis and the latest ESGO classification had the most important impact on patients initially classified at intermediate - high risk that were reclassified in intermediate (10/23) and in low (4/23) risk. Nine patients (11.3%) were overtreated according to the 2020 ESGO classification: six patients in the low - risk group (4 received vaginal brachytherapy and 2 external radiotherapy) and three in the intermediate risk group (3 received external irradiation and 1 received chemotherapy). None of the patients in our cohort would have been undertreated using the 2020 ESGO classification. Patients within the p53 mutated group were the most likely to experience recurrence (37.5%, 3/8) and none of the patients POLE mutated recurred. CONCLUSION: Around one in 4 patients were reclassified in a more accurate prognostic group using molecular diagnosis and the latest ESGO guidelines which could decrease the use of adjuvant therapies to spare morbidity.

Associated Lichen Sclerosis Increases the Risk of Lymph Node Metastases of Vulvar Cancer.

The most important prognostic factor in vulvar cancer is inguinal lymph node status at the time of diagnosis, even in locally advanced vulvar tumors. The aim of our study was to identify the risk factors of lymph node involvement in these women, especially the impact of lichen sclerosis (LS). We conducted a retrospective population-based cross-sectional study in two French referral gynecologic oncology institutions. We included all women diagnosed with a primary invasive vulvar cancer. Epithelial alteration adjacent to the invasive carcinoma was found in 96.8% (n = 395). The most frequently associated was LS in 27.7% (n = 113). In univariate analysis, LS (p = 0.009); usual type VIN (p = 0.04); tumor size >2 cm and/or local extension to vagina, urethra or anus (p < 0.01), positive margins (p < 0.01), thickness (p < 0.01) and lymphovascular space invasion (LVSI) (p < 0.01) were significantly associated with lymph node involvement. In multivariate analysis, only LS (OR 2.3, 95% CI [1.2-4.3]) and LVSI (OR 5.6, 95% CI [1.7-18.6]) remained significantly associated with positive lymph node. LS was significantly associated with older patients (p = 0.005), anterior localization (p = 0.017) and local extension (tumor size > 2 cm: p = 0.001). LS surrounding vulvar cancer is an independent factor of lymph node involvement, with local extension and LVSI.