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To describe the characteristics of the largest European study of MEC of salivary glands and to determine the prognostic factors for overall and disease free survival. Patients with MEC were prospectively included in the Réseau d'Expertise Français sur les Cancers ORL Rares (REFCOR, French Network of Rare Head and Neck Tumors) database between 2009 and 2015. A total of 292 patients were included. Tumors were classified as low grade in 175 cases (60%), intermediate in 39 (13%) and high grade in 78 (27%). Median follow-up was 26 months. The 5-year OS and DFS rates were respectively 83% and 69%. In multivariate analysis, age (p = 0.004), diabetes (p = 0.02) and advanced stage (p = 0.03) were found to have a significant negative impact on OS. Diabetes (p = 0.001), alcohol consumption (p = 0.003) and advanced stage (p = 0.001) were found to have a significant negative impact on DFS. Compare to low grade, high grade tended to have a negative impact on OS (p = 0.05) and had a significant effect on DFS (0.002) while intermediate grade had no significant influence on survival. The surgical treatment had a positive impact on both OS (p = 0.00005) and DFS (p = 0.0005). Postoperative radiotherapy had no impact in multivariate analysis. Advanced clinical stage, high grade tumor, high age, the impossibility of carrying out a complete surgical resection, and diabetes are the main prognostic factors in this prospective series of patients with MEC. Such findings open new research perspectives on the influence of these components on initial patient care. [ABSTRACT FROM AUTHOR]

With the exception of infantile spinal muscular atrophy (SMA) and congenital myotonic dystrophy 1 (DM1), congenital myopathies and muscular dystrophies with neonatal respiratory distress pose diagnostic challenges. Next-generation sequencing (NGS) provides hope for the diagnosis of these rare diseases. We evaluated the efficiency of next-generation sequencing (NGS) in ventilated newborns with peripheral hypotonia. We compared the results of our previous study in a cohort of 19 patients analysed by Sanger sequencing from 2007 to 2012, with a diagnostic yield of 26% (5/19), and those of a new retrospective study in 28 patients from 2007 to 2018 diagnosed using MyoPanel, a neuromuscular disease panel, with a diagnostic yield of 43% (12/28 patients). Pathogenic variants were found in five genes: ACTA1 (n = 4 patients), RYR1 (n = 2), CACNA1S (n = 1), NEB (n = 3), and MTM1 (n = 2). Myopanel increased the diagnosis of congenital neuromuscular diseases, but more than half the patients remained undiagnosed. Whole exome sequencing did not seem to fully respond to this diagnostic limitation. Therefore, explorations with whole genome sequencing will be the next step. • NGS helps in the diagnosis of severe neonatal neuromuscular diseases. • NGS is efficient to diagnose congenital myopathies and muscular dystrophies. • We identified rare pathogenic variants in CACNA1S. • We confirmed the need to carry out whole genome sequencing studies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. Patients and methods: Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. Results: For the phase II patients median TTP was 23.1weeks (95%CI=[15.4; 28.2]) while the median OS was 80.3weeks (95%CI=[57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4w (95%CI=[47.3; 97.6]) while median TTP was 18.1w (95%CI=[16.9; 25.6]). FGFR1 over-expression (HR=4.65; 95%CI=[1.02; 21.21], p =0.047) was correlated with shorter TTP while FGFR1 (HR=4.1 (95% CI=[1.09–15.4]; p =0.036)) and αvβ3 (HR=10.38 (95%CI=[2.70; 39.87], p =0.001)) over-expressions were associated with reduced OS. Conclusion: Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP. [ABSTRACT FROM AUTHOR]

Abstract: Turcot's syndrome is a rare clinical syndrome, characterized by the association between familial adenomatous polyposis (FAP) and a primary central nervous system tumour. Gardner's syndrome is characterized by the association between FAP and several tumour types such as multiple osteomas, fibromas, epidermoid cysts and desmoid tumours. We report here the case of a twenty-six year-old woman with a history of both Turcot's and Gardner syndromes. She had a family history of adenomatous polyposis with a mutation in the APC (Adenomatous Polyposis Coli) gene. At the age of 26, she presented a mucoepidermoid carcinoma of the right parotid gland in which the MECT1-MAML2 fusion was showed. We discuss the possible addition of this latter cancer type in the definition of Gardner's syndrome. [Copyright &y& Elsevier]

Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands. Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS. A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3–T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16). These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3–T4 status and/or intermediate/high histological grade. • The 5-year OS and DFS were 92.8% and 76.2%, respectively. • Male sex, higher T/N status, and high grade were independently associated with a worse DFS. • T3–T4 status and intermediate/high histological grade were associated with N+ status. • After PS matching, prophylactic ND was associated with a trend toward a better DFS. [ABSTRACT FROM AUTHOR]

Herein, we report a new case of Danon''s disease in a 41-year-old Frenchman. This patient displays the typical clinical triad, with cardiomyopathy, mental retardation and myopathy, and a vacuolar myopathy without acid α-glucosidase deficiency. He has also developed a diffuse chorio-capillary ocular atrophy, and represents the second case of successful heart transplantation in this lysosomal disease. Interestingly, analysis of LAMP-2 protein expression in cultured fibroblasts revealed a primary deficiency of this lysosomal membrane protein. This defect resulted from a yet undescribed deletion in exon 7 of lamp-2 gene. [Copyright &y& Elsevier]

• TTN variants are frequent and their pathogenicity is difficult to assess. • Deep phenotyping, segregation studies, transcripts and protein analyses are essential. • Analysis of the consequences on transcripts and protein of all variants is crucial. • RNASeq will be the technique of choice to identify TTN variants consequences. • Reporting challenging titinopathy cases in publications is essential. Next generation sequencing (NGS) has allowed the titin gene (TTN) to be identified as a major contributor to neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and the dominant or recessive pattern of inheritance are unclear. Titin is involved in the formation and stability of the sarcomeres. The effects of the different TTN variants can be harmless or pathogenic (recessive or dominant) but the interpretation is tricky because the current bioinformatics tools can not predict their functional impact effectively. Moreover, TTN variants are very frequent in the general population. The combination of deep phenotyping associated with RNA molecular analyses, western blot (WB) and functional studies is often essential for the interpretation of genetic variants in patients suspected of titinopathy. In line with the current guidelines and suggestions, we implemented for patients with skeletal myopathy and with potentially disease causing TTN variant(s) an integrated genotype-transcripts-protein-phenotype approach, associated with phenotype and variants segregation studies in relatives and confrontation with published data on titinopathies to evaluate pathogenic effects of TTN variants (even truncating ones) on titin transcripts, amount, size and functionality. We illustrate this integrated approach in four patients with recessive congenital myopathy. [ABSTRACT FROM AUTHOR]

Abstract: A patient experienced sudden onset of musculocutaneous symptoms 3 years after being diagnosed with polyarthritis. Biopsies from the duodenum, skin, and muscle established the diagnosis of Whipple disease. Cultures of muscle biopsy specimens grew Tropheryma whipplei. Adequate antibiotic therapy ensured a favorable outcome. To our knowledge, this is the first case in which T. whipplei was recovered from muscle biopsy specimens, confirming the infectious nature of muscle involvement in Whipple disease. [Copyright &y& Elsevier]

Résumé: Nous rapportons l''observation d''une maladie de Whipple qui, ayant débuté par une polyarthrite, s''est révélée — trois ans après — par un syndrome musculocutané d''apparition brutale. Le diagnostic est confirmé par les biopsies duodénales, cutanées et musculaires. L''évolution sous antibiothérapie adaptée est favorable. La mise en culture d''échantillons musculaires permet d''isoler Tropheryma whipplei. À notre connaissance, il s''agit de la première observation où T. whipplei a pu être isolé et cultivé à partir d''un prélèvement musculaire, confirmant la nature infectieuse de cette atteinte dans la maladie de Whipple. [Copyright &y& Elsevier]

Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC. A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software. Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age ≥65 years (hazard ratio [HR] = 1.67), BMI<16.5 (HR = 2.62), and lymph node invasion cN (HR = 2.08). Age, BMI and N stage are the three main clinical prognostic factors determining EFS identified in this prospective series of patients with ACC. Such findings open new research perspectives on the influence of these components on initial patient care. • Head and neck adenoid cystic carcinoma occur more frequently in women (sex ratio: 1.5). • Age, body mass index and N stage are the three main clinical prognostic factors influencing event-free survival. • Tumour size, perineural invasion and the presence of histological grade III also have a negative influence on prognosis. [ABSTRACT FROM AUTHOR]

Summary In early embryos, the DNA damage checkpoint is silent until the midblastula transition (MBT) because of maternal limiting factors of unknown identity. Here we identify the RAD18 ubiquitin ligase as one such factor in Xenopus . We show, in vitro and in vivo, that inactivation of RAD18 function leads to DNA damage-dependent checkpoint activation, monitored by CHK1 phosphorylation. Moreover, we show that the abundance of both RAD18 and PCNA monoubiquitylated (mUb) are developmentally regulated. Increased DNA abundance limits the availability of RAD18 close to the MBT, thereby reducing PCNA mUb and inducing checkpoint derepression. Furthermore, we show that this embryonic-like regulation can be reactivated in somatic mammalian cells by ectopic RAD18 expression, therefore conferring resistance to DNA damage. Finally, we find high RAD18 expression in cancer stem cells highly resistant to DNA damage. Together, these data propose RAD18 as a critical embryonic checkpoint-inhibiting factor and suggest that RAD18 deregulation may have unexpected oncogenic potential. [ABSTRACT FROM AUTHOR]

Abstract: 7β-Hydroxycholesterol cytotoxicity has been shown in vivo and in vitro to be dependent on the accumulation of its esters. We show in our study, using a detergent-free raft preparation and LC/MS lipid content analysis, that membrane microdomains isolated from 7β-hydroxycholesterol-treated C6 cells have a reduced cholesterol: cholesterol ester ratio and accumulate 7keto-hydroxycholesterol, 7β-hydroxycholesterol and 7β-hydroxycholesterol esters. These modifications in lipid content are accompanied by a redistribution of flotillin-1 in the lipid rafts. Transient increases of AMPK phosphorylation and mitochondrial activity during the first 12h of 7β-hydroxycholesterol treatment indicate that C6 cells undergo energy stress and increase oxidative phosphorylation. Even so, ATP levels are maintained during 15h until glucose uptake decreases. The cell''s answers to raft modifications and energy stress are sequential activations of different signaling pathways such as ERK, AMPK and PI3K/Akt. These pathways, known to be activated under energy stress conditions, are transiently activated at 6h (ERK, AMPK) and 12h (Akt) of treatment respectively suggesting a shift from cell survival to cell proliferation. The persistence of 7β-hydroxycholesterol-induced stress led after 24h to P38 activation, loss of GSK3β activation and to cell death. Finally we demonstrate that the observed signaling responses depend on 7β-hydroxycholesterol esterification, confirming that esterification of 7β-hydroxycholesterol is essential for cytotoxicity. [Copyright &y& Elsevier]

Prognostic value of p27Kip1 immunohistochemical expression was evaluated in a series of 95 bladder carcinomas. Low p27Kip1 expression was correlated with higher tumor grade (P=0.01) and stage (P=0.009), associated with poor overall survival (P=0.01) and, for superficial cancers, with disease-free survival (P=0.05). Thirty-five cases exhibited a heterogeneous expression related in some instances to tumoral architecture. Seventeen cases showed a cytoplasmic reactivity related to low nuclear expression (P=0.057). Loss of p27Kip1 expression is a pejorative event in bladder tumors and inhibition of p27Kip1 degradation could offer new therapeutic ways. [Copyright &y& Elsevier]

We describe 2 patients with spinal cord compression that occurred in the course of biopsy-proven giant ceil arteritis (GCA). One case was due to an epidural tumorlike inflammatory lesion, the other to a concentric inflammatory thickening of the meninges. Both patients were highly corticodependent; they had low-titer anti-neutrophil cytoplasmic antibodies but no antimyeloperoxidase or antiproteinase 3 autoantibodies. The diagnosis was established by surgical biopsy. The histological pattern was reminiscent of Wegener granulomatosis. Both patients experienced relapse, despite high doses of corticosteroids, and experienced remission after the introduction of cyclophosphamide. intravenous immunoglobulin pertusions were added for 1 patient. To our knowledge, spinal cord compression by a spinal pseudotumor or inflammatory meningitis has not been reported in the course of GCA. An overlap syndrome between GCA and Wegener granulomatosis is discussed. [ABSTRACT FROM AUTHOR]