COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Expression des voies de signalisation impliquées dans la résistance aux traitements anticancéreux et la dissémination métastatique dans les ostéosarcomes de haut grade

Malgré les progrès considérables obtenus par la polychimiothérapie dans la prise en charge des ostéosarcomes (OS), un nombre important de patients, le plus souvent adolescents ne répond pas au traitement. A ce jour, seul le grade de Huvos et Rosen constitue le facteur pronostique majeur des OS. Nous avons étudié dans une cohorte de 41 patients l'expression tumorale, avant traitement, de protéines impliquées dans les voies de résistance aux traitements anticancéreux et la survie : intégrine b1, b3, b5, ILK, FAK, RhoB, MMP-9, Ang-2 et GSK-3 b et b-caténine. Notre étude montre qu'une plus forte expression de GSK-3 b était associée à une plus mauvaise réponse au traitement et qu'une plus forte expression de FAK était à l'inverse associée à une meilleure réponse au traitement. Nous avons aussi observé qu'une plus forte expression de ILK était corrélée à une plus mauvaise survie. Ainsi, l'étude de l'expression du phénotype tumoral GSK-3 b /FAK, corrélé à la chimiorésistance et l'étude de l'expression de ILK potentiellement impliquée dans la survie, devrait nous permettre d'adapter les protocoles thérapeutiques des OS.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Microenvironnement tumoral

Grâce aux avancées des technologies de biologie moléculaire, des progrès majeurs ont été accomplis ces dernières années dans la compréhension de la biologie tumorale. Si la cible première reste la cellule cancéreuse, le microenvironnement est clairement indissociable de cette dernière et joue un rôle primordial dans la prise en charge diagnostique, à toutes les étapes du parcours clinique et histopathologique. L’analyse du microenvironnement fait en effet partie intégrante non seulement du diagnostic histologique de tumeur (élément essentiel permettant la classification histologique des tumeurs), mais aussi de l’évaluation pronostique de la maladie, et même de la stratégie thérapeutique. Au cours des prochaines années, de nouveaux biomarqueurs pronostiques et/ou prédictifs, représentatifs du stroma tumoral, seront certainement proposés et passeront les phases de validation clinique

ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions

International audienceSubsets of primitive round-cell sarcomas remain difficult to diagnose and classify. Among these is a rare round-cell sarcoma that harbors a CIC gene rearrangement known as CIC-rearranged undifferentiated round-cell sarcoma, which is most commonly fused to the DUX4 gene. Owing to its aggressive clinical behavior and potential therapeutic implications, accurate identification of this novel soft tissue sarcoma is necessary. Definitive diagnosis requires molecular confirmation, but only a few centers are as yet able to perform this test. Several studies have shown that PEA3 subfamily genes, notably ETV4 (belonging to the family of ETS transcription factors), are upregulated in CIC-rearranged undifferentiated round-cell sarcomas. We performed a detailed immunohistochemical analysis to investigate ETV4 expression in CIC-rearranged undifferentiated round-cell sarcomas and their potential mimics (especially Ewing sarcomas). The study cohort included 17 cases of CIC-rearranged undifferentiated round-cell sarcomas, and 110 tumors that morphologically mimic CIC-rearranged undifferentiated round-cell sarcomas: 43 Ewing sarcomas, 25 alveolar rhabdomyosarcomas, 20 poorly differentiated round-cell synovial sarcomas, 10 desmoplastic round-cell tumors, 5 BCOR-CCNB3 sarcomas, 5 lymphoblastic lymphomas, and 2 rhabdoid tumors. All CIC-rearranged undifferentiated round-cell sarcomas (on core needle biopsies and open biopsies) were ETV4-positive with a strong diffuse nuclear pattern. Among the other 110 tumors, only six cases (four Ewing sarcomas, one alveolar rhabdomyosarcoma, and one desmoplastic round-cell tumor) showed focal (o5% of tumor cells) and very weak nuclear expression of ETV4; all other tumors were completely negative for ETV4. We conclude that systematic immunohistochemical analysis of ETV4 makes it possible to diagnose undifferentiated round-cell sarcomas (with no molecular markers for sarcoma-associated translocation) such as CIC-rearranged undifferentiated round-cell sarcoma

Germinal GLT8D1, GATAD2A and SLC25A39 mutations in a patient with a glomangiopericytal tumor and five different sarcomas over a 10-year period

International audienceSoft tissue sarcoma represents about 1% of all adult cancers. Occurrence of multiple sarcomas in a same individual cannot be fortuitous. A 72-year-old patient had between 2007 and 2016 a glomangiopericytal tumor of the right forearm and a succession of sarcomas of the extremities: a leiomyosarcoma of the left buttock, a myxofibrosarcoma (MFS) of the right forearm, a MFS of the left scapula, a left latero-thoracic MFS and two undifferentiated sarcomas on the left forearm. Pathological examination of the six locations was not in favor of disease with local/distant recurrences but could not confirm different diseases. An extensive molecular analysis including DNA-array, RNA-sequencing and DNA-Sanger-sequencing, was thus performed to determine the link between them. The genomic profile of the glomangiopericytal tumor and the six sarcomas revealed that five sarcomas were different diseases and one was the local recurrence of the glomangiopericytal tumor. While the chromosomal alterations in the six tumors were different, a common somatic CDKN2A/CDKN2B deletion was identified. RNA-sequencing of five tumors identified mutations in GLT8D1, GATAD2A and SLC25A39 in all samples. The germline origin of these mutations was confirmed by Sanger-sequencing. Innovative molecular analysis methods have made possible a better understanding of the complex tumorigenesis of multiple sarcomas

Cell-cell fusion of mesenchymal cells with distinct differentiations triggers genomic and transcriptomic remodelling toward tumour aggressiveness

Cell-cell fusion is a physiological process that is hijacked during oncogenesis and promotes tumour evolution. The main known impact of cell fusion is to promote the formation of metastatic hybrid cells following fusion between mobile leucocytes and proliferating tumour cells. We show here that cell fusion between immortalized myoblasts and transformed fibroblasts, through genomic instability and expression of a specific transcriptomic profile, leads to emergence of hybrid cells acquiring dissemination properties. This is associated with acquisition of clonogenic ability by fused cells. In addition, by inheriting parental properties, hybrid tumours were found to mimic the histological characteristics of a specific histotype of sarcomas: undifferentiated pleomorphic sarcomas with incomplete muscular differentiation. This finding suggests that cell fusion, as macroevolution event, favours specific sarcoma development according to the differentiation lineage of parent cells

Fertility sparing technique during pelvic exenteration for recurrent vaginal rhabdomyosarcoma

We present the first case and describe the surgical technique of anterior pelvic exenteration with uterine preservation in a 17-year-old patient with a recurrent vaginal rhabdomyosarcoma.Surgical technique included a skeletonization of uterine pedicles and ligation of superior vesical and vaginal arteries, adapting abdominal radical trachelectomy technique. Cervix was transected to avoid vaginal opening and tumor spillage. Uterus was reimplanted to a vaginal reconstruction, created with a DIEP, and a continent urinary diversion was performed. Pelvic filling was completed with an omental J-flap.Postoperative course was uneventful and the patient was discharged at day 17th. The last days of her stay were dedicated to self-catheterization education and learning the management of Miami pouch. Her menstrual cycle resumed two months after the surgery. Cervix exhibited a normal appearance during clinical examination eight weeks after surgery and postoperative MRI did not show signs of local recurrence. Unfortunately, distant metastatic relapse occurred three months after surgery and the patient died two months later.Fertility preservation at the time of anterior pelvic exenteration is technically feasible in selected young patients. Further cases are needed to assess the reproducibility of this surgical procedure, the reproductive function of the uterus and the rate of uterine recurrences. Keywords: Uterine conservation, Conservative surgery, Genital tract rhabdomyosarcom

Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum

International audienceBiphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor

Recurrent \textitTRIO Fusion in Nontranslocation\textendashRelated Sarcomas

International audienc