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Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

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Objective To describe the clinical characteristics and outcome of patients with Li‐Fraumeni–associated rhabdomyosarcoma (RMS). Method Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li‐Fraumeni database. Central histologic review was performed in 16 cases. Results The median age at diagnosis was 2.3 years, and the median follow‐up was 9.1 years (0.3‐34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle‐cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty‐five patients had localized disease, three had lymph node involvement, and three distant metastases. First‐line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10‐year event‐free, progression‐free, and overall survival rates were 36% (95% CI: 20‐56), 62% (95% CI: 43‐77) and 76% (95% CI: 56‐88), respectively. The 10‐year cumulative risk of second malignancies was 40% (95% CI: 22‐60). Conclusion The high incidence of multiple primary tumors strongly influences the long‐term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.

Background and objective:PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.Methods:PRRT2 was analyzed in 860 probands with hemiplegic migraine and PRRT2 mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.Results:PRRT2 mutations were found in 12 of 163 probands previously tested negative for CACNA1A, ATP1A2 and SCN1A mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%) and SCN1A (15%). The PRRT2 mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole PRRT2 gene.Among the 49 PRRT2 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.Conclusion:PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function PRRT2 mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.

Background: Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear. Patients and methods:The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed.Results: From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively. Conclusion:Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites. K E Y W O R D Sclinical trials, liver metastasis, pediatric oncology, renal tumor, solid tumors, tumors, Wilms tumor

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Introduction In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. Methods Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. Results Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3–9 months following the test. Conclusions This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.