Epidemiology, characteristics, treatments, and outcomes of adult-onset Still's disease in Afro-Caribbeans: Results from a population-based study in Martinique, French West Indies.

OBJECTIVES: To describe the epidemiology, characteristics, response to initial treatment, and outcomes of Adult-Onset Still's disease (AOSD) in the Afro-Caribbean population of Martinique with free and easy access to specialised care. METHODS: We conducted a retrospective study from 2004 to 2022 in the island of Martinique, French West-Indies which total population was 354 800 in 2021. Patients were identified from multiple sources including standardised databases. To be included, patients had to be residents of the island and fulfilled Yamaguchi and/or Fautrel's criteria for AOSD, or have a compatible disease course, without a diagnosis of cancer, auto-immune disease or another auto-inflammatory disorder. Date of diagnosis, clinical and biological characteristics, treatments, and outcomes were collected. RESULTS: The prevalence was 7.6/100 000 inhabitants in 2021. The mean incidence was 0.4/100 000 during study period. Thirty-three patients (70.6% females) with a median follow-up of 35 months [7.5 to 119] were included. Twenty-six patients (78.8%) had a systemic pattern. Patients with a systemic monocyclic pattern had significantly more polyarticular involvement than patients with systemic polycyclic pattern (p = 0.016). Pulmonary involvement occurred in 51.5% of patients at diagnosis and systemic Pouchot score has been identified as an independent predictive factor for pulmonary involvement; OR of 3.29 [CI 95% 1.20; 9.01]. At first flare, all patients but one received oral glucocorticoids, 11 patients (32.4%) received intravenous glucocorticoids pulse and 12 patients (33%) received anti-IL1 therapy. Nineteen patients (57%) relapsed in a median time of 9 months [6 to 12] Three patients (9%) developed hemophagocytosis lymphohistiocytosis, fatal in 1 case. All deceased patients (n = 4, 11.76%) belonged to the systemic polycyclic pattern, with an event-free survival of 13.6 months [IQR 5.7; 29.5] CONCLUSION: AOSD in the Afro-Caribbean population of Martinique shares some similarities with other ethnic groups, but exhibit differences, such as a high proportion of lung involvement. Comparative studies are needed to confirm these results.

PAX3-NCOA1 alveolar rhabdomyosarcoma of the tongue: A rare entity with challenging diagnosis and management.

Alveolar rhabdomyosarcoma (ARMS) is associated with PAX3/PAX7-FOXO1 fusion, which confers specific clinic and biologic characteristics with inferior outcomes. A minority of tumors still histologically classified as "true" ARMS lack the canonical PAX-FOXO1 fusion but have new molecular alterations. We present the first case of PAX3-NCOA1 ARMS with clinical data and follow-up in a two-year-old girl with ARMS of the tongue and nodal extension, treated with chemotherapy, hemi glossectomy, lymph node dissection, and brachytherapy to conserve oral function and limit long-term sequelae. Given the rarity of such variant fusion in ARMS, international collaboration is required to evaluate its prognostic value.

Acute Myeloid Leukemia With Central Nervous System Involvement in Children: Experience From the French Protocol Analysis ELAM02.

Central nervous system (CNS) involvement at diagnosis of pediatric acute myeloid leukemia (AML) is not considered as an independent prognostic factor. This study describes the prognostic value of pediatric AML with CNS involvement at diagnosis. Pediatric patients were treated for de novo AML in the French multicenter trial ELAM02. Lumbar puncture was carried out in the first week, and the treatment was adapted to the CNS status. No patient received CNS radiotherapy. The patients were classified into 2 groups: CNS+ and CNS-. Of the 438 patients, 16% (n=70) had CNS involvement at diagnosis, and 29% showed clinical signs. The patients with CNS disease were younger (40% were below 2 y old), had a higher white blood cell count (median of 45 vs. 13 G/L), and had M4 and M5 morphologies. The complete remission rate was similar at 92.8% for CNS+ and 88.5% for CNS-. There was no significant difference between the CNS+ and the CNS- group in overall survival (76% and 71%, respectively) and event-free survival (57% and 52%, respectively). Regarding the occurrence of first relapse, the CNS+ group had a higher combined relapse rate of 26.1% compared with 10% for the CNS- group. The results indicate that CNS involvement at diagnosis of pediatric AML is not an independent prognostic factor. Triple intrathecal chemotherapy combined with high-dose intravenous cytarabine should be the first-line treatment for CNS disease.

Common Seasonal Pathogens and Epidemiology of Henoch-Schönlein Purpura Among Children.

Importance: Henoch-Schönlein purpura (HSP) is the most common type of vasculitis in children. The factors that trigger the disease are poorly understood. Although several viruses and seasonal bacterial infections have been associated with HSP, differentiating the specific associations of these pathogens with the onset of HSP remains a challenge due to their overlapping seasonal patterns. Objective: To analyze the role of seasonal pathogens in the epidemiology of HSP. Design, Setting, and Participants: This cohort study comprised an interrupted time-series analysis of patient records from a comprehensive national hospital-based surveillance system. Children younger than 18 years hospitalized for HSP in France between January 1, 2015, and March 31, 2023, were included. Exposure: Implementation and relaxation of nonpharmaceutical interventions (NPIs) for the COVID-19 pandemic, such as social distancing and mask wearing. Main Outcomes and Measures: The main outcomes were the monthly incidence of HSP per 100 000 children, analyzed via a quasi-Poisson regression model, and the estimated percentage of HSP incidence potentially associated with 14 selected common seasonal pathogens over the same period. Results: The study included 9790 children with HSP (median age, 5 years [IQR, 4-8 years]; 5538 boys [56.4%]) and 757 110 children with the infectious diseases included in the study (median age, 0.7 years [IQR, 0.2-2 years]; 393 697 boys [52.0%]). The incidence of HSP decreased significantly after implementation of NPIs in March 2020 (-53.6%; 95% CI, -66.6% to -40.6%; P < .001) and increased significantly after the relaxation of NPIs in April 2021 (37.2%; 95% CI, 28.0%-46.3%; P < .001). The percentage of HSP incidence potentially associated with Streptococcus pneumoniae was 37.3% (95% CI, 22.3%-52.3%; P < .001), the percentage of cases associated with Streptococcus pyogenes was 25.6% (95% CI, 16.7%-34.4%; P < .001), and the percentage of cases associated with human rhino enterovirus was 17.1% (95% CI, 3.8%-30.4%; P = .01). Three sensitivity analyses found similar results. Conclusions and Relevance: This study found that significant changes in the incidence of HSP simultaneously with major shifts in circulating pathogens after NPIs for the COVID-19 pandemic indicated that approximately 60% of HSP incidence was potentially associated with pneumococcus and group A streptococcus. This finding suggests that preventive measures against these pathogens could reduce the incidence of pediatric HSP.

Longitudinal follow-up of mixed connective tissue disease and overlapping autoimmune diseases of childhood onset in the Afro-descendant population of the French West Indies.

INTRODUCTION: Overlap autoimmune syndromes (OAS) and mixed connective tissue disease (MCTD) are rare in children. We performed a retrospective, longitudinal and descriptive study of Afro-Caribbean patients from the French West Indies followed for MCTD and OAS to describe their characteristics and outcomes during childhood. METHODS: Retrospective study from January 2000 to 2023. Listings of patients were obtained from multiple sources: computerized hospital archives and national hospital-based surveillance system, registry of pediatricians and adult specialists in internal medicine and the national registry for rare diseases. MCTD was defined according to Kasukawa's criteria. OAS was defined as overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis/autoimmune myositis (DM/AM). RESULTS: Sixteen patients were included over a 23-year period (10 MCTD and 6 OAS). The incidence was 0.23 per 100,000 children-years. The mean age at diagnosis was 11.9 years old (2.4-17) with median follow up of 7.9 years (2.1-19.6). SLE phenotype was present in the highest, followed by SSc and DM/AM. Patients had an average of three flares during childhood (1-7). A quarter (25%) had symptomatic pulmonary arterial hypertension (PAH). Ninety-four percent received steroids during follow-up and 88% required a corticosteroid-sparing therapy. Three patients (19%) developed SLE after more than 10y of follow-up. There were no death and no chronic organ failure. CONCLUSION: This is the largest pediatric cohort of MCTD and OAS in Afro-descendant patients treated in a country with a high standard of care. The clinical evolution did not differ between MCTD and OAS. The main complication was PAH, more frequent in our cohort.

Description and outcomes of Afro-Caribbean children treated for multisystem inflammatory syndrome in the French West Indies.

Introduction: Several studies have reported a higher frequency and greater morbidity and mortality of multisystem inflammatory syndrome in children (MIS-C) of black African descent. Objectives: We aimed to describe the clinical, laboratory and echocardiographic characteristics as well as outcomes of children with MIS-C requiring admission to a pediatric intensive care unit (PICU) in the French West Indies (FWI), where the majority of the population is Afro-Caribbean. Methods: Ambidirectional observational cohort study between April 1, 2020 and August 31, 2022. Children (age ≤18 years) with MIS-C and organ failure were included. Every patient was monitored and treated following the same protocol, with repeated biological tests, echocardiography, intravenous steroids and polyvalent immunoglobulins. The primary outcomes were clinical, laboratory and echocardiography characteristics. Results: Forty children (median age 7 years, range: 5-11) were included. The majority (77 %) were included prospectively. Thirty-five (87 %) had gastrointestinal symptoms, 30 (75 %) presented initial heart failure (with persisting diastolic dysfunction at day 7) and 18 (45 %) had pericarditis. Sixteen (40 %) were in cardiogenic shock and required inotropic support. Median duration of inotropic support and hospitalization in PICU were respectively 4 and 5 days. The evolution curves of the inflammatory variables matched after treatment. The clinical outcomes were favorable. The Delta variant was associated with the highest incidence of MIS-C. Conclusion: This is the first description of MIS-C course among children of Afro-Caribbean descent. The outcomes were good, without any death or cardiac sequelae. Our work does not support an ethnic susceptibility for severity of MIS-C in Afro-Caribbean population.

Juvenile Dermatomyositis in Afro-Caribbean children: a cohort study in the French West Indies.

INTRODUCTION: The epidemiology of Juvenile Dermatomyositis (JDM) in non-Caucasian population is poorly described. We performed a study of patients followed up in the French West Indies for JDM. We aimed to describe clinical and biological specificities during childhood. METHODS: Retrospective study covering the period from Januarys 2000-2023. Listings of patients were obtained from multiple sources, namely computerized hospital archives, registry of referent pediatricians and adult specialists in internal medicine and the French National Registry for rare diseases. JDM and organ involvement were defined according to the international ILAR criteria. RESULTS: Twenty-one patients were included over a 23 year-period. Median age at onset was 8.1 years (Range: 2.5-13.9) with a median follow up of 8 years (Range: 2-19). Two-thirds (14/21) had dysphagia at onset and 33% had respiratory involvement. Thirteen had specific autoantibodies (58%), most frequently anti-Mi-2. The median number of flares during childhood was three (1-9). During childhood, 76% had calcinosis lesions. Clinical evolution seemed to be more aggressive for boys than girls (respectively 4.2 versus 2.2 flares (p = 0.04) and 50% vs 18% needing more than one background therapy, p = 0.03). CONCLUSION: This retrospective study is the largest cohort of pediatric patients of Afro-Caribbean and Black African descent treated for JDM in a high-income health system, and the first to describe the incidence and immunological profile in a population of African descent. They had higher rate of calcinosis and similar respiratory involvement. Overall outcomes during childhood were similar to North America and European countries.

Asserting a Functional Neurological Symptom Disorder with a Complementary Diagnostic Approach: A Brief Report.

INTRODUCTION: Functional neurological symptom disorder (FNSD) is a common diagnosis among adolescents. However, we feel it is a difficult diagnosis to assess because of the diversity of its clinical manifestations, the rapid changes in its nosography over the years, and its common imbrication with established somatic diagnoses. We would like to illustrate this hypothesis through a case presentation and the original diagnostic process that emerged from it. METHODS: We chose to present our diagnosis approach through the case of an 11-year-old boy who showed a progressive loss of motor and sensory function to the point of total dependency, and then suddenly switched between this state and a "normal" physical presentation, while deliriously claiming to be an angel. RESULTS: All possible infectious, autoimmune, metabolic, and toxic disorders were ruled out. After the successive therapeutic failures of antidepressants and neuroleptics, FNSD was diagnosed. CONCLUSION: The DSM-5-TR classification was insufficient to explain the full clinical picture and a complementary approach (biblical, psychoanalytical, and historical) was used to analyze the cause of this atypical presentation.

Calculating the fraction of Kawasaki disease potentially attributable to seasonal pathogens: a time series analysis.

Background: Kawasaki disease is an acute, febrile, systemic vasculitis of children that primarily affects medium-sized blood vessels with a tropism for the coronary arteries. Although the etiological factors remain unknown, infections have been suggested as the trigger of Kawasaki disease. We sought to calculate the fraction of Kawasaki disease potentially attributable to seasonal infections. Methods: This cohort study used a population-based time series analysis from the French hospitalisation database (Programme de Médicalisation des Systèmes d'Information), which includes all inpatients admitted to any public or private hospital in France. We included all children aged 0-17 years hospitalised for Kawasaki disease in France over 13 years. The monthly incidence of Kawasaki disease per 10,000 children over time was analysed by a quasi-Poisson regression model. The model accounted for seasonality by using harmonic terms (a pair of sines and cosines with 12-month periods). The circulation of eight common seasonal pathogens (adenovirus, influenza, metapneumovirus, Mycoplasma pneumoniae, norovirus, rhinovirus, rotavirus, respiratory syncytial virus, and Streptococcus pneumonia) over the same period was included in the model to analyse the fraction of Kawasaki disease potentially attributable to each pathogen. Infections were identified on the basis of polymerase chain reaction or rapid antigen testing in hospital laboratories. Findings: Between Jan 1, 2007, and Dec 31, 2019, we included 10,337 children with Kawasaki disease and 442,762 children with the selected infectious diseases. In the Kawasaki disease cohort, the median age [IQR] was 2 [0-4] years, 6164 [59.6%] were boys. Adenovirus infection was potentially responsible for 24.4% [21.5-27.8] (p < 0.001) of Kawasaki diseases, Norovirus for 6.7% [1.3-11.2] (p = 0.002), and RSV 4.6% [1.2-7.8] (p = 0.022). Sensitivity analyses found similar results. Interpretation: This cohort study of data from a comprehensive national hospitalisation database indicated that approximately 35% of Kawasaki diseases was potentially attributable to seasonal infections. Funding: None.

Systemic lupus of pediatric onset in Afro-Caribbean children: a cohort study in the French West Indies and French Guiana.

BACKGROUND: Systemic diseases of pediatric onset are more frequent in the Afro-Caribbean population. We performed a study of patients followed in the French overseas departments of America (FOAD) for pediatric systemic lupus erythematosus (pSLE). The aims were to describe the clinical and biological specificities during childhood in this population. METHODS: A retrospective study was conducted between January 2000 and September 2021. Patients with pSLE were identified from multiple sources: computerized hospital archives, registry of referring pediatricians, adult specialists in internal medicine and the French National Registry for rare diseases. We studied SLE with pediatric onset defined by international criteria. RESULTS: Overall, 2148 patients were identified, of whom 54 were included. The average follow-up was 8.3 years (range: 0.3-25 years). We observed an increase in new diagnoses over time. At onset, pSLE patients had a median of 10 SLICC criteria (range: 4-12), and the median EULAR/ACR 2019 score was 38 (12-54). At onset, one third of patients had renal involvement, 15% had neurolupus and 41% cardiac involvement. During childhood, 54% had renal involvement, and 26% suffered from neurolupus. Patients suffered a median of 3 flares during childhood, and 26% had more than 5 flares. Patients with younger age at onset had worse outcomes than those who were older at diagnosis, i.e., more flares (median 5, p = 0.02) and requiring an average of 4 background therapies (p = 0.04). CONCLUSION: The outcomes of Afro-Caribbean patients were similar to those in Western population, but with worse disease activity at onset. Further studies should be performed to identify the genetic and environmental factors in this population.

Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.

BACKGROUND: Optimal Phase-II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined. OBJECTIVES: Recurrent/refractory ES phase-I/II trials analysis to improve trials design. METHODS: Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e-cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase-I or Phase-II). RESULTS: The 146 trials identified (77 phase-I/II, 67 phase-II, and 2 phase-II/III) tested targeted (34%), chemo- (23%), immune therapies (19%), or combined therapies (24%). Twenty-three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single-arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression-free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%-25% and 20%-50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3-14.7) and 7.6 months (5-30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%-30%), 4.5 (1.3-10), and 16.6 months (6.9-30), respectively. CONCLUSION: This review supports the need to develop the international randomized phase-II trials across all age ranges with PFS as primary endpoint.

Impact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology.

Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.

Cerebral injuries associated with Zika virus in utero exposure in children without birth defects in French Guiana: Case report.

RATIONALE: A major epidemic of Zika virus (ZIKV) infection occurred in French Guiana and West Indies. French national epidemiological surveillance estimated that 1650 pregnant women contracted the ZIKV during epidemic period from January 2016 to October 2016 in French Guiana. PATIENT CONCERNS: ZIKV infection during pregnancy is a cause of microcephaly and birth defects. DIAGNOSES: In this report, we describe 2 children with proven in utero ZIKV exposure. Their mothers were both symptomatic and ZIKV infection occurred early in pregnancy. Ultrasonography monitoring in utero did not show any abnormality for both patient. They were born at full-term, healthy, without any birth defects and no sign of congenital ZIKV infection. INTERVENTIONS: ZIKV was neither found on placenta fragments nor children blood and urine at birth. Their neurodevelopment outcomes in early-life fitted the expectations. As recommended in national guidelines, we performed cerebral MRIs at 2 months old, showing severe brain abnormalities, especially of white matter areas. After a large screening, we did not find any differential diagnosis for their brain lesions. OUTCOMES: We concluded it was due to their in utero ZIKV exposure. LESSONS: In this report, pathogenicity of ZIKV may involve mother's immunological response or metabolic disorder during the infection.

Conformational studies of peptides: Crystal and molecular structures of L-3,4-dehydroproline and its t-butoxycarbonyl and acetyl amide derivatives.

The crystal structures of L-3,4-dehydroproline, t-butoxycarbonyl-L-3,4-dehydroproline amide, and acetyl-L-3,4-dehydroproline amide have been determined. L-3,4-Dehydroproline is orthorhombic with a = 16.756, b = 5.870, c = 5.275 Å, and Z = 4; t-butoxycarbonyl-L-3,4-dehydroproline amide is orthorhombic with a = 6.448, b = 8.602, c = 21.710 Å, and Z = 4; acetyl-L-3,4-dehydroproline amide is monoclinic with a = 4.788, b = 10.880, c = 7.785 Å, ß = 105.25°, and Z = 2. The final R value for the L-3,4-dehydroproline is 0.046 based on 529 reflections; for t-butoxycarbonyl-L-3,4-dehydroproline amide, 0.050 based on 792 reflections; and for acetyl-L-3,4-dehydroproline amide, 0.058 based on 632 reflections. The structures clearly establish that the free amino acid exists in the zwitterionic form in the crystalline state. The molecular conformations of the t-Boc and acetyl derivatives consist of two planes: one involving the primary amide and the other the remaining atoms of the molecule. The acetyl-L-3,4-dehydroproline amide contains a tertiary amide bond in the cis conformation. To the best of our knowledge, this is the first example of a cis bond in an acetyl derivative of an amino acid or peptide. At variance with the previously reported proline amides, which present ϕ and ψ values corresponding to those of a right-handed α-helical conformation (conformation A), the t-Boc and acetyl derivatives both have ϕ and ψ values corresponding to a collagenlike conformation (conformation F).

PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine.

The cDNA for PRMT7, a recently discovered human protein-arginine methyltransferase (PRMT), was cloned and expressed in Escherichia coli and mammalian cells. Immunopurified PRMT7 actively methylated histones, myelin basic protein, a fragment of human fibrillarin (GAR) and spliceosomal protein SmB. Amino acid analysis showed that the modifications produced were predominantly monomethylarginine and symmetric dimethylarginine (SDMA). Examination of PRMT7 expressed in E. coli demonstrated that peptides corresponding to sequences contained in histone H4, myelin basic protein, and SmD3 were methylated. Furthermore, analysis of the methylated proteins showed that symmetric dimethylarginine and relatively small amounts of monomethylarginine and asymmetric dimethylarginine were produced. SDMA was also formed when a GRG tripeptide was methylated by PRMT7, indicating that a GRG motif is by itself sufficient for symmetric dimethylation to occur. Symmetric dimethylation is reduced dramatically compared with monomethylation as the concentration of the substrate is increased. The data demonstrate that PRMT7 (like PRMT5) is a Type II methyltransferase capable of producing SDMA modifications in proteins.