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Background The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX – a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. Methods FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1–2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150–180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. Discussion FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. Trial registration EudraCT: 2018-003541-42; ClinicalTrials.gov: NCT03828799.

International audience; OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

The pharmacokinetics of gamithromycin were evaluated in 26 male castrated and female crossbred swine administered gamithromycin 15% w/v (Zactran®, Boehringer Ingelheim) intravenously at 6 mg/kg bodyweight or intramuscularly at 3, 6 or 12 mg/kg bodyweight. Blood samples were collected up to Day 10 to establish the plasma profile of gamithromycin, bioavailability and dose proportionality. When administered by intramuscular injection at 6 mg/kg BWT, pharmacokinetic parameters were as follows: area under the curve until last quantifiable plasma concentration, 5.13 ± 0.957 µg*hours/ml; maximum plasma concentration, 960 ± 153 ng/ml at 5 to 15 min; terminal half‐life of 94.1 ± 20.4 hr. Absolute bioavailability was 92.2%. Increase in systemic exposure was proportional to the gamithromycin dose level over the range 3–12 mg/kg BWT. No gender‐related statistically significant difference in exposure was observed. For clinical evaluation of Zactran® against swine respiratory disease, 305 pigs from six commercial farms in three countries in Europe with signs associated with Actinobacillus pleuropneumoniae and/or Haemophilus parasuis and/or Pasteurella multocida and/or Bordetella bronchiseptica were used. At each site, animals were treated once in a 1:1 ratio with a single intramuscular dose of Zactran® (6 mg gamithromycin/kg bodyweight) or Zuprevo® (4% w/v tildipirosin at 4 mg/kg bodyweight; MSD Animal Health) at the recommended dose respectively. Animals were observed and scored daily for 10 consecutive days for signs of swine respiratory disease (depression, respiration and rectal temperature), and animals presenting signs of clinical swine respiratory disease (Depression Score 3 and/or Respiratory Score 3 associated with Rectal Temperature > 40.0°C) were removed from the study and considered as treatment failure. Animals which remained in the study were individually assessed for ʽtreatment successʼ or ʽtreatment failureʼ (Depression Score ≥ 1 and Rectal Temperature > 40.0°C or Respiratory Score ≥ 1 and Rectal Temperature > 40.0°C). Using a non‐inferiority hypothesis test (non‐inferiority margin = 0.10), the proportion of treatment successes in the Zactran® group (97%) was equivalent to or better than that in the Zuprevo® group (93%)., Intramuscular injection of gamithromycin 15% w/v in swine at 6 mg/kg is characterized by rapid absorption and distribution to tissues. Clinical evaluation in an European field study incorporating 305 swine has shown safe and efficacious treatment for swine with bacterial respiratory disease.

A paradoxical reaction is the worsening of prior existing, or the appearance of, new tuberculous lesions, following the initiation of treatment with anti-tuberculous drugs, after the exclusion of poor compliance, malabsorption, drug interaction or multiresistant mycobacteria. Well known and well managed in the context of HIV coinfection, it is not well known outside this context. An increasing number of publications have described this syndrome. This review aims to describe the pathogenic, epidemiological, clinical, prognostic and therapeutic elements of non-HIV-associated paradoxical reactions. It involves a reversal of the Mycobacterium tuberculosis-induced immunodepression along with a heightened detrimental pro-inflammatory profile caused by efficient drug treatment. Extra-thoracic locations, especially lymph nodes and neurological, malnutrition and initial lymphopenia are the principal risk factors. The median delay is 40±20 days after the onset of treatment. Corticosteroids are the mainstay of the management. Anti-TNF-α drugs show good results in corticosteroid refractory cases. The prognosis is good overall except in neurological forms. The place of preventive methods remains to be established.

Background: Bone-only (BO) metastatic breast cancer (MBC), defined as bone as unique site of metastasis at MBC diagnosis, is thought to carry a better prognosis among MBC. However, only small retrospective series and data from selected randomized controlled trials have been reported so far. Based on a national database, we aimed at providing a large comprehensive analysis of BO MBC, and at evaluating its impact on clinical outcome. Methods: The ESME MBC platform (NCT03275311) is a French multicenter retrospective real-life database using a clinical trial-like methodology to collect data from 18 French Comprehensive Cancer Centers. It includes data from each newly diagnosed MBC patient having initiated at least one treatment between 2008 and 2016. BO cases occurring in women were retrieved and compared to the overall non-BO population, regarding treatment effects and survival. Results: Of the 22,463 women selected in the database, 5,041 (22.4%) patients with BO disease were identified. Most (N=4,102, 81.4%) had HR+/HER2- disease while 644 (12.8%) and 295 (5.9%) patients had HER2+ or HR-/HER2- disease, respectively. Compared to non-BO MBC, BO MBC patients were older in the global cohort and in HR-/HER2- patients (mean age 61.0y versus 59.5y, and 59.3y vs 56.4y, all p Conclusion: This large comprehensive study is the largest cohort of BO MBC to date. BO MBC has a distinct presentation from non-BO MBC and carry a better prognosis compared to non-BO MBC. A significant proportion of BO MBC patients have a very long survival and may benefit from aggressive local therapy, as stereotactic radiotherapy. Dedicated studies are warranted to tailor the management of these patients. Funding: This work was supported by UNICANCER. The ESME MBC database is supported by an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analyses and publications are totally managed by R&D UNICANCER independently of the industrial consortium. TableBOBOBOBOnon-BOnon-BOnon-BOnon-BON (%)median OS monthsmedian PFS1 months5-year OS rate %N (%)median OS monthsmedian PFS1 months5-year OS rate %(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)Overall population5,041 (100%)52.1 (50.3-54.1) 13.1 (12.6-13.8) 43.41 (41.66-45.15)15,054 (100%)34.7 (34.0-35.6) 8.5 (8.3-8.7) 30.55 (29.62-31.48)HR+/HER-4,102 (81.4%)52.6 (50.5-54.8)13.6 (13.0-14.3)43.52 (41.56-45.46)9,127 (60.6%) 39.0 (37.8-40.1)9.6 (9.3-9.9)32.69 (31.47-33.93)HER2+644 (12.8%)66.4 (59.8-71.9) 14.9 (12.9-17.3) 54.49 (49.54-59.16)3,265 (21.7%) 46.5 (44.2-48.9)10.6 (10.1-11.3)39.88 (37.77-41.98)HR-/HER2-295 (5.9%)20.8 (18.3-27.4) 5.6 (4.9-7.5)16.21 (11.21-22.02)2,662 (17.7%) 14.3 (13.6-15.1)4.8 (4.6-5.0)10.89 (9.4-12.5)De novo MBC patients1,909 (37.9%)58.6 (55.4-62.1)17.9 (17.0-18.9)48.24 (45.28-51.14)4,399 (29.2%) ---Relapsed MBC patients3,132 (62.1%)48.3 (46.5-50.5)10.7 (10.2-11.2)40.51 (38.34-42.67)10,655 (70.8%)--- Citation Format: Marion Bertho, Julien Fraisse, Anne Patsouris, Paul Cottu, Suzette Delaloge, David Pérol, Anne Jaffré, Anthony Goncalves, Marie-Paule Lebitasy, Véronique D'Hondt, Florence Dalenc, Jean-Marc Ferrero, Christelle Levy, Patrick Arveux, Roman Rouzier, Frédérique Penault-Llorca, Lionel Uwer, Jean-Christophe Eymard, Mathias Breton, Michaël Chevrot, Marianne Leheurteur, Michel Velten, Gaëtane Simon, Jean-Sébastien Frenel. Impact of bone-only metastatic breast cancer on outcome in a real-life setting: A comprehensive analysis of 5,041 women from the ESME database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-19-01.

Simple Summary CYCLON is a nuclear protein, which has been associated with disease progression and treatment resistance in DLBCL, the most common form of aggressive B-cell lymphoma, but also represents a predictive factor of refractory disease and relapse for immuno-chemotherapy-treated DLBCL patients. The molecular mechanisms related to this unstructured protein remain largely uncharacterized. Here, we performed a mass-spectrometry-based identification of the CYCLON protein interactome that suggested it could exert nucleolar functions related to cell proliferation. Among the CYCLON oncogenic network, we performed an immunohistochemical evaluation of the multi-functional nucleolar protein NPM1 in a DLBCL cohort and showed that CYCLON/NPM1 concomitant expression delineates a poor prognosis subgroup of patients. Multivariate survival analyses demonstrated that specific sub-cellular localizations of CYCLON and NPM1 represent independent novel predictors specifically associated with refractory DLBCL. Abstract R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.

The main indication for closing a secundum atrial septal defect (ASD) is a significant left-to-right shunt, with acceptable pulmonary vascular resistances.1 2 Transcatheter closure has become an accepted alternative to surgical repair for most types of ostium secundum ASD. The technique is commonly referred to for patients with a defect under 38 mm in diameter without deficient rims and allows safe and effective ASD closure in most unselected cases. The main limit for percutaneous closure is the size of the defect as well as the existence of appropriate rims.1–3 In many patients referred for transcatheter closure, the question is often ‘How large is too large?’3 In Dolgner et al ’s4 study, the above-mentioned statements are challenged after they report 10% of stroke in a selected study population of 346 patients with a secundum ASD and no known atrial arrhythmias. The authors provide a risk stratification based on the three following independent risk factors for this population: a body mass index >25, smoking and a prominent Eustachian valve. They conclude that ASD closure could be considered in this patient population, even without a significant left-to-right shunt.4 This study is remarkable because this is the …

We examined factors that may impact cabazitaxel treatment duration in a real-life setting in a compassionate use program, expanded access program, and prospective observational study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC previously treated with docetaxel (N = 1,621) received cabazitaxel 25 mg/m2 intravenously every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. The median number of cabazitaxel cycles was six (range, 1&ndash, 49), 708 patients (43.7%) received &gt, 6 cycles. Patients receiving &gt, 6 cycles tended to have a better Eastern Cooperative Oncology Group performance status of 0&ndash, 1 (p = 0.0017 for &le, 6 vs. &gt, 6 cycles). Overall, 348 patients (21.5%) were &ge, 75 years of age, 139 (39.9%) received &gt, 6 cycles. The main reason for discontinuation was disease progression, however, in patients receiving 1&ndash, 2 cycles, the main reason for discontinuation was adverse events. Only 52 patients (3.2%) progressed during cycles 1&ndash, 2. Cabazitaxel was well tolerated in these studies, which included some elderly and frail patients, offering clinicians an important treatment option in the management of mCRPC. Proactive management of adverse events may allow patients to receive a higher number of cabazitaxel cycles and derive greater benefit.

Many interventionists are infatuated by the recent resurgence of the coilwire design with the Super Arrow-Flex® sheath (Teleflex, Inc., NC, United States of America). This exclusive sheath is a highly flexible, durable, conduit intended for use in diagnostic and interventional procedures with several advantages and maximum effectiveness in challenging cases. We report failure to easily advance memory shape occluders through Super Arrow-Flex® sheaths larger than the recommended implant French size. We detail the technical reasons behind this non-previously reported drawback and describe benchside tests as possible solutions.

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

Background New diagnostic tools have been developed to improve the diagnosis of infectious encephalitis. Using a prospective cohort of encephalitis patients, our objective was to identify possible clusters of patients with similar patterns among encephalitis of unknown cause (EUC) and to describe to what extent a patient’s initial presentation may be predictive of encephalitis etiology, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). Methods The National Cohort of Infectious Encephalitis in France is an ongoing prospective cohort study implemented in France in 2016. Patients who present with documented or suspected acute infectious encephalitis were included. Focusing on the variables that describe the initial presentation, we performed a factor analysis of mixed data (FAMD) to investigate a pattern of association between the initial presentation of a patient and the etiologic pathogen. Results As of 1 August 2018, data from 349 patients were analyzed. The most frequent pathogens were HSV (25%), VZV (11%), tick-borne encephalitis virus (6%), Listeria (5%), influenza virus (3%), and EUC (34%). Using the FAMD, it was not possible to identify a specific pattern related to the group of EUC. Age, temporal or hemorrhagic lesions, and cerebral spinal fluid lymphocytosis were significantly associated with HSV/VZV encephalitis. Conclusions No initial clinical/imaging/biology pattern was identified at admission among EUC, despite the improvement in diagnostic tools. In this context, the recommendation for a universal, early, probabilistic, initial treatment against HSV and VZV is still relevant, regardless of the initial clinical presentation of the encephalitis.

International audience; IntroductionHIV is an exclusion criterion for most lung cancer (LC) trials, however LC is the most common non-AIDS-defined malignancy in people living with HIV (PLHIV), poorer prognosis than the general population. Circulating tumor DNA (ctDNA) was a prognostic marker in LC patients from the general population. This study assessed ctDNA’s prognostic value in PLHIV from a dedicated phase II trial.MethodsOverall, 61 PLHIV with advanced non-squamous non-small-cell lung cancer (NSCLC) participated in the IFCT Phase II trial evaluating first-line four-cycle carboplatin (Ca) AUC5 pemetrexed (P) 500 mg/m2 induction therapy every 3 weeks, followed by P maintenance therapy. Blood samples collected before treatment were analyzed to detect ctDNA using ultra-deep targeted next-generation-sequencing (NGS).ResultsAppropriate samples were available from 55 PLVIH and analyzed for ctDNA detection. Including 42 males (76.4 %), 52.9 years median age, 51 smokers (92.7 %), five with non-squamous NSCLC Stage III (9%), 50 Stage IV (91 %), and performance status (PS) 0−2. ctDNA was detected in 35 patients (64 %), 22 with high and 13 with low ctDNA levels. Overall, 77 % were positive for TP53, 29 % for KRAS, and 11 % for STK11 mutations, more than one alteration was detected in 43 % of samples. Multivariate analysis showed that positive ctDNA was significantly associated with shorter PFS (HR, 4.31, 95 %CI: 2.06−8.99, p

Percutaneous closure of secundum atrial septal defect (sASD) in children with interrupted inferior vena cava is challenging, especially in case of deficient aortic rim. Trans-jugular access is generally preferred in this scenario. Patients with situs inversus and sASD also carry technical difficulties for transcatheter closure because of the orientation of the atrial septum. We report a successful case of percutaneous closure of a sASD with deficient aortic rim using an occlutech figulla flex II ASD device through the left internal jugular vein in a child with situs inversus, dextrocardia, and interrupted IVC. This case was facilitated by the absence of left-sided hub of the Occlutech device to provide stable opening of the device into the left atrium, whereas the ball-connection of the delivery system allowed an angle of almost 180 degrees between the device and the atrial septum.

Background Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. Methods The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient’s prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan–Meier method). Results CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2−/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR− (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8–92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5–17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18–3.75, triple-negative and HER2−/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2–8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50–0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65–0.81) for HER2+/HR−, 4.4 months (HR = 1.55, 95% CI: 1.42–1.69) for triple-negative and 7.1 months for HER2−/HR+ patients (p Conclusions Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. Clinical trial registration NCT03275311.

Summary Background & aims Nutrition support is recommended in cachexic patients with cancer. However, there is no clear evidence about its impact on tumour growth. Glycolysis, which is usually higher in cancer than normal cells, can be monitored by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging that is widely used for cancer staging and therapy efficacy assessment. Here, we used 18F-FDG PET/CT imaging to investigate whether artificial nutrition has an impact on tumour glucose metabolism in patients with cancer and cachexia. Methods This prospective study included ten patients with histologically proven head and neck or oesophageal cancer. All patients underwent 18F-FDG PET/CT imaging at baseline and after (parenteral and/or enteral) nutrition support on average for 7 days. Tumour glucose metabolism changes were evaluated using static (SUVmax, SUVmean and SULpeak) and dynamic (glucose metabolic rate and transport constant rates, k) parameters computed from the 18F-FDG PET/CT data. Results Artificial nutrition (median energy intake of 21.83 kcal/kg/day [13.16–45.90], protein intake of 0.84 g/kg/day [0.56–1.64]) was administered. Eight patients (80%) received enteral nutrition and two patients (20%) parenteral support. Comparison of 18F-FDG PET/CT parameters did not highlight any significant difference in tumour glucose metabolism before and after the period of nutrition support. Conclusions In cachexic patients with head and neck or oesophageal cancer, nutrition support administered according to the current guidelines shows no impact on tumour glucose metabolism, assessed by 18F-FDG PET/CT.

The aim was to describe the impact of infective endocarditis (IE) on functional, cognitive and nutritional statuses, and to estimate the influence of these parameters on surgical management and mortality.This was a prospective study over 13 months in 14 French hospitals, including patients ≥75 years of age with definite or possible IE. A comprehensive geriatric assessment (CGA) was performed during the first week of hospitalization, including a retrospective estimation of functional status 2 months before hospitalization, and 3 months after.A total of 120 patients were included (mean age 83.1 ± 5.0 (75-101) years). IE was associated with a dramatic impairment of functional status between 2 months prior hospitalization and the first geriatric evaluation (90.8% able to walk vs. 35.5% (p 0.0001), ADL (Activities in Daily Living) 5.0 ± 1.7 vs. 3.1 ± 2.1 (p 0.0001)). The 19 operated patients (15.8%) had less comorbidities (cumulative illness rating scale geriatric 10.8 ± 8.2 vs. 15.3 ± 7.1 (p 0.0176)), better functional (ADL 5.9 ± 0.4 vs. 4.9 ± 1.8 (p 0.0171) and nutritional (mini nutritional assessment 20.4 ± 5.0 vs. 17.3 ± 6.2 (p 0.0501)) statuses than non-operated patients. Among all infectious, cardiac and geriatric parameters, body mass index (HR 0.9, range 0.8-1, p 0.05) and ADL at the time of the first evaluation (HR 0.7, range 0.6-0.9, p 0.002) were the sole independent predictors of the 3-month (32.5%) and 1-year mortality (42.5%). Three months later, the 57 assessed patients only partially recovered their ADL (3.7 ± 1.9 vs. 5.3 ± 1.4 2 months prior hospitalization and 4.6 ± 1.9 at the first CGA; p 0.0001).Functional and nutritional abilities are crucial components that can be accurately explored through a CGA when managing IE in oldest patients.

BACKGROUND Triplet chemotherapy, with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer (GC). An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results. AIM To determine safety and efficacy of TeFOX perioperative regimen. METHODS This monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized GC. TeFOX consist in docetaxel (50 mg/m²) with oxaliplatin 85 mg/m² and and leucovorin (400 mg/m2) 5 FU bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) every 2 wk. RESULTS Thirty-three consecutive patients were included in this retrospective study. Eighteen patients have a gastroesophageal junction cancer and 11 have a GC. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) had a pathological complete response and 8 (24) patients a nearly complete pathological response. Median OS and PFS were not reached at data base lock. We have observed 6 metastatic relapses and 1 localized relapse. No relapse was observed in patients with pathological complete responses. The most common grade 3-4 adverse events were peripheral neuropathy (21) and asthenia (20). CONCLUSION TeFOX regimen could be safely administrated in perioperative treatment of localized GC. TeFOX and the FLOT regimen have comparable efficacy and safety profiles.

Introduction Soft tissue sarcomas (STS) are rare malignant tumors that require management by an expert center. Monitoring modalities are not consensual. The objective of our study is to report systematic radiological monitoring data obtained by local MRI and by thoracic-abdominal-pelvic computed tomography (TAP CT). Material and methods 113 consecutive patients managed at “Centre Georges Francois Leclerc, Dijon”, between 2008 and 2016, for an initially localized STS were included. Patient follow-up consisted of a local MRI and a TAP CT. Follow-up exams schedule was initially every 4 months during 2 years, followed by every 6 months during 3 years and finally every year during 5 years. Results Median follow-up time was 37.2 months [min = 2.4 – max = 111.6]. After 5 years of surveillance, local recurrence (LR) rate was 8.8% and diagnosed by imaging in 60% of cases. No deep LR was clinically found. Median LR diagnosis time was 23.9 months [min = 2.0 – max = 52.4]. 50% of patients locally treated for their LR were alive without recurrence. Metastatic recurrence (MR) rate was 31%. 42.8% had extra-pulmonary involvement and 17.1% had exclusive extrathoracic metastases. The median time to diagnosis of MR was 17.4 months [min = 2.7- max = 77.2]. High-grade tumors relapsed more (20.4%) and earlier (all before the 5th year) than low grade. Conclusion Local MRI seems particularly suitable for monitoring deep tumors. In addition, the systematic monitoring by TAP CT highlighted a limited number of cases of exclusive extrathoracic metastases. The schedule of local and remote monitoring should primarily be adjusted to tumor grade.

International audience; Eribulin mesylate (EM) was recently approved for metastatic breast cancer (MBC) chemotherapy (CT) in late lines by the FDA, with debated results in second line. We evaluated outcomes in breast cancer patients receiving EM as second, third and fourth line in a national real-life cohort of 16,703 consecutive MBC patients initiating their first metastatic therapeutic line between 2008 and 2014. Primary and secondary objectives were overall survival (OS) and progression-free survival (PFS). An imbalance was seen for HER2+ tumors and concomitant anti-HER2 targeted therapies use, we thus performed a subanalysis in HER2- patients. PFS and OS were significantly better in EM patients in third and fourth lines, compared to "Other chemotherapies" patients (PFS: 4.14 vs. 3.02 months, p = 0.0010; 3.61 vs. 2.53 months, p = 0.0102, third and fourth-line; OS: 11.27 vs. 7.65 months, p = 0.0001; 10.91 vs. 5.95 months, p

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P

Background: Transcatheter closure for atrial septal defect (ASD) with inferior-posterior rim deficiency has been scarcely reported with proper identification of the indications and limits. We aimed to assess the safety and feasibility of transcatheter closure of ASDs with deficient rims, paying particular attention to cases with inferior-posterior rim deficiency. Methods: From January 2008 to January 2013, 241 patients underwent transcatheter ASD closure, including 50 cases (20.7%) with deficient rims, other than the anterior-superior one. Eighteen patients (12 females) presented inferior-posterior rim deficiency. Their median age was 8 (1.4–85) years and their median weight was 24 [9–97] kg. Transcatheter closure was performed in all cases under transesophageal echocardiography (TEE) guidance in children and intracardiac echocardiography (ICE) guidance in adults. Results: Out of 18 patients with inferior-posterior rim deficiency, only 8 underwent successful immediate transcatheter closure. Four cases failed to be closed. Major complications occurred in 6 patients, including 4 device embolizations, 1 pericardial effusion and 1 complete atrioventricular block that resolved after surgical removal of the device. During a median follow up of 54±13 months, a residual right-to-left shunt was documented in 2 more cases, requiring surgery in one case because of cyanosis. Transcatheter closure was successfully performed in the rest of the 223 patients, including in the 32 cases with deficient rims other than inferior-posterior. Conclusions: Transcatheter closure of ASDs with inferior-posterior rim deficiency cannot be recommended.

Summary Background Cardiac catheterization is the gold-standard modality for investigation of cardiovascular morphology before bidirectional cavopulmonary connection, but requires general anaesthesia and is associated with procedural risk. Aims To assess the diagnostic accuracy and safety of computed tomography in diagnosing great vessel stenosis/hypoplasia compared with cardiac catheterization and surgical findings. Methods Twenty-seven patients (10 after Norwood stage I) underwent computed tomography before surgery between January 2010 and June 2016; 16 of these patients also underwent cardiac catheterization. Proximal and distal pulmonary artery, aortic isthmus and descending aorta measurements, radiation dose and complications were compared via Bland-Altman analyses and correlation coefficients. Results The accuracy of computed tomography in detecting stenosis/hypoplasia of either pulmonary artery was 96.1% compared with surgical findings. For absolute vessel measurements and Z-scores, there was high correlation between computed tomography and angiography at catheterization (r = 0.98 for both) and a low mean bias (0.71 mm and 0.48; respectively). The magnitude of intertechnique differences observed for individual patients was low (95% of the values ranged between −0.9 and 2.3 mm and between −0.7 and 1.7, respectively). Four patients (25%) experienced minor complications from cardiac catheterization, whereas there were no complications from computed tomography. Patients tended to receive a higher radiation dose with cardiac catheterization than with computed tomography, even after exclusion of interventional catheterization procedures (median 2.5 mSv [interquartile range 1.3 to 3.4 mSv] versus median 1.3 mSv [interquartile range 0.9 to 2.6 mSv], respectively; P = 0.13). All computed tomography scans were performed without sedation. Conclusions Computed tomography may replace cardiac catheterization in identification of great vessel stenosis/hypoplasia before bidirectional cavopulmonary connection when no intervention before surgery is required. Computed tomography carries lower morbidity, can be performed without sedation and may be associated with less radiation.

Measures of left ventricular (LV) systolic and diastolic function are known predictors of mortality after repair of tetralogy of Fallot. We aimed to characterise LV reverse remodelling achievable with ramipril therapy.A blinded post-hoc analysis of baseline and 6-month follow-up echocardiograms from the APPROPRIATE (ISRCTN: 97515585) randomised double-blinded placebo-controlled trial of ramipril therapy was performed in 64 patients: 32 in ramipril and 32 in placebo group. Tissue Doppler systolic and diastolic myocardial velocities, mitral inflow velocities and time intervals were measured. Left atrial area and left atrial emptying fraction were calculated. There was significant increase in long axis shortening mean (standard deviation); MAPSE [1.9 (4.2) mm vs -0.2 (3.7) mm; p = 0.030], peak lateral systolic velocity; S' lateral [1.0 (2.0) cm/s vs -0.3 (2.2) cm/s; p = 0.025], peak lateral early diastolic velocity; E' lateral [0.57 (2.4) cm/s vs -3.3 (3.9) cm/s; p 0.001], transmitral to lateral mitral annular early diastolic velocity ratio; E/E' lateral [-0.7 (1.9) vs 1.5 (1.9); p 0.001] over the study period in the ramipril compared to the placebo group. Significantly higher measurements were observed in the ramipril arm of the subgroup of patients with right ventricular restrictive physiology in terms of peak late diastolic velocity; A [5.9 (13.5) cm/s vs -5.8 (12.5) cm/s; p = 0.041] and early to late diastolic transmitral velocity ratio; E/A [-0.18 (0.42) vs 0.23 (0.48); p = 0.037].Six months' ramipril treatment appears to limit progression of both diastolic and systolic LV function in adults late after tetralogy of Fallot repair. With increased appreciation that even subtle LV disease predicts tetralogy of Fallot outcomes, further clinical trials of drug therapies are justified.

Objective To assess the effectiveness of corticosteroids among older adults with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen. Methods We used routine care data from 36 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids with at least 0.4 mg/kg/day equivalent prednisone (treatment group) versus standard of care (control group). Participants were adults aged 80 years or older with PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or CT scan images typical of COVID-19 pneumonia, requiring oxygen ≥3 L/min, and with an inflammatory syndrome (C-reactive protein ≥40 mg/L). The primary outcome was overall survival at day 14. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. Results Among the 267 patients included in the analysis, 98 were assigned to the treatment group. Their median age was 86 years (interquartile range 83–90 years) and 95% had a SARS-CoV-2 PCR-confirmed diagnosis. In total, 43/98 (43.9%) patients in the treatment group and 84/166 (50.6%) in the control group died before day 14 (weighted hazard ratio 0.67, 95% CI 0.46–0.99). The treatment and control groups did not differ significantly for the proportion of patients discharged to home/rehabilitation at day 14 (weighted relative risk 1.12, 95% CI 0.68–1.82). Twenty-two (16.7%) patients receiving corticosteroids developed adverse events, but only 11 (6.4%) from the control group. Conclusions Corticosteroids were associated with a significant increase in the overall survival at day 14 of patients aged 80 years and older hospitalized for severe COVID-19.

Kawasaki disease (KD) can be associated with high morbidity and mortality due to coronary artery aneurysms formation and myocardial dysfunction. Aim of this study was to evaluate the diagnostic performance of non-invasive myocardial work in predicting subtle myocardial abnormalities in Kawasaki disease (KD) children with coronary dilatation (CADL). A total of 100 patients (age 8.7 ± 5 years) were included: 45 children with KD and CADL (KD/CADL) (Z-score > 2.5), 45 age-matched controls (CTRL) and, finally, an additional group of 10 children with KD in absence of coronary dilatation (KD group). Left ventricular (LV) systolic function and global longitudinal strain (GLS) were assessed. Global myocardial work index (MWI) was calculated as the area of the LV pressure-strain loops. From MWI, global Constructive Work (MCW), Wasted Work (MWW) and Work Efficiency (MWE) were estimated. Despite normal LV systolic function by routine echocardiography, KD/CADL patients had lower MWI (1433.2 ± 375.8 mmHg% vs 1752.2 ± 265.7 mmHg%, p . MWI, MCW and MWE were significantly reduced in KD children despite normal LVEF and normal GLS. These abnormalities seems independent from CADL. Thus, in KD with normal LVEF and normal GLS, estimation of MWI may be a more sensitive indicator of myocardial dysfunction.

Introduction Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown aetiology. We aimed to better understand familial recurrence pattern. Methods An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, leading to investigate 1043 unrelated ccTGA probands. Results Atrioventricular block at diagnosis and laterality defects were observed in 35.4% and 29.9%, respectively. ccTGA associated with primary ciliary dyskinesia in 10 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (d-TGA: 28.4%), laterality defects (13.6%) and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and d-TGA and 9 familial co-segregation of ccTGA and laterality defects. In one family there was co-segregation of ccTGA, d-TGA and heterotaxy syndrome in 3 distinct relatives. Conclusion ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, d-TGA, laterality defects and in some cases primary ciliary dyskinesia strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Background In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection. Methods After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown. Findings A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients. Interpretation We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.

Funding Acknowledgements Type of funding sources: None. Introduction The paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and Kawasaki disease (KD) have overlapping features. This study aimed to describe the strain segmental analysis among both entities. Methods Retrospective review of strain segmental analysis within 4 weeks of presentation of symptoms among children diagnosed with PIMS-TS between April and June 2020 and a historic cohort of typical KD from the Royal Brompton Hospital, London. Results We included 33 PIMS-TS patients (23 males, 69.7%) at a mean age of 8 ± 4,9 years old and 45 KD patients (31 males, 68,9%) at a mean age of 5,8 ± 4,5 years old. PIMS-TS patients were older at presentation (p = 0.038). Left ventricle ejection fraction (LVEF) was normal in both groups (63,3% vs 63,5%; p= 0,89), 4/33 PIMS-TS children (12,1%) had coronary arteries abnormalities (CAA), whereas 100% of KD cohort had CAA. Both groups had a normal global longitudinal strain (GLS),but in PIMS-TS it was significantly reduced compared to the KD group (-20% vs -22%; p = 0,008). Basal segments were the most affected in PIMS-TS with significant difference in the basal anterior and anterolateral strain compared to KD (respectively -18,2% vs -23,4%; p < 0,001 and - 16,7% vs -22,7%; p < 0,001). PIMS-TS had a greater anterior, anterolateral and posterior segments involvement with a significant reduction in the anterolateral mid-wall longitudinal strain (-18,3% vs -22%; p = 0,002). Apical segments were less involved, with significant difference only in the septal and inferior apical strain (respectively p = 0.001 and p = 0,032). Conclusions These preliminary data showed that after 4 weeks from the onset of symptoms, all PIMS-TS patients had a normal LVEF but they had a significant reduction in GLS and different segmental involvement compared to KD cohort. We hypothesize that these findings may be related to direct myocardial damage in PIMS-TS rather than caused by coronaries perfusion abnormalities. Abstract Figure. Bull"s eye

Background Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD. Methods We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected. Results We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design. Conclusions In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity.

International audience; Among the enteric viruses implicated in foodborne outbreaks, the human norovirus and hepatitis viruses A and E (HAV and HEV) represent a serious public health concern. International standard ISO 15216 proposes methods for detecting HAV and norovirus (genogroups I and II) RNA from soft fruit, leaf, stem and bulb vegetables, bottled water or food surfaces. These methods had not previously been validated for detecting the targeted viruses in other foodstuffs such as multicomponent foods, nor for detecting other viruses in foodstuffs. The aim of this study was to characterise a method derived from the vegetable method described in ISO 15216 to detect HAV, HEV and norovirus in artificially-contaminated multicomponent foodstuffs according to the recent international standard ISO 16140-4. Results showed that the mean recovery rates for all settings did not differ according to the operator. The mean extraction yields ranged from 0.35% to 40.44% for HAV, 5.19% to 100% for HEV, 0.10% to 40.61% for norovirus GI and 0.88% to 69.16% for norovirus GII. The LOD(95) was 10(2) genome copies/g for HAV, HEV and norovirus GII and 10(3) genome copies/g for norovirus GI. The LOQ was 2.90 × 10(4), 1.40 × 10(3), 1.60 × 10(4) and 1.30 × 10(4) genome copies/g for HAV, HEV, norovirus GI and norovirus GII respectively. The MNV-1 process control was detected in 120 out of 128 RNA extracts analysed and was recovered with an efficiency of between 3.83% and 50.22%. The mean inhibition rates of quantitative real-time RT-PCR reaction ranged from 3.25% to 28.70% and varied significantly with the type of food matrix. The described method could be used to detect viruses in composite food products for routine diagnosis needs.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.

Funding Acknowledgements Type of funding sources: None. Background Left ventricular non-compaction cardiomyopathy (LVNC) is associated with poor clinical outcome in childhood, with heart failure, arrhythmias, and embolic events as main clinical manifestations. LV twist has recently been demonstrated having good predictive value in diagnosing LVNC in young patients. However, how LV twist may influence long-term clinical outcome of LVNC children and adolescents is still unknown. The aim of this study was to analyse a set of echocardiographic parameters to find imaging predictors of worse clinical outcomes in a long-term follow-up of LVNC children and young patients. Methods Children and adolescents, followed from May 2012 to June 2020, were enrolled in a retrospective study. All patients underwent 2-dimensional speckle tracking echocardiography and cardiovascular magnetic resonance imaging (1.5 Tesla) at our Institution’s first evaluation. Death, heart failure hospitalization, aborted sudden cardiac death, ventricular arrhythmias (sustained and non-sustained ventricular tachycardia), and embolisms (i.e. stroke, peripheral arterial embolism and/or pulmonary thromboembolism) were registered and referred to as major adverse cardiovascular events (MACEs). Results Recruited for the study were 47 children (mean age: 11.1± 5; age range: 0–18 years). Twenty-three patients fulfilled the cardiovascular magnetic resonance imaging diagnostic criteria for LVNC (LVNC group), while the remaining 24 did not and were included in the LV hypertrabeculation group (LVHT). They were followed for 4.9 ± 1.0 years, and MACEs were registered. Thirteen children (56% of LVNC, 28% of total) had at least one MACE. Global longitudinal, circumferential and radial strains (GLS, GCS, GRS), LV twist and LVEF resulted being significantly reduced in children with MACEs at follow-up. A multivariable analysis was performed by combining four parameters: LV ejection fraction, GLS, GCS, LV twist. These independent variables were chosen according to univariable analyses and clinical relevance. The results from the analysis demonstrated that LV twist was the only independent predictor (P = 0.033, coeff. B 0.726) of worse clinical outcomes in young patients with LVNC. Conclusions LV twist is a promising tool to stratify and predict prognosis in LVNC young patients. Our findings show the importance of LV twist assessment to detect the severity of LVNC and to plan for early clinical intervention.

Percutaneous closure of PDA in premature babies can be achieved with a high degree of success as an alternative to surgical ligation. Early and mid-term follow-up confirms promising results. Future efforts should be aimed at optimizing patient selection and timing of the procedure. Further studies are needed to assess the result and outcome of this technique versus current treatment strategies including medical treatment.

Background Most tuberculosis (TB) cases in high-income countries occur in foreign-born people, most of them coming from high incidence countries. However, migrants return more or less frequently to their birth countries. The aim of the study was to estimate the influence of travelling to high incidence countries on the diagnosis delay of tuberculosis in France. Methods a monocentric retrospective study of 224 consecutive cases followed at the Bas-Rhin Tuberculosis Prevention Centre. Results 59.3% of cases were born abroad. Migrants who did not develop TB soon after arrival and, who travelled since then to high incidence countries, had a mean diagnosis delay, since their last trip, comparable to median diagnostic delay among immigrants who did not travel since their arrival (3.2 vs 4.4 years, p = 0.42). Diagnostic delays are shorter among those reporting an exposition to TB during their journey (1.5 years vs 3.7 years, p = 0.2). Conclusion These results suggest a targeted information on the risk of TB and LTBI among those persons and screening for tuberculosis and LTBI, in certain cases, including vulnerable patients (dialysis, under immunosuppressant drugs including anti-TNF, HIV).

OBJECTIVES: To describe presentation, hospital course, and predictors of bad outcome in multisystem inflammatory syndrome in children (MIS-C). METHODS: Retrospective data review of a case series of children meeting the published definition for MIS-C who were discharged or died between March 1, 2020, and June 15, 2020, from 33 participating European, Asian, and American hospitals. Data were collected through a Web-based survey and included clinical, laboratory, electrocardiographic, and echocardiographic findings and treatment management. RESULTS: We included 183 patients with MIS-C: male sex, 109 (59.6%); mean age 7.0 ± 4.7 years; Black race, 56 (30.6%); obesity, 48 (26.2%). Overall, 114 of 183 (62.3%) had evidence of severe acute respiratory syndrome coronavirus 2 infection. All presented with fever, 117 of 183 (63.9%) with gastrointestinal symptoms, and 79 of 183 (43.2%) with shock, which was associated with Black race, higher inflammation, and imaging abnormalities. Twenty-seven patients (14.7%) fulfilled criteria for Kawasaki disease. These patients were younger and had no shock and fewer gastrointestinal, cardiorespiratory, and neurologic symptoms. The remaining 77 patients (49.3%) had mainly fever and inflammation. Inotropic support, mechanical ventilation, and extracorporeal membrane oxygenation were indicated in 72 (39.3%), 43 (23.5%), and 4 (2.2%) patients, respectively. A shorter duration of symptoms before admission was found to be associated with poor patient outcome and for extracorporeal membrane oxygenation and/or death, with 72.3% (95% confidence interval: 0.56–0.90; P = .006) increased risk per day reduction and 63.3% (95% confidence interval: 0.47–0.82; P < .0001) increased risk per day reduction respectively. CONCLUSIONS: In this case series, children with MIS-C presented with a wide clinical spectrum, including Kawasaki disease–like, life-threatening shock and milder forms with mainly fever and inflammation. A shorter duration of symptoms before admission was associated with a worse outcome.

Introduction: Following the SARS-CoV-2 pandemic peak, children suffering from a multiorgan inflammatory disease that often leads to shock have been reported. This condition shares features with Kawasaki disease, but its etiopathogenesis is unknown. Hypothesis: We aimed to describe presentation and hospital course for this pediatric inflammatory multisystemic syndrome associated with COVID-19 (PIMS-TS). Methods: Data were collected from a retrospective review of children from 33 participating European, Asian and American sites. Results: We included 183 patients (109 males, 59·6%) with PIMS-TS, at a mean age of 7·0 (±4·7) years. Fifty-six (30·6%) had black ethnicity and obesity was present in 48 (26·2%) cases. Overall, 114/183 (62·3%) had biological evidence of current or recent SARS-CoV-2 infection. At admission, all presented with fever, 117/183 (63·9%) with gastrointestinal symptoms and 79/183 (43·2%) with shock, that was associated with more frequent black ethnicity, higher inflammatory markers and more cardiac involvement. Twenty-seven patients (14·7%) fulfilled criteria for Kawasaki disease. They were younger with no shock, fewer gastrointestinal, cardio-respiratory and neurological symptoms. Among the remaining PIMS-TS patients, 77 (49·3%) had mainly fever and inflammation with less cardiac involvement. For the entire cohort of 183 patients, the mean duration of admission was 8·6 (±5·6) days. Inotropic support, mechanical ventilation and ECMO were indicated in 72 (39·3%), 43 (23·5%) and 4 (2·2%) patients, respectively. Three patients (1·6%) died. A shorter duration of symptoms before admission was a risk factor for worse outcome and for ECMO/death, with 63% increased risk per day reduction (95%CI 0·39-0·93, p=0·03) and with 51·4% increased risk per day reduction (95%CI 0·36-0·9, p=0·03), respectively. Conclusions: We describe the first largest international series of children with PIMS-TS. Life-threatening shock is a common presentation. A shorter duration of symptoms prior to admission characterizes the fulminant form of the disease with potentially worse outcome.

Background: PIMS-TS is heterogeneous in presentation, with significant proportion showing cardiac involvement. Data on cardiac outcomes is sparse and no consensus yet exists on follow-up management. Aim: To describe clinical and cardiac features during and soon after the acute phase of PIMS-TS patients. Methods: Prospective analysis and comparison of biochemical, electrocardiographic (ECG) and echocardiographic (TTE) data obtained during admission and on follow-up within 2 weeks of discharge. Cardiac MRI (CMR) was done mainly in those with myocardial hit (high Troponin, ECG changes or left ventricular dysfunction on TTE if available) during admission. Results: 35 patients met criteria for PIMS-TS, (23 males, 66%) with a mean age 5 years. 49% were of Black, Asian or Minority Ethnicity (BAME). 75% of tested were IgG positive. Mean interval from symptom onset to admission was 5 days (range 1-12 days). Features included fever (100%), conjuctivitis (66%) oral mucositis/pharyngitis (60%), gastrointestinal symptoms (54%), rash (51%), erythema/oedema of extremities (31%) and cervical lymphadenopathy (31%). Presentation grouped into 3 types - 7/35 (20%) met AHA criteria for Kawasaki Disease (KD), 5 (14%) presented with shock and 23 (66%) had atypical presentations. 1 patient was treated for KD 6 years ago, no other co-morbidities noted in the cohort. Six (17%) needed PICU support (mean 1.8 days, range 1-4). 80% had normal ECGs during admission but abnormal repolarisation (11%), ischaemic changes (3%), arrhythmia (9%) were seen. 26% (9/35) had left ventricular (LV) dysfunction, of whom 7 had high serum Troponin (mean 183ng/mL SD 250) and Brain Natriuretic Peptide (BNP, mean 627ng/L SD 287). Coronary abnormalities were noted in 12 (34%). All blood markers (Troponin, BNP, Platelet count, C-reactive protein, D-dimer, Ferritin) returned to normal levels by discharge/follow-up. Follow-up global longitudinal strain (GLS) was normal in 94% (33/35). 5 (14%) had mild coronary ectasia. Of 16 CMR’s done Conclusions: Most biochemical and cardiac derangement during the acute phase normalised within weeks. Further study is on-going.

Background During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia. Conclusions To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.

Background Severe pulmonary regurgitation (PR) and progressive right ventricular (RV) dilation and disfunction are common in patients with repaired Tetralogy of Fallot (r-TOF) and should be carefully monitored during the follow up of these patients. In this contest, Echocardiography and Cardiac Magnetic Resonance (CMR) have a complementary diagnostic role. Purpose To correlate Echo and CMR parameters in children ( Methods Paediatric patients with r- TOF with at least moderate PR at the echo evaluation who underwent a CMR study within six months were included by using hospital databases. All patients underwent standard echo-Doppler study including RV end-diastolic area (RVEDA), end-systolic area (RVESA), fractional area change (FAC) and TAPSE; PR was assessed by Color Doppler, continuous-wave (CW) Doppler and derived parameters such as pressure half time (PHT), PR index, ratio of diastolic and systolic time-velocity integrals (DSTVI) of the main pulmonary artery. By speckle tracking we measured also RV global longitudinal strain (RVGLS) and right atrial strain (RAS). All the patients underwent CMR to assess PR and right ventricular volumes and ejection fraction (EF). Of these, 36 patients underwent cardiopulmonary exercise test (CPET). Results Fourty-six children (aged 13.7±3.0 years) were included. Echo derived RV areas correlated significantly with CMR RV volumes (r=0.72, p21.9 cm2/m2 had a good sensitivity (83.3%) and specificity (73.5%) to identify a RV end-diastolic volume (RVEDV) ≥150 ml/m2. No correlation was found among TAPSE, FAC, RVGLS and RVEF calculated by CMR nor between PHT, PR index and DSTVI and PR-RF. Only A' wave velocity showed a significant but modest correlation with CMR RF (r=0.57, p Conclusion In children, flow reversal in pulmonary branches identifies hemodynamically significant PR at CMR. RV area by echocardiogram is a valid first-line parameter to screen RV dilation. Our study suggests that, also for the RV, there is longitudinal systolic dysfunction in presence of preserved RV EF. RAS is the best predictor of peak Vo2 and should be added in the follow up of these patients. Funding Acknowledgement Type of funding source: None

Background Norwood procedure represents the first of three surgical steps toward Hypoplastic left heart syndrome (HLHS) complete palliation. Two are the main surgical techniques allowing the reconstruction of Norwood circulation: the right ventricle-pulmonary artery shunt (RVPAS) and the modified Blalock-Taussing shunt (mBTS). However, still little is known about the impact on right ventricle (RV) function of the required ventriculotomy for the RVPAS. Purpose The aim of the study was to investigate the changes in RV function in HLHS patients after RVPAS vs mBTS. Methods The cohort included 27 consecutive HLHS patients (10 in the modified Blalock-Taussig shunt group and 17 in the RVPAS group) who successfully underwent Norwood procedure in a single tertiary paediatric cardiology centre. Longitudinal strain (LS) and strain rate (LSR), tricuspid annulus peak systolic excursion (TAPSE) and fractional area change (FAC) were evaluated in all patients before Norwood and in three different breakpoints in the steady state after Norwood procedure (30 days after Norwood, 90 days after Norwood, 140 days after Norwood). Results Ventricular loading conditions (diuretic treatment, blood pressure and tricuspid regurgitation) were similar in both groups. No significant differences were found at different time points between RVPAS and mBTS group in terms of LS, LSR, TAPSE and FAC. However, when we compared RV function before and after Norwood procedure, 90 days after the procedure, patients who did not undergo RV ventriculotomy (mBTS group) showed significant improvement in LS compared to pre-surgical assessment (mBTS: +27.35±43.47% vs RVPAS: −8,20±25.25%, p=0,03). This finding was consistent but no longer statistically significant at 140 days after Norwood (mBTS: +13.81±21.99% vs RVPAS: −4.90±27.97%, p=0,12). Conclusion After Norwood procedure mBTS patients showed a significant increase in LS when compared with patients who underwent RVPAS. This finding was consistent but no longer significant at 140 days after Norwood probably because the number of patients was too small to reach a significant level. These data support the use of LS in HLHS patient's evaluation and may be of value to find a patient-tailored timing for the second surgical stage. TAPSE, FAC, LS and LSR trends Funding Acknowledgement Type of funding source: None

Introduction Non-small-cell lung cancer (NSCLC) is one of the most common and deadly cancers. Several molecular drivers of oncogene addiction are now known to be strong predictive biomarkers for target therapies. Advances in large Next Generation Sequencing (LNGS) have improved the ability to detect potentially targetable mutations. However, the integration of LNGS into clinical management in an individualized manner remains challenging. Methods In this single-center observational study we included all patients with advanced NSCLC who underwent LNGS. Somatic and germline exome analysis was performed with a restriction on 323 cancer related genes. Variants were classified and Molecular Tumour Board (MTB) made therapeutic propositions. Results We performed LNGS analysis in 281 patients with advanced NSCLC between March 2015 and January 2018. Technical failure occurred in only 3% of cases. Three hundred and fifty-six targetable mutations were detected. At least one targetable mutation was found in 209 patients. For all these patients, the MTB was able to recommend treatment with a targeted agent based on the evaluation of the tumour’s genetic profile and treatment history. Twenty-nine patients (13.9%) were subsequently treated with an MTB-recommended targeted therapy. We did not observe any improvement in terms of clinical benefit for these patients. Conclusions In this case series, we show that including LNGS into routine clinical management was feasible but does not appear to provide clinical benefit in the management of patients with advanced NSCLC.

Coronavirus disease 2019 (COVID-19) has affected patients across all age groups, with a wide range of illness severity from asymptomatic carriers to severe multi-organ dysfunction and death. Although early reports have shown that younger age groups experience less severe disease than older adults, our understanding of this phenomenon is in continuous evolution. Recently, a severe multisystem inflammatory syndrome in children (MIS-C), with active or recent COVID-19 infection, has been increasingly reported. Children with MIS-C may demonstrate signs and symptoms of Kawasaki disease, but also have some distinct differences. These children have more frequent and severe gastrointestinal symptoms and are more likely to present with a shock-like presentation. Moreover, they often present with cardiovascular involvement including myocardial dysfunction, valvulitis, and coronary artery dilation or aneurysms. Here, we present a review of the literature and summary of our current understanding of cardiovascular involvement in children with COVID-19 or MIS-C and identifying the role of a pediatric cardiologist in caring for these patients.

Persistent patent ductus arteriosus (PDA) is very common in preterm infants, especially in extremely preterm infants. Despite significant advances in management of these vulnerable infants, there has been no consensus on management of PDA—when should we treat, who should we treat, how should we treat and in fact there is no agreement on how we should define a hemodynamically significant PDA. Medical management with non-steroidal anti-inflammatory drugs (NSAIDs) remains the first line of therapy with moderate success rate in closing the PDA. Paracetamol has been reported to be a safe and equally effective medical therapy for closure of PDA. However, additional studies on its long-term safety and efficacy in extremely low birth weight infants are needed before paracetamol can be recommended as standard treatment for a PDA in preterm infants. Surgical ligation of PDA is not without an increased risk of mortality and co-morbidities. Recently, there has been a significant interest in percutaneous transcatheter closure of PDA in preterm infants, including extremely low birth weight infants. Transcatheter PDA closure in preterm ELBW infants is technically feasible with high PDA occlusion success rates and acceptable complication rates as compared to surgical ligation. Many centers have reported promising early- and mid-term follow-up results. However, they need to be further tested in the prospective well-designed studies and randomized controlled trials comparing the results and outcomes of this technique with current treatment strategies including medical treatment before they can be used as the new standard of care for PDA closure in extremely low birth weight infants.

The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). Our hypothesis was that CXCR2 expression could also be altered in breast cancer. Here, we have analyzed the potential role of CXCR2 in breast cancer in a retrospective cohort of 105 breast cancer patients. Expression of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) was analyzed by immunohistochemistry on tumor samples. We demonstrated that CXCR2 stained mainly stromal cells and in particular neutrophils. CXCR2, CD11b and CD66b expression were correlated with high grade breast cancers. Moreover, TNBC displayed a higher expression of CXCR2, CD11b and CD66b than hormone receptor positive or Her2 positive tumors. High levels of CXCR2 and CD11b, but not CD66b, were associated with a higher infiltration of T lymphocytes and B lymphocytes. We also observed a correlation between CXCR2 and AP-1 activity. In univariate analyses, CXCR2, but not CD11b or CD66b, was associated with a lower risk of relapse, CXCR2 remained significant in multivariate analysis. Our data suggest that CXCR2 is a stromal marker of TNBC. However, higher levels of CXCR2 predicted a lower risk of relapse.

Background & Aims Covalently closed circular DNA (cccDNA) is the episomal form of the HBV genome that stably resides in the nucleus of infected hepatocytes. cccDNA is the template for the transcription of 6 major viral RNAs, i.e. preC, pg, preS1/2, S and HBx RNA. All viral transcripts share the same 3' end and are all to various degrees subsets of each other. Especially under infection conditions, it has been difficult to study in depth the transcription of the different viral transcripts. We thus wanted to develop a method with which we could easily detect the full spectrum of viral RNAs in any lab. Methods We set up an HBV full-length 5'RACE (rapid amplification of cDNA ends) method with which we measured and characterized the full spectrum of viral RNAs in cell culture and in chronically infected patients. Results In addition to canonical HBx transcripts coding for full-length X, we identified shorter HBx transcripts potentially coding for short X proteins. We showed that interferon-β treatment leads to a strong reduction of preC and pgRNAs but has only a moderate effect on the other viral transcripts. We found pgRNA, 1 spliced pgRNA variant and a variety of HBx transcripts associated with viral particles generated by HepAD38 cells. The different HBx RNAs are both capped and uncapped. Lastly, we identified 3 major categories of circulating RNA species in patients with chronic HBV infection: pgRNA, spliced pgRNA variants and HBx. Conclusions This HBV full-length 5'RACE method should significantly contribute to the understanding of HBV transcription during the course of infection and therapy and may guide the development of novel therapies aimed at targeting cccDNA. Lay summary Especially under infection conditions, it has been difficult to study the different hepatitis B virus transcripts in depth. This study introduces a new method that can be used in any standard lab to discriminate all hepatitis B viral transcripts in cell culture and in the serum of patients.

Background Balloon dilation and stenting of the atrial septum are techniques used to unload left heart cavities in acute or end-stage heart failure in children. However, they carry significant risks such as tamponade or device embolization. Case Presentation We report the first case of a child with an end-stage mitochondrial cardiomyopathy on a venoarterial extracorporeal membrane oxygenator as a bridge to heart transplant where an atrial flow regulator device has been implanted. Conclusions This case illustrates the feasibility and safety of atrial flow regulator implantation in this setting. This procedure allowed to wean inotropic support while awaiting heart transplantation.

Background Viral infections are known to exacerbate asthma in adults. Previous studies have found few asthmatics among SARS-CoV-2 pneumonia cases. However, the relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known. Objective We assessed the frequency of asthma exacerbation in asthmatic patients hospitalized for SARS-CoV-2 pneumonia and compared symptoms laboratory and radiological findings in asthmatic and non-asthmatic patients with SARS-CoV-2 pneumonia. Methods We included 106 patients between March 4 and April 6, 2020, who were hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 were asthmatics. To assess the patients’ asthma status, three periods were defined: the last month before the onset of COVID-19 symptoms (p1), pre-hospitalization (p2) and during hospitalization (p3). Severe asthma exacerbations were defined according to GINA guidelines during p1 and p2. During p3, we defined severe asthma deterioration as the onset of breathlessness and wheezing requiring systemic corticosteroids and inhaled beta-2-agonist. Results We found no significant difference between asthmatics and non-asthmatics in terms of severity (length of stay, maximal oxygen flow needed, non-invasive ventilation requirement and ICU transfer). 52.2% of the asthmatic patients were Gina 1. One patient had a severe exacerbation during p1, two patients during p2, and five patients were treated with systemic corticosteroids and inhaled beta-2-agonist during p3. Conclusion Our results demonstrate that asthmatic patients appeared not to be at risk for severe SARS-CoV-2 pneumonia. Moreover, SARS-CoV-2 pneumonia did not induce severe asthma exacerbation., Highlights box: 1. What is already known about this topic? Asthmatic patients are rare in epidemiological studies of SARS-CoV-2 pneumonia. 2. What does this article add to our knowledge? Being asthmatic is not a risk factor for severe SARS-CoV-2. 3. How does this study impact current management guidelines? SARS-CoV-2 pneumonia may not induce severe asthma exacerbation.

International audience; Aims: In univentricular hearts, selective lung vasodilators such as phosphodiesterase type 5 (PDE5) inhibitors would decrease pulmonary resistance and improve exercise tolerance. However, the level of evidence for the use of PDE5 inhibitors in patients with a single ventricle (SV) remains limited. We present the SV-INHIBITION study rationale, design, and methods.Methods and results: The SV-INHIBITION trial is a nationwide multicentre, randomized, double blind, placebo-controlled, Phase III study, aiming to evaluate the efficacy of sildenafil on the ventilatory efficiency during exercise, in teenagers and adult patients (>15 years old) with an SV. Patients with a mean pulmonary arterial pressure >15 mmHg and a trans-pulmonary gradient >5 mmHg, measured by cardiac catheterization, will be eligible. The primary outcome is the variation of the VE/VCO2 slope, measured by a cardiopulmonary exercise test, between baseline and 6 months of treatment. A total of 50 patients are required to observe a decrease of 5 ± 5 points in the VE/VCO2 slope, with a power of 90% and an alpha risk of 5%. The secondary outcomes are clinical outcomes, oxygen saturation, 6 min walk test, SV function, NT-proBNP, peak VO2 , stroke volume, mean pulmonary arterial pressure, trans-pulmonary gradient, SF36 quality of life score, safety, and acceptability.Conclusions: The SV-INHIBITION study aims to answer the question whether PDE5 inhibitors should be prescribed in patients with an SV. This trial has been built focusing on the three levels of research defined by the World Health Organization: disability (exercise tolerance), deficit (SV function), and handicap (quality of life).Trial registration: ClinicalTrials.gov NCT03997097.

Background Pulmonary regurgitation (PR) and right ventricular (RV) dilatation and disfunction are common in patients with repaired Tetralogy of Fallot (r-TOF). Aims To compare Echo data with the gold standard CMR in a paediatric population of r-TOF with significant PR, to assess the reliability of standard and advanced echo parameters. In addition, to evaluate their correlation with peak oxygen consumption (VO2). Methods and results All patients underwent standard echo-Doppler study, speckle tracking analysis, and CMR to assess PR and RV size and function. Thirty-six patients underwent also cardiopulmonary exercise test. Fourty-six patients (aged 13.7 ± 3.0) were included. Echo derived RV areas correlated with CMR RV volumes (p 21.9 cm2/m2 had a good sensitivity (83.3%) and specificity (73.5%) to identify a RV end-diastolic volume ≥ 150 ml/m2. RVEF was preserved in all patients, while TAPSE was reduced in 78.2% and RVGLS in 60.8%. Flow-reversal in pulmonary branches showed a sensitivity of 95.8% and a specificity of 59.1% to identify CMR pulmonary regurgitant fraction (RF) ≥ 35%. None of the CMR parameters correlated with peak VO2. Among the Echo data only right atrial strain (RAS) correlated with peak VO2. Conclusion In children, flow-reversal in pulmonary branches identifies hemodynamically significant RF with a good sensitivity but poor specificity. RV area by echocardiogram is a valid first-line parameter to screen RV dilation. RV longitudinal systolic dysfunction coexists with a still preserved EF. RAS correlates strongly with peak VO2 and should be added in their follow up.