L'endomicroscopie confocale (une nouvelle méthode d'analyse quantitative des cryptes coliques de patients sains ou atteints de maladie de Crohn)

Contexte : L'endomicroscopie confocale utilise des critères subjectifs, qualitatifs pour décrire les anomalies inflammatoires de la muqueuse digestive. Objectifs : Evaluer la faisabilité d'une étude quantitative architecturale des cryptes coliques et fonctionnelle de perméabilité de la muqueuse colique par endomicroscopie et comparer les résultats obtenus entre témoins sains et patients atteints de maladie de Crohn (MC). Patients et méthodes : 10 patients atteints de MC et 6 témoins sains ont été inclus. 15 images par patients ont été sélectionnées pour la réalisation de mesures architecturales (Rapport de diamètre maximal et minimal des cryptes, nommé DMc/dmc, et de la lumière des cryptes, nommé DMl/dml, distance intercrypte, diamètre vasculaire) et fonctionnelle (rapport d'intensité de fluorescence, RIF). Les mesures architecturales des cryptes étaient comparées à des mesures réalisées sur biopsies marquées au bleu de méthylène (BMBM). Résultats : Il existait une corrélation significative entre les DMl/dml et les DMc/dmc mesurés endomicroscopiquement et ceux mesurés sur BMBM (r=0,67;p=0,006 / r=0,65; p=0,009 respectivement). Les patients atteint de MC présentaient un DMl/dml significativement plus grand (p=0,016). Individuellement, 50% des patients en rémission endoscopique avaient un DMl/dml anormal par rapport à la médiane des témoins. Les mesures de distance intercrypte ne différaient pas entre les groupes. Les diamètres vasculaires étaient plus petits chez les patients avec inflammation endoscopique (p=0,02). Les RIF étaient plus importants chez les patients avec inflammation endoscopique mais de façon non significative. Conclusion : Un rapport DMl/dml supérieur à 1,7 semblerait être un bon marqueur d'inflammation colique mais doit être validé sur de plus grandes cohortes. Le développement de mesures automatisées et de l'étude fonctionnelle sont probablement à développer en endomicroscopie.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Efficacy and safety of endoscopic papillectomy: a multicenter, retrospective, cohort study on 227 patients

International audienceBACKGROUND: Endoscopic papillectomy is a minimally invasive treatment for benign tumors of the ampulla of Vater or early ampullary carcinoma. However, reported recurrence rates are significant and risk factors for recurrence are unclear. OBJECTIVE: The aims of this study were to evaluate the efficacy and safety of endoscopic papillectomy and to identify risk factors for recurrence and adverse events. METHODS: All patients who underwent endoscopic papillectomy at five tertiary referral centers between January 2008 and December 2018 were included. Recurrence was defined as the detection of residue on one of the follow-up endoscopies. Treatment success was defined as the absence of tumor residue on the last follow-up endoscopy. RESULTS: A total of 227 patients were included. The resections were en bloc in 64.8% of cases. The mean lesion size was 20 mm (range: 3-80) with lateral extension in 23.3% of cases. R0 resection was achieved in 45.3% of cases. The recurrence rate was 30.6%, and 60.7% of recurrences were successfully treated with additional endoscopic treatment. Finally, treatment success was achieved in 82.8% of patients with a median follow-up time of 22.3 months. R1 resection, intraductal invasion, and tumor size > 2 cm were associated with local recurrence. Adverse events occurred in 36.6% of patients and included pancreatitis (17.6%), post-procedural hemorrhage (11.0%), perforation (5.2%), and biliary stenosis (2.6%). The mortality rate was 0.9%. CONCLUSION: Endoscopic papillectomy is an effective and relatively well-tolerated treatment for localized ampullary tumors. In this series, R1 resection, intraductal invasion, and lesion size > 2 cm were associated with local recurrence

High-Density of FcγRIIIA+ (CD16+) Tumor-Associated Neutrophils in Metastases Improves the Therapeutic Response of Cetuximab in Metastatic Colorectal Cancer Patients, Independently of the HLA-E/CD94-NKG2A Axis

International audienceAntibody-dependent cellular cytotoxicity (ADCC) in the anti-tumor effect of cetuximab in metastatic colorectal cancer (mCRC) is only based on the impact of FcγRIIIA (CD16) polymorphisms as predictive of therapeutic response. However, nature, density and therapeutic impact of FcγRIIIA + (CD16) effector cells in tumor remain poorly documented. Moreover, the inhibition of cetuximab-mediated ADCC induced by NK cells by the engagement of the new inhibitory CD94-NKG2A immune checkpoint has only been demonstrated in vitro . This multicentric study aimed to determine, on paired primary and metastatic tissue samples from a cohort of mCRC patients treated with cetuximab: 1) the nature and density of FcγRIIIA + (CD16) immune cells, 2) the expression profile of HLA-E/β2m by tumor cells as well as the density of CD94 + immune cells and 3) their impact on both objective response to cetuximab and survival. We demonstrated that FcγRIIIA + (CD16) intraepithelial immune cells mainly correspond to tumor-associated neutrophils (TAN), and their high density in metastases was significantly associated with a better response to cetuximab, independently of the expression of the CD94/NKG2A inhibitory immune checkpoint. However, HLA-E/β2m, preferentially overexpressed in metastases compared with primary tumors and associated with CD94 + tumor infiltrating lymphocytes (TILs), was associated with a poor overall survival. Altogether, these results strongly support the use of bispecific antibodies directed against both EGFR and FcγRIIIA (CD16) in mCRC patients, to boost cetuximab-mediated ADCC in RAS wild-type mCRC patients. The preferential overexpression of HLA-E/β2m in metastases, associated with CD94 + TILs and responsible for a poor prognosis, provides convincing arguments to inhibit this new immune checkpoint with monalizumab, a humanized anti-NKG2A antibody, in combination with anti- FcγRIIIA/EGFR bispecific antibodies as a promising therapeutic perspective in RAS wild-type mCRC patients

Safety of endoscopic retrograde cholangiopancreatography in the pediatric population: a multicenter study

INTRODUCTION: The aims of this retrospective multicenter study were to assess the technical success and adverse events of endoscopic retrograde cholangiopancreatography (ERCP) procedures in children in French and Belgian centers. METHODS: All children aged 1 day to 17 years who underwent ERCP between January 2008 and March 2019 in 15 tertiary care hospitals were retrospectively included. RESULTS: 271 children underwent 470 ERCP procedures. Clinical long-term follow-up was available for 72 % of our patients (340/470 procedures). The median age at intervention was 10.9 years. ERCP was therapeutic in 90 % (423/470) and diagnostic in cases of neonatal cholestasis in 10 % of the patients. The most common biliary indication was choledocholithiasis; the most common pancreatic indication was chronic pancreatitis. Biliary cannulation was successful in 92 % of cases (270/294); pancreatic cannulation in 96 % of cases (169/176); and planned therapeutic procedures in 92 % of cases (388/423). The overall complication rate was 19 % (65/340). The most common complication was post-ERCP pancreatitis (PEP) in 12 % of cases (40/340) and sepsis in 5 % (18/340). On univariate analyses, pancreatic stent removal was protective against PEP (odds ratio [OR] 0.1, 95 % confidence interval [CI] 0.01 - 0.75; P = 0.03), and sepsis was associated with history of liver transplantation (OR 7.27, 95 %CI 1.7 - 31.05; P = 0.01). Five patients had post-ERCP hemorrhage and two had intestinal perforation. All complications were managed with supportive medical care. There was no procedure-related mortality. CONCLUSION: Our cohort demonstrates that ERCP can be performed safely with high success rates in many pancreaticobiliary diseases of children. The rate of adverse events was similar to that in previous reports

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

International audiencePrimary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions:A propensity score-matched cohort

Background Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAPrelated and sporadic ampullary lesions (SALs). Methods This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. Results Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2% [95 %CI 71.2-87.3] vs. 46.5% [95 %CI 36.6-56.4]); P &lt; 0.001). The initial R0 rate was significantly lower in FAP patients (63.4% [95%CI 53.8-72.9] vs. 83.2% [95%CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1% [95%CI 88.0-98.1] vs. SAL 97.0% [95%CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7%. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8% [95%CI 12.7-28.8]) and 16 SAL patients (15.8% [95%CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). Conclusions Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.</p

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions:A propensity score-matched cohort

Background Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAPrelated and sporadic ampullary lesions (SALs). Methods This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. Results Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2% [95 %CI 71.2-87.3] vs. 46.5% [95 %CI 36.6-56.4]); P &lt; 0.001). The initial R0 rate was significantly lower in FAP patients (63.4% [95%CI 53.8-72.9] vs. 83.2% [95%CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1% [95%CI 88.0-98.1] vs. SAL 97.0% [95%CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7%. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8% [95%CI 12.7-28.8]) and 16 SAL patients (15.8% [95%CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). Conclusions Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.</p