BACKGROUND:Gastrointestinal stromal tumors (GISTs) occur in ∼7% of neurofibromatosis type 1 (NF1) patients. Data about their natural history remain scarce and neither risk classifications, prognosis model nor adjuvant treatment have been validated in this population. METHODS:This national retrospective study included consecutive operated NF1-GIST cases from 31 reference centers in France, mostly from the NETSARC+ network. Factors associated with relapse were used to build a new prognostic score (RECKGIST). To address potential bias between adjuvant group and follow-up group, a propensity score was used. RESULTS:A total of 119 patients were included between 2008 and 2023, of whom 61% were women. Median age was 53 years (range 20-78 years). The main primary location was the small bowel (86%) and the stomach (11%). Median size and mitotic count (mit) were 45 mm [95% confidence interval (CI) 45-58 mm] and 2 mit/5 mm2 (95% CI 3-9 mit/5 mm2), respectively. The vast majority were KIT/PDGFRA wild type (mutation KIT 2%, PDGFRA 3%). The median follow-up was 6 years. For GISTs <30 mm (n = 35), none relapsed. For GISTS >30 mm (n = 84), 18 developed metastases (21%). There was no difference in relapse according to tumor location (P = 0.45) or tumor rupture (P = 0.11), whereas KIT/PDGFRA-mutated GISTs were at higher risk of relapse [recurrence-free survival (RFS) at 10 years of 30% versus 82.5% for wild type, P = 0.03]. Miettinen and Joensuu classification did not predict relapse accurately. For the RECKGIST score A (size ≤30 mm, n = 34) group, 10-year RFS was 100%; it was 78.5% in the RECKGIST B group (size >30 mm and 0 < mit ≤ 5, n = 60), and 45.5% in the RECKGIST C group (size >30 mm and mit >5, n = 20) (P < 0.0001). After matching, 10-year RFS was similar between adjuvant and surveillance groups (P = 0.34). CONCLUSIONS:For NF1-GISTs <30 mm, prognosis without relapse is excellent. RECKGIST score accurately predicts recurrence and needs to be validated in an external cohort, but it may help treatment decision making. No efficacy of adjuvant treatment was observed.

Platinum-etoposide combination chemotherapy is the first-line standard-of-care for pts with advanced, poorly-differentiated, gastroenteropancreatic (GEP) NEC. However, nearly all pts will develop resistance and there is no standard second-line treatment. PRODIGE 41 – BEVANEC (NCT02820857) is an academic, non-comparative, phase 2 trial. Main inclusion criteria were histologically proven, grade 3, locally advanced or metastatic GEP-NEC or NEC of unknown primary, and documented progressive disease during or after first-line therapy. Pts were randomized 1:1 to receive 5 mg/kg Bevacizumab (B) with FOLFIRI, or FOLFIRI alone, every 14 days until progression or unacceptable toxicity. The primary objective was to demonstrate a 6-month overall survival (OS) rate of ≥50% in the experimental arm (efficacy: if at least 26 of 52pts alive at 6 months), power, 85%; one-sided alpha risk, 10%). Other endpoints included progression-free survival (PFS), objective response rate (ORR), response duration, biochemical response and safety. From Sep 2017 to Feb 2022, 133 pts were randomized in 26 centers; 126 pts received at least one course of chemotherapy and were evaluable for the primary endpoint. Median age was 67 years (range 26–85), 66% males, 90% with ECOG PS 0-1. The primary tumor was mainly colorectal (n=38), pancreas (n=33), oesogastric (n=22) and unknown (=23). The primary objective was met (30 pts alive at 6 months ± 5 pts still in follow-up less than 6 months) with Folfiri-B. Median PFS and OS were 3.7 months (95%CI [1.9-5.6]) and 7.0 months (95%CI [4.6-11.5]) with Folfiri-B, and 3.5 months (95%CI [1.9-5.1]) and 8.9 months (95%CI [5.7-10.7]) with Folfiri. Biochemical response, ORR (25.5% vs 18.3%) and response duration were numerically higher in Folfiri-B vs Folfiri. Three patients stopped B because of toxicity; one treatment-related death occurred in Folfiri-B and most frequent grade ≥ 3 AEs were neutropenia (12%), asthenia (10%) and diarrhoea (10%). Folfiri-B reached the primary endpoint in 2nd line NECs pts.

18-Fluoro-L-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA PET-CT) is a nuclear medicine imaging modality indicated for the diagnosis and staging of neuroendocrine tumors (NETs), particularly for the midgut tumors, due to its excellent sensitivity and specificity. Its performance for the detection of foregut-derived NETs (duodenopancreas and proximal jejunum) and for the detection of hindgut-derived NETs is poor and inferior to PET somatostatin receptor imaging such as DOTATOC PET-CT and even inferior to somatostatin analog scintigraphy (octreoscan). There are few studies in the literature on heterotopic pancreas (HP) which is a rare entity, and which can be in some cases a false positive in 18F-DOPA PET-CT. We report a case of HP showing focal uptake on 18F-DOPA PET-CT mimicking an intestinal NET. This case suggests that HP should be included as a possible false positive on 18F-DOPA PET-CT. (C) 2021 Elsevier Masson SAS. All rights reserved.

Background: Metastatic signet-ring cell colorectal carcinoma is rare. We analyzed its clinicopathological and molecular features, prognostic factors and chemosensitivity.Methods: Retrospective study from 2003 to 2017 in 31 French centers, divided into three groups: curative care (G1), chemotherapy alone (G2), and best supportive care (G3).Results: Tumors were most frequently in the proximal colon (46%), T4 (71%), and poorly differentiated (86%). The predominant metastatic site was peritoneum (69%). Microsatellite instability and BRAF mutation were found in 19% and 9% (mainly right-sided) of patients and RAS mutations in 23%. Median overall survival (mOS) of the patients ( n = 204) was 10.1 months (95%CI: 7.9;12.8), 45.1 for G1 ( n = 38), 10.9 for G2 ( n = 112), and 1.8 months for G3 ( n = 54). No difference in mOS was found when comparing tumor locations, percentage of signet-ring cell contingent and microsatellite status. In G1, relapse-free survival was 14 months (95%CI: 6.5-20.9). In G2, median progression-free survival (PFS) was 4.7 months (95%CI: 3.6;5.9]) with first-line treatment. Median PFS was higher with biological agents than without (5.0 vs 3.9 months, p = 0.016).Conclusions: mSRCC has a poor prognosis with specific location and molecular alterations resulting in low chemosensitivity. Routine microsatellite analysis should be performed because of frequent MSI-high tumors in this population. (c) 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Context: Although 24-hour urinary 5-hydroxyindolacetic acid (24u5HIAA) is a key biomarker in midgut neuroendocrine tumors (NETs), it may be inaccurate and inconvenient. Objective: We compared the diagnostic performances of 24u5HIAA, overnight urinary 5HIAA (Ou5HIAA), and plasmatic 5HIAA (p5HIAA) in midgut NETs. Methods: This prospective, multicenter study included 80 patients with metastatic midgut NETs and 17 control patients with irritable bowel syndrome. 24u5HIAA, Ou5HIAA, and p5HIAA were measured in urine and plasma collected on 2 consecutive days following a specific recommended diet. Reproducibility of the biomarkers was evaluated by the Spearman test. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUROC). Correlations with the main clinical features and declared observance to the specific diet were assessed using AUROC and logistic regression models. Results: The reproducibility of 24u5HIAA, Ou5HIAA, and p5HIAA were excellent (rho=0.916; 0.897; 0.978, respectively, P<.001) with significant discrimination between patients and controls (AUROC=0.795, P<.001; 0.757, P =.001; 0.717, P=.005, respectively). All 3 markers were correlated with the presence of carcinoid syndrome (AUROC=0.702, P=.006; 0.701, P=.006; 0.697, P=.007, respectively), carcinoid heart disease (AUROC=0.896; 0.887; 0.923, P<.001, respectively, P<.001), and liver metastatic involvement greater than 30% (AUROC=0.827; 0.807; 0.849, P<.001, respectively, P<.001), independent from other traditional prognostic factors. Biomarker levels were similar between patients with optimal or suboptimal diet observance. Conclusion: Ou5HIAA and p5HIAA could be used as more convenient alternatives to 24u5HIAA in patients with metastatic midgut NETs. Prospective long-term studies with repeated dosages are needed.

L’œsophagite à éosinophile est connue pour être une complication des immunothérapies orales en allergie alimentaire mais beaucoup moins dans le cadre d’immunothérapie sublinguale aux aéroallergènes. Nous présentons le cas d’un patient de 39 ans dont l’immunothérapie sublinguale (ITSL) aux pollens de bouleau s’est compliquée de manifestations à type de blocage alimentaire, douleur rétrosternale après 2 mois de traitement à l’origine de la découverte d’une oesophagite à éosinophiles, prouvée par biopsie. L’oesophagite a régressée après suspension de l’ITSL et s’est aggravée après reprise de l’ITSL (contrôle endoscopique et biopsie à chaque fois). Une enquête a été menée auprès du Centre de Pharmacovigilance. 3 cas ont été rapportés au niveau des Centres de Pharmacovigilances français ; ainsi qu’une trentaine d’autres cas au niveau international. Ce cas illustre l’importance de dépister les symptômes d’oesophagite à éosinophiles, de les documenter avec une endoscopie et des biopsies et de la déclarer au Centre de Pharmacovigilance car il existe probablement une importante sous déclaration des cas d’oesophagite induits par les ITSL.

Background Half of patients newly diagnosed with esophagus squamous cell cancer (ESCC) has a metastatic ESCC (mESCC) and half of patients with initial loco-regional disease presents disease recurrence after surgery and/or chemoradiation. Although not validated by a phase III trial, first-line palliative chemotherapy combines fluoropyrimidine with platinum salt. Patients with disease progression after platinum-based chemotherapy and good performance status may benefit from a second-line chemotherapy. Based on phase I/II trials or retrospective studies, the most commonly used regimens in second-line setting of mESCC are paclitaxel monotherapy or irinotecan monotherapy or combined with 5FU (FOLFIRI). Up to now, there is no randomized trial available. Trial design OESIRI is a multicenter, open-label, randomized phase II trial designed to evaluate efficacy and safety of nanoliposomal irinotecan (NalIRI) plus 5FU versus paclitaxel as second-line therapy in mESCC. Main inclusion criteria are histologically proven mESCC after failure of first-line platinum-based chemotherapy and WHO performance status ≤ 2. Patients initially treated by surgery and chemotherapy or definitive chemoradiation are eligible if relapse occurred less than 6 months after the end of the treatment. In the experimental arm, patients will receive, every 14 days, intravenous (IV) infusion of NalIRI (80 mg/m2) followed by 5FU (2400 mg/m2 over 46 h). In the control arm, patients will receive at days 1, 8 and 14 of a 28 days-cycle, an IV infusion of paclitaxel (80 mg/m2). The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. The clinical hypotheses are to extent the 9-months survival rate from 40% to 60%. With a one-sided type one error α of 5%, a power of 85%, a 5% rate of patients lost to follow-up, 53 patients per arm (n = 106) will be randomized. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. Circulating tumor DNA will be monitored to assess its predictive value of response to treatment. Inclusions started in January 2019 and theoretical end of recruitment is January 2022. Legal entity responsible for the study Federation Francaise de Cancerologie Digestive. Funding Servier. Disclosure All authors have declared no conflicts of interest.

Introduction Small rectal neuroendocrine tumours are good candidates for endoscopic resection provided that complete pathological resection (R0) is obtained and their risk of metastatic progression is low. We conducted a large multicentre nationwide study to evaluate the outcomes of the management of non-metastatic rectal neuroendocrine tumours <= 2 cm diagnosed endoscopically. Patients and methods The medical records, the endoscopic and pathological findings of patients with non-metastatic rectal neuroendocrine tumours <= 2 cm managed from January 2000-June 2018 in 16 French hospitals, were retrospectively analysed. The primary objective was to describe the proportion of R0 endoscopic resections. Results A total of 329 patients with 345 rectal neuroendocrine tumours were included, 330 (96%) tumours were managed by local treatments: 287 by endoscopy only and 43 by endoscopy followed by transanal endoscopic microsurgery. The final endoscopic R0 rate was 134/345 (39%), which improved from the first endoscopy (54/225, 24%), to the second (60/100, 60%) and the third endoscopy (20/26, 77%). R0 was associated with endoscopic technique (90% for advanced techniques, 40% for mucosectomy and 17% for polypectomy), but not with tumour or patient characteristics. Twenty patients had metastatic disease, which was associated with tumour size >= 10 mm (odds ratio: 9.1, 95% confidence interval (3.5-23.5)), tumour grade G2-G3 (odds ratio: 4.2, (1.5-11.7)), the presence of muscular (odds ratio: infinity, (11.9-infinity)) and lymphovascular invasion (odds ratio: 57.2, (5.6-578.9)). Conclusions The resection of small rectal neuroendocrine tumours often requires multiple procedures. Training of endoscopists is necessary in order to better recognise these tumours and to perform the appropriate resection technique.

Les petites tumeurs neuroendocrines (TNE) du rectum sont de bons candidats à la résection endoscopique, à condition que celle-ci soit carcinologiquement complète (R0) et que le risque d'évolution métastatique soit faible. Cependant les résections endoscopiques doivent encore faire la preuve de leur efficacité. Nous avons donc mené une étude nationale multicentrique pour évaluer les résultats de la prise en charge endoscopique des TNE rectales initialement non métastatiques ≤2 cm.

Background: Diagnosis and management of poorly differentiated gastro-enteropancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC.Patients and methods: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded.Results: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE > 2 upper limit of normal [ULN]; HR = 3.2), CgA > 2 ULN (HR = 1.7) and lactate dehydrogenase > 2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72).Conclusions: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden. (C) 2017 Elsevier Ltd. All rights reserved.

Les tumeurs neuroendocrines (TNE) digestives sont un groupe de tumeurs rares mais dont l’incidence est en augmentation. L’analyse anatomopathologique est capitale pour établir le diagnostic et évaluer le grade tumoral qui repose sur la différentiation et l’indice de prolifération. Les TNE sont souvent diagnostiquées à un stade avancé du fait de l’apparition retardée de symptômes aspécifiques et peuvent être associées à une hypersécrétion hormonale. La chromogranine A est le principal marqueur biochimique des TNE. Le bilan d’extension repose sur l’imagerie conventionnelle (scanner, IRM) et l’imagerie isotopique dont la scintigraphie des récepteurs de la somatostatine qui sera probablement bientôt remplacée par la tomographie par émission de positons. Les principaux facteurs pronostiques incluent le stade tumoral, le volume métastatique, la différentiation histologique et l’indice de prolifération. Les deux urgences thérapeutiques sont les syndromes hormonaux et les tumeurs peu différenciées. Le traitement des TNE bien différenciées localisées repose sur la résection endoscopique ou chirurgicale en fonction de la localisation et des facteurs d’agressivité. Le traitement chirurgical est le seul traitement potentiellement curatif des formes métastatiques mais est rarement possible et est associé à une récidive quasi constante. Les traitements médicaux incluent les analogues de la somatostatine, la chimiothérapie systémique, la chimioembolisation intra-artérielle hépatique, les thérapies ciblées et la radiothérapie vectorisée interne. La stratégie thérapeutique repose sur la localisation de la tumeur primitive, l’agressivité tumorale, le volume métastatique et la présence de métastases extrahépatiques. Elle doit prendre en compte le risque de toxicité cumulée chez des patients dont la survie est souvent longue.Digestive neuroendocrine tumors (NETs) are a group of rare tumors with increasing incidence. Pathological analysis is critical to establish the diagnosis and evaluate tumor grade that relies on differentiation and proliferation index. NETs are mostly diagnosed at an advanced stage because of late occurrence of nonspecific symptoms, and can be associated with hormone hypersecretion. Chromogranin A is the main biochemical marker of NETs. Extension workup relies on conventional imaging (CT-scan, MRI) and isotopic imaging including somatostatin-receptor scintigraphy, which should be soon replaced by positron-emitting scintigraphy. The main prognostic factors include tumor stage, metastatic volume, histological differentiation and grade. Hormonal syndromes and poorly differentiated tumors are the two therapeutic emergencies. The treatment of localized well-differentiated tumors relies on endoscopic or surgical resection depending on the location and aggressiveness. Surgical removal is the only potentially curative treatment of metastatic NETs but is rarely feasible and is associated with almost constant relapse. Other antitumor therapies include somatostatin analogs, systemic chemotherapy, liver trans-arterial chemo-embolization, targeted therapies and peptide-receptor radionuclide therapy. Management strategy relies on primary tumor location, tumor aggressiveness, metastatic volume and the presence of extra-hepatic metastases. It must take into account the risk of cumulated toxicity in patients whose survival is often prolonged.

A staging system for cirrhosis has been recently proposed based on varices, ascites and bleeding (J Hepatol 2006;44: 217–31). We aimed at validating the concept of clinical stages for cirrhosis and assessing the role of hepatocellular carcinoma (hcc), encephalopathy (pse) and jaundice. A total of 1858 patients from prospective cohorts were included in the study at the seven participating centers. Survival analysis was performed by the Kaplan-Meier method by individual patient data. Predictive accuracy for 1-year mortality of Pugh score and MELD across stages was assessed by c-statistics. Etiology was from HBV 6%, HCV 35%, alcohol 41%, alcohol and HCV 11%, other 7%; mean age±sd was 56±23, male sex 62%. At diagnosis 667 patients had compensated (330 without and 337 with esophageal varices) and 1146 decompensated cirrhosis,608 with ascites, 248 portal hypertensive bleeding,and 290 ascites and bleeding. In a mean±sd follow-up of 73±79 months 996 patients died and 116 were transplanted.1- and 5-year survival was respectively 99% and 86% for compensated patients without and 96.5% and 72% with varices,85% and 78% for those with bleeding alone,74% and 46% with ascites and 70% and 33% with ascites and bleeding. While 1-year survival after hcc, pse and jaundice was respectively 55%,53% and 58%, they were the first decompensating event respectively in only 4.5%, 4.5% and 3%.Based on survival, five major clinical stages with significantly different outcomes were identified: 1 compensated, no varices, 2 compensated with varices, 3 bleeding, no ascites, 4 ascites (and/or hcc, pse, jaundice), 5 bleeding and ascites (±hcc, pse, jaundice). 1-year transition rate between stages and mortality from each stage is summarized in the figure. c-statistics for 1-year mortality for Pugh and MELD were respectively: 0.76 and 0.68 (p<0.00001). Corresponding values across stages were: 0.85 and 0.77, stage1; 0.66 and 0.48, stage2; 0.71 and 0.64 stage 3; 0.67 and 0.71, stage4; 0.73 and 0.69, stage 5.

POSTERSand liver enzymes including ALT determination using the newly introduced method at 37°C) (Ann Int Med 2002; 137: 1).In the whole population of blood donors, the median and 95 th percentile of ALT distribution were 29 U/L and 55 U/L in males, vs. 20 U/L and 33 U/L in females.In the population at low risk for liver disease (451 subjects), the corresponding values were 26 U/L and 42 U/L in males, vs. 19 U/L and 33 U/l in females. Conclusions:The introduction of the new standardized methods in clinical chemistry laboratories will has a significant impact on ALT measurement.Healthy ranges in our population was set at 42 U/L in males and 33 U/L in females, substantially higher than the limits so far recommended in the clinical setting.These results strongly underline the importance of multidisciplinary discussion when new laboratory methods are introduced.