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Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of seven cycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5 months (95% CI: 9.8-21.2) and was shorter in patients age 60 years (HR 2.56, 95% CI: 1.16-5.64), p = .020) and 1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p = .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p = .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

Background & Aims: Crohn's disease (CD) patients included in the Tailored Treatment With Infliximab for Active Crohn's Disease (TAILORIX) trial started infliximab in combination with an immunosuppressant for 1 year. The aim of the present study was to determine the long-term disease course beyond the study period. Methods: We compared the outcomes of patients who did or did not reach the primary end point of the TAILORIX trial, defined as sustained corticosteroid-free clinical remission from weeks 22 through 54, with no ulcers on ileocolonoscopy at week 54. The primary outcome of this follow-up study was the progression-free survival of CD defined by anal or major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. Results: The 95 patients (median disease duration, 4.5 mo; interquartile range, 1.0–56.6 mo) analyzed, including 45 (47%) who achieved the primary end point, were followed up for a median duration of 64.2 months (interquartile range, 57.6–69.9 mo) after the end of the study period. There was no significant difference in CD progression-free survival at 1, 3, and 5 years between patients who achieved the TAILORIX primary end point and patients who did not (P =.64). No difference was observed between both groups for each component of CD progression: anal surgery, major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. Conclusions: Achieving a sustained clinical remission off steroids with complete endoscopic remission in this cohort of 95 patients with early CD was not associated with less disease progression. Prospective trials to define the therapeutic goals that change the natural history of CD and prevent complications are needed.

International audience; Background Phase III trials have demonstrated the efficacy and safety of ustekinumab in ulcerative colitis (UC), but few real-life long-term data are currently available. Aims To assess the real-world effectiveness and safety of ustekinumab in patients with UC. Methods From January to September 2019, all consecutive patients with active UC treated with ustekinumab in a GETAID centre were included. Patients were evaluated at week 52. Remission was defined as a partial Mayo Clinic score

Introduction: Clinical presentations of small intestinal neuroendocrine neoplasms (SiNENs) can range from asymptomatic to life-threatening complications. Other than primary tumor(s), mesenteric mass (MM) can provide local tumor-related (LTR) symptoms. Although some expert centers propose routine primary resection to avoid complications in stage IV patients, some guidelines suggest avoiding primary tumor resection unless in the presence of symptoms. This study was aimed to identify factors associated with the presence or development of LTR symptoms. Methods: From 2012 to 2019, SiNEN patients with appropriate initial morphological imaging were included. All initial imaging was reviewed. Associations between factors and LTR symptoms were assessed by logistic regression. Results: Among 144 SiNEN patients, 66 met the inclusion criteria. Multivariate analysis identified on initial morphological imaging (i) any visible primary tumor (p < 0.01) and (ii) MM contact ≥180° with the superior mesenteric vessels (p ≤ 0.02), as independent factors associated with LTR symptoms in the whole study population as well as in the subgroup of primary resected patients. Among the 14 (21%) patients with both factors on initial cross-sectional conventional imaging, 12 (18%) were straightaway symptomatic at diagnosis and the remaining became symptomatic during the follow-up. All asymptomatic patients, without upfront surgery and without any predictive factor 16/18 (89%), stayed asymptomatic during the 2.7-year median follow-up. The absence of association between these 2 factors yielded a sensitivity of 100%, a specificity of 62%, and a negative predictive value of 100% for the occurrence of LTR symptoms. Conclusion: The presence of any visible primary tumor and/or MM superior mesenteric vessels contact ≥180° at initial cross-sectional imaging are 2 easily identifiable factors, which can help physicians for the decision-making regarding timing and type of surgery for SiNENs. Larger multicenter studies should endorse these results.

Bone metastases (BM) affect 10-30% of patients with small intestine neuroendocrine tumors (siNET), but little descriptive data are available regarding their distribution throughout the skeleton or potential risk factors. Aim of the study is to better describe the imaging characteristics, distribution, and risk factors of siNET bone metastases using 18F-FDOPA PET/CT.All patients with well-differentiated siNET who underwent an 18F-DOPA PET/CT examination in our institution were retrospectively screened between October 2017 and February 2020. Location, SUVmax and CT density of each BM were collected. Sex, metabolic tumor volume (MTV) excluding bone, and metastatic sites other than bone were studied to determine risk factors of BM.Among the 69 patients included, 11 patients (15.9%) presented BM on 18F-FDOPA (65 metastases). The most frequently involved sites were: thoracic spine, pelvic bones and ribs. About 64% of patients presented multiple BM. On coupled CT scan, 63% of BM were not visible. Using an optimal threshold of 19.2 ml, MTV was an independent predictor of BM (p = 0.004) with a derived sensitivity of 100% [65.0-100.0] and a specificity of 70.9% [57.7-81.2]. Hepatic metastatic involvement was also a significant predictor of BM (p = 0.044).The development of BM in siNETs appears to be a late event, occurring in patients with a high tumor burden and hepatic involvement. They are often multiple and predominate in the axial skeleton.

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 (ρ = 0.916; 0.897; 0.978, respectively, P 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.

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by inactivating mutations in the MEN1 gene. In the literature, few cases of MEN1 have been reported because of mosaic MEN1 mutations. Objective We performed an extensive molecular characterization in several lesions and blood samples, including plasmatic circulating cell-free DNA (ccfDNA) in an exceptional case of a patient with MEN1 mosaicism causing primary hyperparathyroidism, multiple pancreatic neuroendocrine tumors (NETs), and a metastatic thymic NET. Methods Blood, ccfDNA and multiple tissue analysis were performed by next-generation sequencing. Results MEN1 mosaicism was confirmed by multiple tissue analysis. Somatic analysis of the largest pancreatic NET revealed the same MEN1 second-hit mutation as found in the thymic lesion, demonstrating its metastatic origin from the thymic lesion. Moreover, in ccfDNA we found the mosaic MEN1 mutation but also the somatic second-hit mutation found in the thymic primary tumor, revealing the presence of circulating tumor DNA (ctDNA). After surgical removal of the pancreatic metastasis, the mutated fraction of both mutations decreased, before increasing again several weeks before a new clinical relapse, suggesting that thymic ctDNA may be used as an early tumor biomarker. Conclusion This exceptional MEN1 case highlighted (1) the importance of looking for MEN1 mosaicism, (2) that MEN1 mosaicism can cause very aggressive disease, and (3) the interest in analyzing ccfDNA for confirming MEN1 mosaicism but also as a potential tumor biomarker for NET.

MEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper, we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling.

Peritoneal carcinomatosis (PC) concerns up to 30% of patients with a neuroendocrine tumor (NET), especially of the small intestine. Aggressive management of carcinomatosis seems to be justified, especially with regard to possible mechanical complications. 18F-FDOPA PET/CT is known to be the most sensitive imaging modality for the detection of small bowel NET metastases, yet its performance in the detection of PC is not well studied. The main objective of our study is to evaluate the performances of preoperative 18F-FDOPA PET/CT in the prediction of surgical peritoneal cancer index.All patients referred to our center for an 18F-FDOPA PET/CT from October 2017 to January 2021 were retrospectively screened. Images were analyzed by a blinded nuclear medicine physician, and peritoneal abnormalities were reported to comply with the surgical peritoneal cancer index standard. Per patient analysis and per region analysis were then conducted.Thirty-three patients were included; 6 patients (35 regions) presented a peritoneal carcinosis. Peritoneal Carcinomatosis Index (PCI) estimated on 18F-FDOPA PET/CT was significantly and strongly correlated to surgical PCI (r = 0.96, P0.001). Patient-based sensitivity, specificity, negative predictive value, and positive predictive value for 18F-FDOPA PET/CT were 100%, 93%, 100%, and 75%, respectively. The agreement between 18F-FDOPA and surgery regarding PC was excellent (Cohen κ = 0.82 on per patient analysis, 0.74 on per region analysis).A preoperative estimation of PCI is achievable based on 18F-FDOPA PET/CT for small intestine NET and could allow to optimize surgical procedures and patient selection.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Background Although histological healing is raising interest in ulcerative colitis to predict recurrence, its meaning in Crohn’s disease (CD) remains unknown. We aimed to study the performances of different histological indices to predict recurrence of CD patients with mucosal healing. Methods Crohn’s disease patients with mucosal healing diagnosed between 2010 and 2018 were included if there was available clinical and endoscopical data. Nancy Histological index (NHI), Geboes score (GS), Robarts Histopathology index (RHI), Global Histological Disease Activity Score (GHAS), and Inflammatory Bowel Disease—Distribution Chronicity Activity score (IBD-DCA) were independently assessed by 3 pathologists. Results Eighty-eight patients were included, of which 28 relapsed (32%) within 30.5 months. All 4 histological indices were associated with recurrence, with significant relapse risk (NHI, odds ratio [OR], 1.67; GHAS, OR, 2.33; RHI, OR, 1.19; GS, OR, 2.09; and IBD-DCA, OR, 2.14). Microscopic activity was significantly associated with relapse only with the IBD-DCA score. Predicting performances of all these scores were poor. Calibration curves indicate that the GHAS and IBD-DCA are the closest to the ideal predicted probability curve and thus could better predict recurrence than the other scores. Interobserver agreement varied from poor for GHAS (k = .39) to good for RHI (k = .68). Conclusions Histological scores are valuable indicators to predict recurrence. Histological assessment of activity seems insufficient to predict CD course with most of the score evaluated, highlighting the need for new indices or adaptation of actual scores to CD specificities.

Introduction Streptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours. Methods A prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate. Results After screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (P = 0.0097). Altogether, 39 patients (35%) experienced grade 1–2 renal toxicity, while no grade 3−4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations. Conclusions Strongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 μg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:5 pages:947-+ ispartof: location:United States status: published

We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.

Introduction: Although chemotherapy combining 5-fluorouracil (5FU)-dacarbazine (DTIC) or temozolomide (TEM)-capecitabine (CAP) is extensively used in patients with neuroendocrine tumors (NET), they were never compared. We compared their tolerance and efficacy in advanced NET. Methods: We evaluated the records of consecutive patients with pancreatic or small-intestine advanced NET who received 5FU-DTIC or TEM-CAP between July 2004 and December 2017 in 5 French centers. Tolerance, tumor response and progression-free survival (PFS) were compared. Factors associated with PFS were analyzed using Cox multivariate regression model. To reduce the confounding bias of the nonrandomized design, PFS was compared using propensity score analyses. Results: Ninety-four (5FU-DTIC) patients and 153 (TEM-CAP) patients were included. Pancreatic NET represented 82.3% of cases and 17.1, 61.8 and 10.9% of patients had G1, G2 or G3 NET respectively. Progression at baseline was reported in 92.7% of patients with available data. Grades 3–4 adverse events occurred in 24.7 and 8.5% of TEM-CAP and 5FU-DTIC patients respectively (p = 0.002). The overall response rate was 38.3 and 39.2% respectively (p = 0.596). Median PFS on raw analysis was similar to 5FU-DTIC and TEM-CAP (13.9 vs. 18.3 months, respectively p = 0.86). TEM-CAP was associated with an increased risk of progression on the raw multivariate analysis (hazard ratio [HR] 1.90, 95% CI [1.32–2.73], p = 0.001) and when adjusted on propensity score (HR 1.65, 95% CI [1.18–2.31], p = 0.004). Conclusion: PFS may be longer with 5FU-DTIC than TEM-CAP in patients with advanced NET. Although patients often prefer oral chemotherapy, 5FU-DTIC is a relevant alternative. A randomized comparison is needed to confirm these results.

International audience; PURPOSE: To assess dimension measurement variability of liver metastases from neuroendocrine tumors (LMNET) on different magnetic resonance imaging (MRI) sequences.MATERIAL AND METHODS: In this institutional review board-approved retrospective study from January 2011 to December 2012, all liver MRI examinations performed at our department in patients with at least one measurable LMNET according to response evaluation criteria in solid tumors (RECIST1.1) were included. Up to two lesions were selected on T2-weighted MR images. Three reviewers independently measured long axes of 135 hepatic metastases in 30 patients (16 men, 14 women, mean age 61±11.4 (SD) years; range 28-78 years), during two separate reading sessions, on T2-weighted, diffusion-weighted MRI (DWI) (b; 50, 400, 800 s/mm2) and arterial, portal and late phases after intravenous administration of a gadolinium chelate. Intraclass-correlation coefficients and Bland-Altman plots were used to assess intra-and interobserver variability.RESULTS: Intra- and interobserver agreements ranged between 0.87-0.98, and 0.88-0.97, respectively. Intersequence agreements ranged between 0.92 [95%CI: 0.82-0.98] and 0.98 [95%CI: 0.93-0.99]. 95% limits of agreement for measurements were -10.2%,+8.9% for DWI (b=50s/mm2) versus -21.9%,+24.2% and -15.8,+17.2% for arterial and portal phases, respectively.CONCLUSION: An increase

Background Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated. Aim To evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients. Methods We performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery. Results Eighty-eight of the 122 (72%) CD patients beginning ustekinumab from March 2011 to December 2014, responded to ustekinumab and were followed up until November 2016. Median time on ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continued ustekinumab with a clinical response and 38 (43%) stopped treatment (32 for failure, five for remission and one for pregnancy). Endoscopic response was observed in 82% of patients with endoscopic evaluation and mucosal healing in 39%. Ustekinumab failure-free persistence rates were 78% at 12 months, 66% at 24 months and 55% at 36 months. No predictive factor of ustekinumab failure-free persistence was identified. One severe adverse event was observed (anal adenocarcinoma). Conclusion In this cohort of refractory CD patients receiving long-term ustekinumab therapy, more than 50% of patients continued ustekinumab treatment with no loss of response, intolerance or surgery and with a good safety profile.

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.

Background & Aims Vedolizumab is used to treat patients with ulcerative colitis (UC), although there is a delay before it is effective. Induction therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with vedolizumab as maintenance therapy could be an option for patients with an active steroid-refractory UC. We assessed the efficacy and safety of this combination. Methods We performed a retrospective observational study, collecting data from 12 referral centers in France that were included in the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif. We collected information on 39 patients with an active steroid-refractory UC (31 with active severe UC and 36 failed by treatment with a tumor necrosis factor antagonist) who received a calcineurin inhibitor as induction therapy along with vedolizumab as maintenance therapy. Inclusion date was the first vedolizumab infusion. The outcomes were survival without colectomy, survival without vedolizumab discontinuation, and safety. Results After a median follow-up period of 11 months, 11 patients (28%) underwent colectomy. At 12 months, 68% of the patients survived without colectomy (95% CI, 53%–84%) and 44% survived without vedolizumab discontinuation (95% CI, 27%–61%). No deaths occurred and 4 severe adverse events were observed. Conclusions In a retrospective analysis of 39 patients with an active steroid-refractory UC (most refractory to a tumor necrosis factor antagonist), we found that initial treatment with a calcineurin inhibitor in combination with vedolizumab allowed more than two thirds of patients to avoid colectomy. Further studies are needed to assess the safety of this strategy.

Background Inflammatory bowel diseases (IBD) have a high incidence in the female population of childbearing age. Ustekinumab (UST) and vedolizumab (VDZ) are used in IBD after failure of immunosuppressants and//or anti-TNF therapy. Data on the use and safety of these novel biologics in pregnancy are rare. Methods We conducted a retrospective cohort study in the GETAID and identified female IBD patients who received at least one injection of UST or VDZ during pregnancy or within the 2 months before conception. The aims of the study were to assess the maternal and neonatal complications in these patients and to assess the management of VDZ or UST during pregnancy. Results Seventy-three pregnancies in 68 patients were reported in 21 centres. The median time between UST or VDZ introduction and pregnancy was 11.8 months (IQR: 5.2–17.6) and 10 months (IQR: 5.7–19.5), respectively. Twenty-nine pregnancies occurred in 27 patients on UST resulting in 26 (90%) live births, two (7%) spontaneous abortions, and one (3%) elective termination. Maternal complications were reported in two patients (gestational diabetes and threat of preterm birth). Five (19%) neonatal complications were reported (3 preterm deliveries, one low birth weight and one cardiac malformation). Six (21%) patients received UST in the 2 months before conception and stopped UST with a relapse in one patient (17%). UST was maintained during pregnancy in 22 (79%) patients: 13 patients discontinued UST in the first trimester with a relapse in 4 (31%) patients and 9 patients maintained UST during all pregnancy with a relapse in 3 (33%) patients. Forty-four pregnancies occurred under VDZ resulting in 38 (86%) live births, 5 (11%) spontaneous abortions and one (3%) medical interruption. Maternal complications were reported in 5 women (4 pre-eclampsia and one pregnancy cholestasis). Fourteen (37%) neonatal complications were reported: 7 (18%) premature births, 6 (16%) low birth weights and one (3%) congenital corpus callosum hypoplasia. Fifteen (34%) patients received VDZ in the 2 months before conception and discontinued VDZ with a relapse in 8 (53%) patients. VDZ was maintained during pregnancy in 29 (66%) patients: 16 patients discontinued VDZ in the 1st trimester with a relapse in 8 (50%) patients and 13 patients maintained VDZ during all the pregnancy with a relapse in one (8%) patient. Conclusion We reported 73 pregnancies under VDZ or UST. Except one cardiac malformation on UST and one congenital corpus callosum hypoplasia on VDZ, no serious neonatal or maternal complications were observed. However, additional prospective evaluations regarding pregnancy outcomes with new biologics are needed.

Anti-tumor necrosis factor (TNF)-α agents may induce skin reactions, in particular in patients with inflammatory bowel diseases (IBD). The objective of this study was to determine the efficacy of ustekinumab in these patients. IBD patients facing therapeutic issues because of cutaneous reactions or tolerance issues, consequently treated with ustekinumab in our department, were included. Retrospective review of case records and clinical photographs was carried out. Twenty-six patients were included. Twenty-three patients were treated for Crohn's disease and three for ulcerative colitis. Fourteen patients presented psoriasiform lesions, nine eczematiform lesions, four anaphylactoid reactions, two alopecia areata-like lesions, one injection-site reaction, one cutaneous polyarteritis nodosa and five other skin reactions. Most of them resolved under ustekinumab. In detail, eczematiform lesions completely resolved in all cases, psoriasiform lesions completely resolved in 12 cases (85.7%) and had partial response in two cases (14.3%). Two cases of alopecia areata showed complete response (complete hair regrowth). Fourteen patients showed complete digestive response, 10 patients partial digestive response (seven of which needed IBD treatment optimization) and only two failure. In conclusion, ustekinumab is a drug of choice in patients with IBD who cannot tolerate TNF blockers.

BACKGROUND & AIMS: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. METHODS: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index

Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, with an increasing incidence and good overall prognosis. Although recent guidelines have been published, endoscopic techniques have expanded substantially and the most recent reports should be taken into account for clinical practice. The objectives of this report were to review the latest advances on prognosis, pre-interventional explorations, treatment – with particular focus on endoscopy – and surveillance of well-differentiated rectal NETs, excluding poorly differentiated and metastatic tumors.

ObjectiveThe efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohn's disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success.DesignWe performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort.ResultsFrom January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion.ConclusionsA successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation.Clinical Trial registration numberNCT01183403; Results.

Background Familial small-intestine neuroendocrine tumors (SI-NETs) are an exceptional inherited entity. Underlying predisposing mechanisms are unelucidated, but inositol polyphosphate multikinase ( IPMK ) gene alterations might promote their tumorigenesis. Methods A retrospective-prospective nationwide cohort was constituted, by including patients with proven SI-NETs and at least one relative with the same disease. We performed constitutional and somatic IPMK sequencing, and somatic DNA comparative genomic hybridization (CGH). Results We included 17 patients from 8 families, who were characterized by high prevalence (57%) of multiple SI-NETs, and high frequency of distant metastases (82%) and carcinoid syndrome (65%). No IPMK mutation was found in constitutional or tumor DNA. CGH array revealed recurrent chromosome-18 deletions but no alteration in the IPMK region. Conclusion We report here the first European series of patients with familial SI-NETs. Predisposing mechanisms may not involve the IPMK -encoding sequence or chromosomal region and might not differ from those of sporadic SI-NETs.

Herpes simplex virus 1 (HSV-1) esophagitis diagnosis is routinely based on the endoscopic findings confirmed by histopathological examination of the esophagitis lesions. Virological diagnosis is not systematically performed and restricted to viral culture or to qualitative PCR assay from esophagitis biopsy specimens. The aim of this study was to assess the interest of quantitative real-time PCR assay in HSV-1 esophagitis diagnosis by comparing the results obtained to those of histological examination associated with immunohistochemical staining, which is considered the “gold standard.” From 53 esophagitis biopsy specimens, the PCR assay detected HSV-1 in 18 of 19 histologically proven to have herpetic esophagitis and in 9 of 34 that had esophagitis related to other causes, demonstrating sensitivity, specificity, positive predictive value, and negative predictive value of 94.7%, 73%, 66.7%, and 96%, respectively. Interestingly, HSV-1 was not detected in 16 specimens without the histological aspect of esophagitis. The viral loads normalized per μg of total extracted DNA in each biopsy specimen detected positive by HSV PCR were then compared and appeared to be significantly higher in histopathologically positive herpetic esophagitis (median = 2.9 × 10 6 ± 1.1 × 10 8 ) than in histopathologically negative herpetic esophagitis (median = 3.1 × 10 3 ± 6.2 × 10 3 ) ( P = 0.0009). Moreover, a receiver operating characteristics analysis revealed that a viral load threshold greater than 2.5 × 10 4 copies would allow an HSV-1 esophagitis diagnosis with a sensitivity and specificity of 83.3% and 100%, respectively. In conclusion, this work demonstrated that HSV quantitative PCR results for paraffin-embedded esophageal tissue was well correlated to histopathological findings for an HSV-1 esophagitis diagnosis and could be diagnostic through viral load assessment when histopathological results are missing or uncertain.

VIPomas are rare-functioning neuroendocrine tumors (NETs). Overproduction of vasointestinal peptide (VIP) leads to the Verner–Morrison syndrome, whose management is challenging when refractory to somatostatin analogs. Two patients with progressive metastatic pancreatic NETs and refractory VIPoma symptoms were treated with sunitinib. This led to fast and sustained total relief of VIPoma symptoms, enabling earlier discharge from hospital and improvement in their quality of life. In both cases, sunitinib discontinuation led to the quick recurrence of watery diarrhea, which resolved within a few days after reintroducing sunitinib. The anti-secretory effect of sunitinib on VIPoma syndrome was probably not related to any anti-tumor effect. These observations agree with the rare reported cases of anti-secretory effects with targeted therapies. The sunitinib-driven inhibition of multiple-tyrosine kinase receptors might act on secretory pathways and describe sunitinib's ability to improve VIPoma symptoms. Sunitinib could be a therapeutic option to control refractory VIPoma symptoms in patients with NETs.

Although numerous reports have described inflammatory bowel diseases (IBDs) complicated with cytomegalovirus (CMV) infection, the virus participation as an exacerbating factor remains unclear. The aim of this study was thus to clarify the clinical significance of CMV infection complicating exacerbation and to correlate CMV detection with various characteristics in IBD patients. Sixty-seven colonic biopsies obtained from 53 patients admitted for IBD exacerbation were retrospectively analyzed by real-time PCR assay. The CMV genome was detected in seven (10.4%) colonic biopsies related to seven patients (three ulcerative colitis and four Crohn's diseases). Among the patients with IBD studied, patients with evidence of CMV infection were older (P = &ethinsp;0.047), were more likely male gender (relative risk [RR] 4.48; 95% confidence interval [CI] 0.94–21.36), received corticosteroids (RR 3.2; CI 0.79–13.02) or azathioprine (RR 3.17; CI 0.80–12.57) treatments, presented more extended lesions (RR for rectum-sigmoid-left colon 3.75 (0.0–69.37) and for pancolitis 2.45 (0.36–16.23)), and had a more severe disease (RR 3.3; CI 0.87–12.48) than those without CMV infection. Viral loads measured in the colonic mucosa of infected patient ranged from 5 to 236961 genome copies by microgram of total extracted DNA. No relationship was observed between the severity of the disease and the viral load level. Furthermore, CMV disappeared in five infected IBD patients in remission without antiviral agents. In conclusion, these results showed infrequent CMV detection in colonic biopsies of IBD patients during exacerbation leaving open the question of the relationship between CMV reactivation and the onset or the severity of IBD exacerbation. J. Med. Virol. 82:1694–1700, 2010. © 2010 Wiley-Liss, Inc.

International audience; Background & Aims Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. Methods We performed a retrospective observational study, collecting data from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. Results Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14–25.77; P=.03). Over a median follow-up period of 9.8 months (inter-quartile range, 5.3–14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of ustekinumab were 93% and 68%, respectively. Conclusions Almost two thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from ustekinumab therapy, not requiring steroids for up to 12 months afterward. While we await results from ongoing trials, ustekinumab can be considered for use in these patients.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1: 1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score 1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore 1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)-a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1% P =.15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2% P =.04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group-a difference of 9.5% (95% CI: -7.5% to 26.5% P =.28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7% P =.03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9% P =.006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

International audience; Background & aims - Phase 3 trials have shown the efficacy of vedolizumab, which binds to integrin α4β7, in patients with Crohn's disease (CD) or ulcerative colitis (UC). We investigated the effectiveness and safety of vedolizumab in patients who failed anti-tumor necrosis factor therapy. Methods - From June through December 2014, there were 173 patients with CD and 121 patients with UC who were included in a multicenter nominative compassionate early access program granted by French regulatory agencies. This program provided patients with access to vedolizumab before it was authorized for marketing. Vedolizumab (300 mg) was administered intravenously at weeks 0, 2, and 6, and then every 8 weeks. Disease activity was assessed using the Harvey-Bradshaw Index for CD and the partial Mayo Clinic score for UC. We report results obtained after the 14-week induction phase. Results - Among the 294 patients treated with vedolizumab (mean age, 39.5 ± 14.0 y; mean disease duration, 10.8 ± 7.6 y; concomitant steroids, 44% of cases), 276 completed the induction period, however, 18 discontinued vedolizumab because of a lack of response (n = 14), infusion-related reaction (n = 2), or infections (n = 2). At week 14, 31% of patients with CD were in steroid-free clinical remission and 51% had a response; among patients with UC, 36% were in steroid-free clinical remission and 50% had a response. No deaths were reported. Severe adverse events occurred in 24 patients (8.2%), including 15 (5.1%) that led to vedolizumab discontinuation (1 case of pulmonary tuberculosis and 1 rectal adenocarcinoma). Conclusions - In a cohort of patients with CD or UC who failed previous anti-tumor necrosis factor therapy, approximately one third of patients achieved steroid-free clinical remission after 14 weeks of induction therapy with vedolizumab. This agent had an acceptable safety profile in these patients.

Background: Computed tomography scan is the current standard cross-sectional imaging modality for neuroendocrine tumor (NET) workup. Diffusion-weighted magnetic resonance imaging (DW-MRI) has proven to be more sensitive than standard sequences to diagnose liver metastases; whole-body DW-MRI may be more sensitive than whole-body MRI. Clinical implications have not yet been assessed. Thus, we evaluated radiological and clinical contributions of liver and whole-body DW-MRI to manage NETs. Methods: Twenty-five abnormal liver and 22 abnormal whole-body standard MRIs were first analyzed retrospectively. MR images were then reanalyzed after adding DW sequences. The standard of reference for metastasis confirmation was a combination of radiological follow-up and histological proof. Clinical impact was defined as MRI changes of liver invasion (unilobar to bilobar and/or 50% of liver) or therapeutic management changes made during a dedicated multidisciplinary meeting after whole-body MRI. Results: Thirty-two patients with mainly small intestine NETs (24/32) were studied. Adding DW to standard liver MRI yielded additional findings for 45% of the patients with 1.78 times more new lesions, mainly infracentimetric; it induced a management change for 18% of the patients. DW sequences added to whole-body MRI yielded additional findings for 71% of the patients, with 1.72 times more lesions, mainly infracentimetric, and induced a change in management for 19% of the patients. Conclusion: Adding DW sequences to standard MRI revealed additional metastases and led to modifications of patient management. Prospective studies are needed to confirm these results.

Background In gastric MALT lymphomas persisting after Helicobacter pylori ( H. pylori ) eradication, a treatment by moderate-dose radiotherapy (RT) has been proposed but its efficacy has not been confirmed in large prospective series with long term endoscopic follow-up. Method Patients with localised gastric MALT lymphoma persisting after H. pylori eradication were offered moderate-dose RT (30Gy, 2Gy/fraction) and followed with annual endoscopies. All biopsies before and after RT were reviewed by a committee of pathologists. Results From 1995 to 2011, out of the 232 patients followed prospectively, 53 received RT for persistence of lymphoma after H. pylori eradication: either macroscopic ulcer ( n =31), or microscopic lymphomatous infiltrate ( n =22), after a mean follow-up of 12 and 31months, respectively. All lymphomas were localised (45 stage IE and 8 stage IIE) and 38 (72%) were H. pylori -positive. The mean clinical and endoscopic follow-up from diagnosis was 7.6years (2.2–19.1). No acute or late toxicity occurred. A complete remission was achieved in all patients but one (98%) with no relapse after a median follow-up of 4.9years (1.3–16.6) after completion of RT. Overall survival and 5-year disease specific survival were 94% and 100%, respectively. One patient died of gastric adenocarcinoma. Conclusion Moderate-dose RT (30Gy) is effective and safe for localised gastric MALT lymphoma persisting after H. pylori eradication.

Background Pancreatic neuroendocrine tumors (PNETs) may evolve and cause hormonal hypersecretion-related symptoms that were not present at the initial diagnosis, termed metachronous hormonal syndromes (MHSs). Their setting, characteristics, and outcomes are not well-described. Objective To describe MHSs in patients with sporadic PNETs. Design Retrospective, multicenter study. Setting 4 French referral centers. Patients Patients with PNETs who developed MHSs related to hypersecretion of insulin, gastrin, vasoactive intestinal peptide, or glucagon between January 2009 and January 2014. Measurements Tumor extension, biological markers, and treatments at initial PNET diagnosis and MHS onset. Pathologic specimens were evaluated centrally, including Ki-67 index and hormone immunolabeling. Results Of 435 patients with PNETs, 15 (3.4%) were identified as having MHSs involving the hypersecretion of insulin (5 patients), vasoactive intestinal peptide (5 patients), gastrin (2 patients), or glucagon (4 patients). Metachronous hormonal syndromes developed after a median of 55 months (range, 7 to 219) and in the context of PNET progression, stability, and tumor response in 8, 6, and 1 patients, respectively. The median Ki-67 index was 7% (range, 1% to 19%) at PNET diagnosis and 17.5% (range, 2.0% to 70.0%) at MHS onset. Immunolabeling of MHS-related peptides was retrospectively found in 8 of 14 of pathologic PNET specimens obtained before MHS diagnosis. Median survival after MHS onset was 28 months (range, 3 to 56). Seven patients with MHSs died during follow-up, all due to PNETs, including 4 patients with insulin-related MHSs. Limitation Retrospective data collection and heterogeneity of pathologic specimen size and origin. Conclusion Metachronous hormonal syndromes were identified more often in the context of PNET progression and increased Ki-67 indices. Patients with insulin-related MHSs may have decreased survival rates. Primary funding source None.

Introduction: In patients with small intestinal neuroendocrine tumors (siNETs), surgical resection of the primary tumor and associated mesenteric lymph nodes (LNs) is recommended, but is not well standardized and can be risky in patients with superior mesenteric vessel involvement. Objective: We aimed to evaluate the correlation between the length of resected small bowel and the number of removed LNs, and to propose a preoperative morphological classification of siNET-associated LNs. Methods: The records of patients operated on for siNETs at two expert centers between August 2005 and November 2013 were analyzed. Two specialist radiologists reviewed the preoperative imaging and classified mesenteric LNs into five stages according to their proximity to the trunk and/or branches of the superior mesenteric artery. Results: 72 patients were included. The mean number of removed LNs was 12 ± 15 and the length of removed small intestine was 53 ± 43 cm. No correlation existed between the length of small bowel resection and the number of removed LNs. Overall, 9 (12%), 13 (18%), 36 (50%), 14 (19%) and 0 patients were classified into LN stages 0, I, II, III and IV. The correlation rate between the two observers was 0.98. Patients with LN stage III (hardly resectable) had more removed LNs than those with LN stages 0, I or II (easily removable). Conclusion: Optimal lymphadenectomy is not always associated with extended small bowel resection. In the era of small bowel-sparing surgery, the preoperative classification of mesenteric LNs could help to standardize the surgical management of patients with siNETs.

Well-differentiated digestive neuroendocrine tumors (NET) are a heterogeneous group of neoplasms usually associated with slow growth but a high rate of metastases, including peritoneal carcinomatosis (PC). Herein, we aimed to comprehensively review the current knowledge of PC in terms of implications for the management and prognosis of patients with NET, including the latest studies and expert statements. NET-derived PC concerns about 17% of NET patients and up to 30% of those with small intestine primary NET. It has an independent pejorative prognostic impact. The extent of PC in NET patients and its severity can be expressed by analogy to other malignancies. However, it must be placed in the context of NET disorders, which usually vary from other PC-related malignancies. Recently, a gravity PC score was proposed by a consensus European Neuroendocrine Tumor Society (ENETS) expert group, but it requires validation. In addition, the form of peritoneal involvement (nodular or fusiform/infiltrative) might influence its prognosis and management. Aggressive surgical management seems justified for subsets of NET-related PC but requires careful selection of the candidates most likely to benefit. Cytoreductive surgery prolongs survival, especially when the peritoneal lesions are completely resected. Too little is known about the benefit of hyperthermic intraperitoneal chemotherapy for NET-derived PC, but if it confers an advantage, it would have to be counterbalanced by its high morbidity.

Well-differentiated neuroendocrine tumors (NETs) are a group of heterogeneous rare tumors. They are often slow-growing and patients can have very long survival, even at the metastatic stage. The evaluation of tumor progression and therapeutic responses is currently based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria. As for other malignancies, RECIST criteria are being reexamined for NETs in the era of targeted therapies because tumor response to targeted therapies is rarely associated with shrinkage, as opposed to prolonged progression-free survival. Therefore, size-based criteria no longer seem to be suitable to the assessment of NET progression and therapeutic responses, especially considering targeted therapies. New imaging criteria, combining morphological and functional techniques, have proven relevant for other malignancies treated with targeted therapies. To date, such studies have rarely been conducted on NETs. Moreover, optimizing the management of NET patients also requires considering clinical, biological, and pathological aspects of tumor evolution. Our objectives herein were to comprehensively review current knowledge on the assessment of tumor progression and early prediction of therapeutic responses and to broaden the outlook on well-differentiated NETs, in the era of targeted therapies.

BACKGROUND AND AIM Only a limited number of studies have evaluated the small intestinal damage associated with chronic low-dose aspirin (LDA) therapy. We assessed, using capsule endoscopy, the prevalence and the characteristics of small bowel damage in chronic LDA users compared with patients taking an anticoagulant (AC) and those taking no antithrombotic drugs. PATIENTS AND METHODS We retrospectively reviewed 75 capsule endoscopy recordings from three groups of patients with unexplained iron-deficient anemia: 28 patients receiving LDA, 15 receiving an AC, and 32 not receiving any antithrombotic drug. The severity and location of small intestinal mucosal breaks were assessed in a blinded manner by two endoscopists. RESULTS All LDA users received uncoated aspirin. The number of small bowel mucosal breaks in patients receiving LDA (median 1, extremes 0-125) was significantly higher than that in those taking an AC (0, 0-1) (P=0.0005) or no antithrombotic drugs (0, 0-23) (P

BACKGROUND:: Inflammatory bowel disease (IBD) is associated with a high risk of deep venous thromboembolism. However, few data are available so far on portomesenteric vein thrombosis (PMVT). The aim of this study was to describe the characteristics of PMVT in patients with IBD. METHODS:: A retrospective study was conducted at 13 GETAID (Groupe d'Etude Therapeutique des Affections Inflammatoires du Tube Digestif) centers from January 1995 to June 2010. The following data were collected, using a standardized questionnaire: characteristics of IBD, disease status at the time of PMVT, PMVT characteristics and mode of discovery, concomitant prothrombotic disorders, anticoagulant therapy, and evolution of PMVT. RESULTS:: Fifty cases (29 men and 21 women; median age, 41 years) were identified, including 14 patients with ulcerative colitis and 36 with Crohn's disease. Thirty-one patients (62%) presented with acute PMVT. Twenty-four patients had previously undergone surgical treatment, and IBD was active in 23 cases (77%) of acute thrombosis. The discovery of PMVT was fortuitous in 40% of our cases. Among the 43 patients screened for a prothrombotic disorder, abnormalities were observed in 17 patients (40%) (mainly hyperhomocysteinemia, n = 12). Forty-four patients (88%) were treated with anticoagulants. Recanalization of the vein was significantly more successful in patients with acute thrombosis (65% versus 37%, P = 0.05). CONCLUSIONS:: PMVT can occur when IBD is inactive, and its diagnosis was fortuitous in 40% of our cases. Screening for prothrombotic disorders is essential because it is positive in more than one third of cases.

Background Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. Methods Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. Results 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn9s colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). Conclusions Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. Trial registration number IRB 001508, Paris 7 University.

OBJECTIVE: To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD). METHODS: This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score