Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study.

PURPOSE: Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice. PATIENTS AND METHODS: Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models. RESULTS: From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001). CONCLUSION: ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02502656.

Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability.

BACKGROUND: Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. AIMS: To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. METHODS: All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. RESULTS: One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. CONCLUSION: dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.

Chemotherapy use in end-of-life digestive cancer patients: a retrospective AGEO observational study.

BACKGROUND: The use of chemotherapy (CT) near the end-of-life (EOL) is an important issue in oncology since it could degrade quality of life. CT near EOL is still poorly studied, with no dedicated study in gastrointestinal (GI) cancer patients. AIM: To analyze in GI cancer patients the factors associated with the use of CT within 3- and 1-month before patients' death. METHODS AND PARTICIPANTS: All consecutive patients who died from a GI cancer in 10 French tertiary care hospitals during 2014 were included in this retrospective study. Clinical, demographical and biological data were collected and compared between patients receiving or not CT within 3- and 1-month before death. Variables associated with overall survival (OS) was also determined using of univariate and multivariate analyses with a Cox model. RESULTS: Four hundred and thirty-seven patients with a metastatic GI cancer were included in this study. Among them, 293 pts (67.0%) received CT within 3-months before death, and 121 pts (27.7%) received CT within 1-month before death. Patients receiving CT within 3-months before death were significantly younger (median age: 65.5 vs 72.8 years, p < 0.0001), with a better PS (PS 0 or 1: 53.9 vs 29.3%, p < 0.0001) and a higher albumin level (median: 32.8 vs 31.0 g/L, p = 0.048). Similar results were found for CT within 1 month before death. Palliative care team intervention was less frequent in patients who received CT in their last month of life (39.7% vs 51.3%, p = 0.02). In multivariate analysis, median OS from diagnosis was shorter in the group receiving CT within 1-month before death (HR = 0.59; 95% CI [0.48-0.74]). CONCLUSION: In GI-cancer patients, CT is administered within 3- and 1-month before death, in two and one third of patients, respectively. Patients receiving CT within 1-month before death, had more aggressive disease with poor OS. Palliative care team intervention was associated with less administration of CT in the last month of life. These results highlight the need to better anticipate the time to stop CT treatment in the end-of-life and the importance of an active collaboration between oncology and palliative care teams.

Prevalence and prognosis of microsatellite instability in oesogastric adenocarcinoma, NORDICAP 16-01.

BACKGROUND: The prevalence and prognosis association of microsatellite instability (MSI) in oesogastric junction and gastric adenocarcinoma (OGC) have been reported with conflicting results. METHODS: Patients with OGC from 2010 to 2015 were enrolled in this retrospective multicenter study. MSI was determined by genotyping. MLH1 promoter methylation and BRAFV600E mutation were screened in the MSI tumors. RESULTS: Among 315 tumors analyzed, 39 (12.4%) were of the MSI phenotype. Compared to MSS tumors, MSI tumors were more frequent in patients >70 years (17% vs 9%, p=0.048) and in gastric antral primary (20% versus 5% in junction tumor and 12% in fundus tumor. Among 29 MSI tumors analyzed, 28 had a loss of MLH1 protein expression and 27 had MLH1 promotor hypermethylation. None had a BRAF V600E mutation. The 4-year cumulative incidence of recurrence for patients with resected tumor was significantly lower in dMMR tumors versus pMMR tumors (17% versus 47%, p=0.01). For the patients with unresectable tumor the median overall survival was 11 months in MSS group and 14 months in MSI group (p=0.24). CONCLUSION: MSI prevalence in OGC was 12.4%, associated with antral localization and advanced age. Patients with MSI tumors had a lower cumulative incidence of recurrence after surgery. MSI phenotype was mainly associated with loss of MLH1 protein expression, MLH1 promotor hypermethylation and had no BRAFV600E mutation.

The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSé-Crizotinib Program.

BACKGROUND: The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas. OBJECTIVE: The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options. PATIENTS AND METHODS: MET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib. RESULTS: MET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5-70), the best overall response rate was 55.6% (95% CI 21.2-86.3), with median progression-free survival of 3.2 months (95% CI 1.0-5.4), and overall survival of 8.1 months (95% CI 1.7-24.6). Safety was consistent with that previously reported for crizotinib. CONCLUSIONS: Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation. TRIAL REGISTRATION NUMBER: NCT02034981. DATE OF REGISTRATION: 14 January 2014.

Characteristics of patients with overlap functional gastrointestinal disorders.

BACKGROUND AND AIM: Functional gastrointestinal disorders (FGIDs) are frequently overlapped. The present study was designed to (i) search the clinical differences between patients with single FGID and overlap FGIDs and (ii) define the most common FGIDs associations to identify homogenous subgroups of patients. METHODS: A total of 3555 outpatients with FGID filled out the Rome III adult diagnostic questionnaire, Bristol stool form, and four 10-point Likert scales to report the severity of constipation, diarrhea, bloating, and abdominal pain. An unsupervised algorithm was used to estimate the number of groups directly from the data. A classification tree separated patients into different subgroups, according to FGIDs. Multinomial logistic regression was used to characterize the groups of patients with overlap disorders. RESULTS: Patients reported 3.3 ± 1.9 FGIDs (range 1-10, median = 3); 736 reported only one FGID, while 2819 reported more than one FGID (3.8 ± 1.7). Patients with single FGID had higher body mass index (P < 0.001), never report irritable bowel syndrome (IBS), and rarely report fecal incontinence and anorectal pain (< 1% for each disorder). The non-supervised clustering of the 2819 patients with overlap FGIDs divided this population into 23 groups, including five groups associated with only one disorder (IBS-diarrhea, dysphagia, functional constipation, levator ani syndrome, and IBS-unspecified). Ten groups were related to two overlap disorders and eight groups to three or more disorders. Three disorders were not explicitly associated with a given group: IBS-mixed, proctalgia fugax, and nonspecific anorectal pain. CONCLUSION: Patients with FGID mostly report overlap disorders in a limited number of associations, each significantly associated with a few disorders.

Psychological profiles of irritable bowel syndrome patients with different phenotypes.

BACKGROUND/AIMS: Abnormal psychological profiles are frequently found in patients with functional gastrointestinal disorders (FGIDs). The present study aimed to evaluate the psychological profiles of FGID patients with irritable bowel syndrome (IBS), and IBS phenotypes. METHODS: In 608 FGID patients, including 235 with IBS, have filled a Rome III questionnaire and the French version of the Minnesota Multiphasic Personality Inventory 2. Data analysis was performed using univariate analysis and multivariate logistic regression. RESULTS: This study shows that IBS patients have abnormal psychological profiles with more significant symptom exaggeration and decreased test defensiveness than non-IBS patients. They have a significantly higher score for all clinical scales. Logistic regression analysis showed in IBS patients a decrease of body mass index (P= 0.002), and test defensiveness score K (P= 0.001) and an increase of Hypochondriasis (P< 0.001) and Masculinity-Femininity scale (P= 0.018). By comparison with non-IBS patients, IBS-constipation, IBS-diarrhea, and mixed IBS patients have increased Hypochondriasis value and Depression score, mixed IBS patients have higher Psychasthenia score and higher Hypomania score. No item was significantly different in the IBS-unspecified group. CONCLUSIONS: This study shows that IBS patients have different psychological profiles than other FGID patients and that psychological characteristics are associated with IBS phenotypes except for patients with unsubtyped IBS.

Aflibercept in Combination With FOLFIRI as First-line Chemotherapy in Patients With Metastatic Colorectal Cancer (mCRC): A Phase II Study (FFCD 1302).

BACKGROUND: FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line. PATIENTS AND METHODS: Patients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H0: 55% and H1= 75%. Data were analyzed in intention to treat. RESULTS: Forty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification. CONCLUSION: Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.

Effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS-Lynch): study protocol for a multicenter, double-blind, placebo-controlled randomized controlled trial.

Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20-25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial-a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial-was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT02813824 . Registered on 27 June 2016. The trial was prospectively registered.

Clinical, Physiological, and Psychological Correlates of the Improvement of Defecation during Menses in Women with Functional Gastrointestinal Disorders.

BACKGROUND/AIMS: Little is known about the improvement in defecation frequently reported by women around menses. We aimed to describe clinical, physiological, and psychological correlates of this improvement in those with functional bowel disorders. PATIENTS AND METHODS: We recruited 478 consecutive premenopausal adult females with no indication of gynecologic or psychiatric disease, who were attending an outpatient functional bowel disorders clinic. Patients completed a Rome III questionnaire, psychological evaluation stool form, and a 10-point Likert scale for constipation, diarrhea, bloating, and abdominal pain. These patients underwent physiological tests, anorectal manometry, and colonic transit time and were classified according to the presence or the absence of improvement in defecation during menses. The reverse selection procedure was used for model selection during multivariate logistic regression where statistically significant variables (p < 0.01) remained in the adjusted model. RESULTS: Ninety-seven patients (20%) reported easier defecation during menstruation. These patients were younger (p < 0.001) but had similar body mass indices and psychological profiles as the other patients. Clinically, they only reported more frequent irritable bowel syndrome (IBS) with constipation (p = 0.007), with harder stools (p = 0.005) and delayed left colon transit time (p = 0.002). No anorectal manometric parameter was different between the 2 groups. CONCLUSION: Improvement of constipation during menses is mainly associated with younger age and constipation-IBS phenotype and not with functional constipation.

BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study.

In patients with metastatic colorectal cancer (mCRC), RAS and BRAF mutations are currently determined by tumor sample analysis. Here, we report BRAF mutation status analysis in paired tumor tissue and plasma samples of mCRC patients included in the AGEO RASANC prospective cohort study. Four hundred and twenty-five patients were enrolled. Plasma samples were analyzed by next-generation sequencing (NGS). When no mutation was identified, we used two methylated specific biomarkers (digital droplet PCR) to determine the presence or absence of circulating tumor DNA (ctDNA). Patients with conclusive ctDNA results were defined as those with at least one mutation or one methylated biomarker. The kappa coefficient and accuracy were 0.79 (95% CI: 0.67-0.91) and 97.3% (95% CI: 95.2-98.6%) between the BRAF status in plasma and tissue for patients with available paired samples (n = 405), and 0.89 (95% CI: 0.80-0.99) and 98.5% (95% CI: 96.4-99.5%) for those with conclusive ctDNA (n = 323). The absence of liver metastasis was the main factor associated to inconclusive ctDNA results. In patients with liver metastasis, the kappa coefficient was 0.91 (95% CI, 0.81-1.00) and accuracy was 98.6% (95% CI, 96.5-99.6%). We demonstrate satisfying concordance between tissue and plasma BRAF mutation detection, especially in patients with liver metastasis, arguing for plasma ctDNA testing for routine BRAF mutation analysis in these patients.

Clinical and psychological characteristics of patients with globus.

BACKGROUND/AIMS: Psychological factors are involved in many functional gastrointestinal disorders including globus. The aim of the present study was to assess the clinical and psychological correlates associated with globus. PATIENTS AND METHODS: 707 patients (69% female, 45.2 ± 16.5 years, BMI 27.2 ± 11.7 kg/m2) filled an MMPI-2 questionnaire and a standard Rome III clinical questionnaire and were included in this cross sectional study. Data analysis was performed using a univariate analysis and a multivariate logistic regression with a backwards selection procedure on significant scales after a univariate analysis. RESULTS: 140 patients (20%) reported suffering from globus. Globus appeared to be associated with older age (P = 0.001; OR = 1.022; 95% CI = [1.009-1.035]), increased BMI (P = 0.007; OR = 1.029; 95% CI = [1.008-1.051]), higher prevalence of regurgitations (P = 0.008; OR = 2.189; 95% CI = [1.228-3.902]), heartburn (P = 0.001 OR = 2.227; 95% CI = [1.406-3.530]), dysphagia (P < 0.001; OR = 2.399; 95% CI = [1.500-3.837]), epigastric pain (P < 0.001; OR = 3.768; 95% CI = [1.880-7.552]) and nonspecific dyspepsia (P = 0.018; OR = 1.786; 95% CI = [1.106-2.881]), and a higher score of hysteria (P = 0.008 OR = 1.034; 95% CI = [1.009-1.059]). By comparison with patients who reported globus and scores of hysteria in the normal range (n = 73), patients complaining of globus associated with high scores of hysteria (n = 67) have high scores of hypochondriasis (P < 0.001; OR = 1.235; 95% CI = [1.142-1.336]), high levels of Psychopathic deviate (P = 0.005; OR = 1.091; 95% CI = [1.026-1.161]) and a higher, but not significant, prevalence of complaints of regurgitation (P = 0.052; OR = 4.022; 95% CI = [0.989-16.351]). CONCLUSION: Approximately 50% of the patients complaining of globus have a high score of hysteria associated with other personality disorders, and complain more frequently of regurgitation than other patients complaining of globus. These results tend to confirm that globus has a strong, although not systematic, connections with some specific personality disorders.

Invitation letter with a standardized form is a reliable tool to exclude increased risk patients from organized fecal immunological testing-based colorectal cancer screening program.

In Europe, screening guidelines for colorectal cancer (CRC) recommend colonoscopy for high-risk patients and fecal immunological testing (FIT) for the standard-risk group. Currently, there is not any validated screening tool to exclude high-risk patients. The aim of the study is to evaluate the validity of exclusion and evaluate the follow-up of patients identified as increased risk for CRC. In this retrospective study using a prospective database, patients at increased risk were identified using the standardized form and then excluded from the FIT screening invitation. A specific questionnaire was sent to all patients at increased risk in order to confirm the reason for the exclusion and evaluate their follow-up. Among 220 695 eligible individuals, 16 693 (7.5%) were excluded after being characterized at increased risk using the standardized form. The questionnaire was sent to these 16.693 excluded patients and completed by 5076 (30.7%) patients. Validity of exclusion was confirmed in 92% of cases. Endoscopic follow-up was in agreement with guideline in 89% of persons at increased risk (inflammatory bowel disease 93%, personal history of CCR 92%, of colonic polyps 82%, family history of CRC 77%). This study suggests that the standardized form is a reliable tool to correctly exclude from the screening program 92% of patients at increased risk for CRC.

Painful or Mild-Pain Constipation? A Clinically Useful Alternative to Classification as Irritable Bowel Syndrome with Constipation Versus Functional Constipation.

PURPOSE: Abdominal pain is not used to characterize constipated patients. This study aimed to compare clinical, psychological, and physiological features in patients with IBS-constipation (IBS-C) with those in patients with functional constipation (FC) according to the intensity of abdominal pain. METHODS: All patients filled a standard Rome III questionnaire. In addition, they indicated the intensity of constipation, diarrhea, bloating, and abdominal pain on a 10-point Likert scale, and their stool form with the Bristol Stool Form Scale. Anxiety and depression were assessed with the Beck Depression Inventory and the State-Trait Anxiety Inventory. Physiological evaluation included anorectal manometry and total and segmental colonic transit time. MAIN RESULTS: A total of 546 consecutive patients, 245 with IBS-C and 301 with FC, were included. Painful constipation (PFC) was found by cluster analysis and subsequently defined as having a value over four on the Likert scale for abdominal pain. PFC was found in 67% of IBS-C patients and in 22% of FC patients. PFC patients have digestive disorders with greater frequency and report higher levels of constipation and bloating, despite similar stool form. They have higher scores of depression, state and trait anxiety, and shorter terminal transit time than mild-pain constipated patients. Compared to IBS-C patients, PFC patients report higher levels of abdominal pain (P < 0.001). Psychological and physiological parameters were similar in PFC and IBS-C patients. CONCLUSION: Painful constipation and mild-pain constipation could be an alternative way to identify constipated patients than using the diagnosis of IBS-C and FC for clinical evaluation and drug studies.

Sleep quality and functional gastrointestinal disorders. A psychological issue.

OBJECTIVE: Sleep disorders are often associated with functional gastrointestinal disorders (FGIDs). This study aims to evaluate the association of sleep disorders with specific FGIDs and to assess the related importance of psychological disorders. METHODS: We included 1009 consecutive patients with FGIDs (70.9% females). The patients completed a Rome III questionnaire and after a psychological evaluation on anxiety and depression they were classified according to their sleep disorders using a 7-point grading scale: Groups 1-3, drowsiness (severe, moderate, mild); Group 4, no change; Groups 5-7, insomnia (mild, moderate, severe). Multinomial logistic regression using sleep group as a dependent variable with no sleep change as reference and body mass index, FGIDs, anxiety and depression as independent variables were used for statistical analysis. RESULTS: Altogether 667 (66.1%) patients reported changes in sleep disorders, of whom 487 (48.3%) had decreased sleep and 180 (17.8%) had increased sleep while 342 (33.9%) reported no change. Depression was lower in patients with no change in sleep pattern and increased with the severity of their sleep disorder (P < 0.001). State-anxiety is associated with moderate drowsiness (P = 0.024), while trait anxiety is associated with mild insomnia (P = 0.048). FGIDs associated with sleep disorders included chest pain, epigastric pain syndrome, irritable bowel syndrome with constipation, diarrhea, bloating, fecal incontinence and proctalgia fugax. CONCLUSION: Sleep disorders are associated with FGIDs, especially in the presence of depressive symptoms.

Metabolic markers of protein maldigestion after a 15N test meal in minipigs with pancreatic exocrine insufficiency.

The effect of pancreatic exocrine insufficiency (PEI) on protein malabsorption is little documented, partly due to methodological barriers. We aimed to validate biomarkers of protein malabsorption using a 15N test meal in a minipig model of PEI. Six pancreatic duct-ligated minipigs were used as a model of PEI and four nonoperated animals as a control. All animals were equipped with an ileocecal reentrant cannula. Minipigs were given a test meal containing [15N]casein. The PEI animals repeated the test three times, in the absence of any pancreatic enzymes, or after pancreatic substitution at two levels [ A or B: 7,500 or 75,000 (lipase) and 388 or 3881 (protease) FIP U]. Ileal chyme, urine, and blood were collected postprandially. Nitrogen and 15N were measured in digestive and metabolic pools. We obtained a gradient of ileal protein digestibility from 29 ± 11% in PEI to 89 ± 6% in the controls and a dose- dependent response of enzymes. Insulin and gastric inhibitory polypeptide secretions were decreased by PEI, an effect that was counteracted with the enzymes at level B. The total recovery of 15N in urinary urea and plasma proteins was 14 ± 5.1% in the control group and decreased to 5.5 ± 2.1% by PEI. It was dose dependently restored by the treatment. Both 15N recovery in plasma and urine were correlated to protein digestibility. We confirm that the 15N transfer in those pools is a sensitive marker of protein malabsorption. Nevertheless, an optimization of the test meal conditions would be necessary in the view of implementing a clinical test. NEW & NOTEWORTHY We designed an intervention study to create a gradient of ileal protein digestibility in minipigs with pancreatic exocrine insufficiency and to validate reliable metabolic markers using a 15N oral meal test. 15N recovery in plasma proteins and to a higher extent in urine was sensitive to protein malabsorption. This test is minimally invasive and could be used to reveal protein malabsorption in patients.

Change of appetite in patients with functional digestive disorder. Association with psychological disorders: A cross-sectional study.

BACKGROUND AND AIMS: Changes in appetite are a frequent complaint in patients with functional gastrointestinal disorders (FGIDs). The aims of this study are to evaluate whether the changes in appetite are associated with specific FGIDs and to explore associations of these changes with symptoms of anxiety or depression. METHODS: This study included 1009 consecutive FGID patients (71% female), aged 48.9 years who all filled out a Rome III questionnaire for the evaluation of FGIDs, submitted to a psychological evaluation of symptoms of anxiety, and completed the Beck Depression Inventory questionnaire. The patients were classified according to their appetite change using a 7-point grading scale and split into three groups: those with appetite loss, those with no change in appetite, and those with increased appetite. RESULTS: Among the 1009, 496 patients (49%) reported a change in appetite, of which 332 (33%) patients reported a decrease in appetite and 164 (16%) patients reported an increase in appetite. Appetite was not affected in 51% of patients. Changes in appetite depended on gender, body mass index and psychometric evaluation scores. Increased appetite did not have specific FGIDs associations, while decreased appetite was associated with esophageal, gastroduodenal, bowel, and anorectal symptoms. The presence of depressive symptoms was also a predictor for the majority of FGIDs in decreased appetite, while anxiety trait was significant for globus and dysphagia. CONCLUSIONS: Decreased appetite was associated with FGIDs, especially in the presence of depressive symptoms. A reduced appetite would help to predict psychological disorders associated with FGIDs. FINANCIAL DISCLOSURE: None declared. LEGAL REGISTRATION: This study was a registered study in the French National Drug Agency (ANSM, Agence Nationale de Securité du Medicamentet des produits de santé, Study Number 2016-A01120-51). COMPETING INTERESTS: Michel Bouchoucha, Marinos Fysekidis, Florence Mary, Gheorghe Airinei, Cyriaque Bon, and Robert Benamouzig have no competitive interests.

Clinical, psychological, and physiological correlates of patients who defecate after meal.

BACKGROUND AND AIMS: Food is the most important synchronizer of gastrointestinal motility and secretion. Many patients with functional bowel or anorectal disorders complain of fecal urge and stool output after eating. PATIENTS AND METHODS: In this prospective observational study, 408 consecutive outpatients with functional bowel and/or anorectal disorders (74% female, 50.2±15.6 years, 24.8±5.0 kg/m²) filled Rome III questionnaires. Depression and anxiety scores, a physiological evaluation (total and segmental colonic transit time, colonic transit response to eating using a standard 1000 kcal test meal, and anorectal manometry), were measured. Univariate analysis and multivariate logistic regression were carried out according to the presence or not of stool output after eating. RESULTS: Defecation after eating was found in 21% of patients. These patients were not different according to the demographic characteristics of sex ratio (P=0.702), age (P=0.830), and BMI (P=0.314). In contrast, they had lower state anxiety (P=0.032), but similar scores of depression (P=0.240) and trait anxiety (P=0.933). They had similar manometric characteristics (anal pressure and rectal sensitivity), but a greater response to eating in all segments of the colon. There was an increase in the frequency of functional diarrhea (odds ratio=2.576, 95% confidence interval=1.312-5.056; P=0.006) and levator ani syndrome (odds ratio=2.331, 95% confidence interval=1.099-4.944; P=0.017), but no other functional bowel disorder including irritable bowel syndrome and its subtypes was found. CONCLUSION: Stool output after eating is associated with clinical disorders but not physiological parameters. This symptom is not associated with irritable bowel syndrome, but a higher frequency of functional diarrhea.

Perioperative chemotherapy with FOLFOX in resectable gastroesophageal adenocarcinoma in real life practice: An AGEO multicenter retrospective study.

PURPOSE: Perioperative chemotherapy with 5-fluorouracil and cisplatin, with or without epirubicin, improves overall survival in resectable gastroesophageal junction and gastric adenocarcinoma. The aim of this retrospective multicenter study was to evaluate the safety and efficacy of perioperative chemotherapy with a FOLFOX-based regimen. PATIENTS AND METHODS: We enrolled patients with resectable gastric or gastroesophageal adenocarcinoma, who had at least 3 cycles of a pre-operative FOLFOX-based regimen. The primary end point was the feasibility of the peri-operative chemotherapy. RESULTS: We enrolled 109 patients from 2007 to 2012 in 12 centres. Their median age was 66, 67% were men and 73% had gastric tumours. The median number of chemotherapy courses was 6 with a median of 4 pre-operative cycles and 2 post-operative cycles. Twenty-three patients received at least 8 cycles of chemotherapy. In univariate analysis, the Karnofsky index at inclusion was the only factor associated with 8 cycles of chemotherapy. An R0 resection was achieved in 100 patients (95.2%). CONCLUSION: The FOLFOX-based perioperative regimen achieves favourable results in real life practice. The optimal number of chemotherapy cycle remains to be determined. FOLFOX regimen may be used as an alternative treatment option to a cisplatin-based regimen in resectable gastroesophageal adenocarcinoma. A prospective randomized trial is needed to confirm these results.