Dietary Patterns, Ultra-processed Food, and the Risk of Inflammatory Bowel Diseases in the NutriNet-Santé Cohort.

BACKGROUND: The incidence of inflammatory bowel diseases (IBDs) tended to increase for several decades. Diet is suspected to be a major determinant of the occurrence of these diseases. This prospective study aimed to assess the associations among occurrence of IBD, dietary patterns, and ultra-processed food in the French NutriNet-Santé cohort. METHODS: Participants of the NutriNet-Santé cohort who completed at least three 24-hour dietary records were included. Incident IBD cases were identified from 3 questionnaires and confirmed by phone or email interview. Major dietary patterns (DPs) were computed using a principal component analysis (PCA) based on 29 food groups' consumption, whereas proportions of ultra-processed foods (UPFs) were obtained using the NOVA classification. Multivariable Poisson models were performed to evaluate associations among DP quintiles, UPF proportion (UPFp) in the diet, and incident IBD. RESULTS: A total of 105,832 participants were included, contributing 238,924 person-years in a mean follow-up of 2.3 ± 2.2 years. Among them, 75 participants reported an incident IBD. Three major DPs were retained: "healthy," "traditional," and "western." No significant association was found for DPs and UPFp after adjustments for covariates. CONCLUSIONS: In this study, neither DPs nor UPF proportion in the diet were significantly associated with the risk of incident IBD after adjustments for covariates. Further studies are needed to investigate the long-term association between diet and IBD.

Dietary Zinc Intake and Inflammatory Bowel Disease in the French NutriNet-Santé Cohort.

INTRODUCTION: This study aimed to assess the association between incident Crohn's disease (CD) or incident ulcerative colitis (UC) and dietary zinc intake. METHODS: NutriNet-Santé cohort's participants who completed at least three 24-hour dietary records were included and incident CD or UC cases were identified. Multivariable Poisson models were performed to assess associations between tertiles of zinc intake and CD or UC. RESULTS: Among the 105,832 participants, 27 reported incident CD and 48 reported incident UC. The relative risks of CD decreased with dietary zinc intakes. Compared with participants with the lowest tertile of zinc intake, the relative risks for CD were 0.60 (95% confidence interval [0.22-1.66]) and 0.12 (95% confidence interval [0.02-0.73]) for the second and the highest tertiles, respectively (Ptrend = 0.02). No significant association was observed for UC. DISCUSSION: Dietary zinc intake was inversely associated with incident CD.

High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery.

PURPOSE: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. EXPERIMENTAL DESIGN: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. RESULTS: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. CONCLUSION: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

Intraductal papillary mucinous neoplasms of the pancreas and European guidelines: importance of the surgery type in the decision-making process.

BACKGROUND: The European Consensus 2018 established a new algorithm with absolute and relative criteria for intraductal papillary mucinous neoplasms of the pancreas (IPMN) management. The aim of this study was to validate these criteria and analyse the outcomes in function of the surgical procedure and IPMN subtype. METHODS: Clinical, radiological and surgical data (procedure, morbidity/mortality rates) of patients who underwent surgery for IPMN between 2007 and 2017. The predictive value of the different criteria was analysed. RESULTS: 124 patients (men 67%; mean age 65 years) underwent surgery for IPMN (n = 62 malignant tumours; 50%). Jaundice, cyst ≥4 cm and Wirsung duct size 5-9.9 mm or ≥ 10 mm were significantly associated with malignancy (4.77 < OR < 11.85 p < 0.0001). The positive predictive value of any isolated criterion ranged from 71 to 87%, whereas that of three relative criteria together reached 100%. The mortality and morbidity (grade III-IV complications according to the Dindo-Clavien classification) rates were 3 and 8%, respectively. Morbidity/mortality after duodenopancreatectomy and total pancreatectomy were significantly higher for benign IPMN (p = 0.01). CONCLUSION: Considering the morbidity associated with extended surgery, particularly for benign IPMN, the results of the present study suggest that high-risk surgery should be considered only in the presence of three relative criteria and including the surgery type in the decision-making algorithm.

CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma.

Tumor-released extracellular vesicles (EVs) contain tumor-specific cargo distinguishing them from healthy EVs, and making them eligible as circulating biomarkers. Glypican 1 (GPC1)-positive exosome relevance as liquid biopsy elements is still debated. We carried out a prospective study to quantify GPC1-positive exosomes in sera from pancreatic ductal adenocarcinoma (PDAC) patients undergoing up-front surgery, as compared to controls including patients without cancer history and patients displaying pancreatic preneoplasic lesions. Sera were enriched in EVs, and exosomes were pulled down with anti-CD63 coupled magnetic beads. GPC1-positive bead percentages determined by flow cytometry were significantly higher in PDAC than in the control group. Diagnosis accuracy reached 78% (sensitivity 64% and specificity 90%), when results from peripheral and portal blood were combined. In association with echo-guided-ultrasound-fine-needle-aspiration (EUS-FNA) negative predictive value was 80% as compared to 33% for EUS-FNA only. This approach is clinically relevant as a companion test to the already available diagnostic tools, since patients with GPC1-positive exosomes in peripheral blood showed decreased tumor free survival.

Front-of-Pack Labeling and the Nutritional Quality of Students' Food Purchases: A 3-Arm Randomized Controlled Trial.

Objectives. To assess the effects of the Nutri-Score label (relative to the Reference Intakes label or no label) on the nutritional quality of students' food purchases. Methods. A 3-arm randomized controlled trial was conducted in France in 2017; 2907 participants were randomized into 1 of the 3 study arms (Nutri-Score, Reference Intakes, no label) and invited to purchase groceries from an experimental Web-based supermarket. The main outcome was the overall nutritional quality of purchases, measured according to a modified version of the Food Standards Agency Nutrient Profiling System (FSAm-NPS/HCSP) score. Results. The mean (±SD) FSAm-NPS/HCSP score was lower in the Nutri-Score group (2.02 ±3.56) than in the Reference Intakes group (2.69 ±3.44), reflecting higher nutritional quality; however, there was no significant difference between the Nutri-Score and no-label (2.45 ±3.28) groups or between the Reference Intakes and no-label groups. Shopping cart content was lower in calories and saturated fatty acids and higher in fruits and vegetables in the Nutri-Score arm than in the other arms. Conclusions. The Nutri-Score label appeared to improve the nutritional composition of students' food purchases relative to the Reference Intakes label or no label.

Sociodemographic correlates of eating disorder subtypes among men and women in France, with a focus on age.

BACKGROUND: On the population level, the association of age and other sociodemographic factors with eating disorders (ED) is unclear. METHODS: We used cross-sectional data from the French general population-based NutriNet-Santé e-cohort (n=49 603 adults; 76.3% women; mean age=50.4±14.6 years). ED were evaluated in 2014 with the 5-item SCOFF screening questionnaire and the Expali algorithmic tool. Likely cases of restrictive, bulimic, hyperphagic and other ED were the dependent variables. Age, marital status, education, occupation, physical activity and smoking were the independent variables. Associations were estimated via gender-stratified multivariable polytomous logistic regression. RESULTS: Among women, age displayed inverse linear associations with both restrictive and bulimic ED, underscoring 18-25 years as the most vulnerable period (adjusted OR=3.37, 95% CI: 2.24 to 5.08 for restrictive ED; adjusted OR=2.98, 95% CI: 2.37 to 3.74 for bulimic ED, respectively). A similar association was observed in men regarding bulimic ED. In women, age was not associated with hyperphagic ED for which living alone, low education, low physical activity, being a homemaker/disabled/unemployed/retired, a manual worker or a former/current smoker had increased importance. In men, 18-39 years emerged as the least vulnerable period regarding hyperphagic ED (adjusted OR=0.74, 95% CI: 0.56 to 0.99). Across gender, having postsecondary education had significant inverse associations with all except restrictive ED, whereas being a student had a significant positive association with restrictive ED. CONCLUSIONS: The findings support gender-specific associations of age with four ED subtypes and could inform future prevention initiatives targeting specific ED among specific age groups. TRIAL REGISTRATION NUMBER: NCT03335644; Pre-results.

Eating Patterns in Patients with Compensated Cirrhosis: A Case-Control Study.

BACKGROUND: There is growing evidence suggesting that maintaining an adequate nutritional status for patients with liver cirrhosis (LC) is relevant to prevent complications. The present study aimed to describe dietary behaviours of patients with compensated and non-complicated LC and comparing them with those of subjects from the general population. METHODS: In this case-control study, patients were volunteers enrolled in the ALICIR (ALImentation et CIRrhose) study, an observational survey nested in two French prospective cohorts of patients with biopsy-proven compensated cirrhosis related either to excessive alcohol consumption (CIRRAL) or to hepatitis B or C virus infection (CirVir). Controls were selected from the NutriNet-Santé cohort. Dietary data were collected through a semi quantitative food frequency questionnaire. Dietary and nutritional data were compared using multi-adjusted paired Student's tests. RESULTS: Between June 2014 and February 2016, 174 patients of CirVir (N = 97) or CIRRAL (N = 77) were matched with 348 controls from the NutriNet-Santé cohort, according to gender, age, BMI and educational level. Compared to controls, patients (mean ± SD) consumed more sodas (236.0 ± 29.8 mL vs. 83.0 ± 33.0 mL) and water (1787.6 ± 80.6 mL vs. 933.6 ± 85.3 mL), and lower amounts of salty snacks (4.2 ± 1.42 g vs. 9.0 ± 1.6 g) and alcoholic beverages (71.8 ± 23.4 g vs. 151.2 ± 25.9 g), with all p values < 0.0001. Dietary behaviours differed according to LC aetiology. CONCLUSIONS: Dietary behaviour of patients significantly differed from subjects from the general population.

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma.

OBJECTIVES: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer. METHODS: The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment. RESULTS: A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02). CONCLUSIONS: The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.

Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.

Mutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcome.

Outcomes of nonresected main-duct intraductal papillary mucinous neoplasms of the pancreas.

AIM: To compare characteristics and outcomes of resected and nonresected main-duct and mixed intraductal papillary mucinous neoplasms of the pancreas (IPMN). METHODS: Over a 14-year period, 50 patients who did not undergo surgery for resectable main-duct or mixed IPMN, for reasons of precluding comorbidities, age and/or refusal, were compared with 74 patients who underwent resection to assess differences in rates of survival, recurrence/occurrence of malignancy, and prognostic factors. All study participants had dilatation of the main pancreatic duct by ≥ 5 mm, with or without dilatation of the branch ducts. Some of the nonsurgical patients showed evidence of mucus upon perendoscopic retrograde cholangiopancreatography or endoscopic ultrasound and/or after fine needle aspiration. For the surgical patients, pathologic analysis of resected specimens confirmed a diagnosis of IPMN with involvement of the main pancreatic duct or of both branch ducts as well as the main pancreatic duct. Clinical and biologic follow-ups were conducted for all patients at least annually, through hospitalization or consultation every six months during the first year of follow-up, together with abdominal imaging analysis (magnetic resonance cholangiopancreatography or computed tomography) and, if necessary, endoscopic ultrasound with or without fine needle aspiration. RESULTS: The overall five-year survival rate of patients who underwent resection was significantly greater than that for the nonsurgical patients (74% vs 58%; P = 0.019). The parameters of age (< 70 years) and absence of a nodule were associated with better survival (P < 0.05); however, the parameters of main pancreatic duct diameter > 10 mm, branch duct diameter > 30 mm, or presence of extra pancreatic cancers did not significantly influence the prognosis. In the nonsurgical patients, pancreatic malignancy occurred in 36% of cases within a mean time of 33 mo (median: 29 mo; range: 8-141 mo). Comparison of the nonsurgical patients who experienced disease progression with those who did not progress showed no significant differences in age, sex, symptoms, subtype of IPMN, or follow-up period; only the size of the main pancreatic duct was significantly different between these two sub-groups, with the nonsurgical patients who experienced progression showing a greater diameter at the time of diagnosis (> 10 mm). CONCLUSION: Patients unfit for surgery have a 36% greater risk of developing pancreatic malignancy of the main-duct or mixed IPMN within a median of 2.5 years.

Improving the pre-screening of eligible patients in order to increase enrollment in cancer clinical trials.

BACKGROUND: The performance of randomized controlled trials (RCTs) is often hindered by recruitment difficulties. This study aims to explore the pre-screening phase of four prostate cancer RCTs to identify the impact of a systematic pre-selection of eligible patients for RCT recruitment. METHODS: The pre-screening of four RCTs opened at the Comprehensive Cancer Center in Rennes was analyzed retrospectively (French Genitourinary Tumor Group (GETUG) 14, 15, 16, and 17). Data were extracted from electronic multidisciplinary cancer (MDC) reports and manually completed by physicians and medical secretaries. These data were the main source of information for clinicians to discuss treatment alternatives during MDC sessions. The pre-screening decisions made by the clinicians during these MDC meetings were compared with those made after a systematic review of the MDC reports by a clinical research assistant (CRA). Any inconsistencies in decisions between the CRA and the MDC physicians were corrected by the principal investigator (PI). RESULTS: The pre-screening rate was 9.1% during the MDC meetings, while it was estimated to be 12.9% after the final review by the PI, and 29% after the systematic review by the CRA. The study showed that 77% and 67% of the MDC reports did not mention clinical and pathological Tumor, lymph node and metastasis classification of malignant tumors (TNM) staging, respectively, and that 35 of the CRA's 47 proposals rejected by the PI concerned implicit information (not specified in the MDC reports). Only one patient was proposed by the PI, and none by the CRA. CONCLUSIONS: These results confirm that pre-screening could be improved by a systematic review of the medical reports. They also highlight the fact that missing data in electronic MDC reports leads to over-enrollment of non-eligible patients, but not to over-exclusion of eligible patients. Thus, our study confirms the potential gain in using semi-automated pre-selection of MDC reports, in order to avoid missing out on patients eligible for RCTs. TRIAL REGISTRATION: The trials evaluated in this study were previously registered with clinicaltrials.gov (registration number: NCT00104741 on 3 March 2005; NCT00104715 on 3 March 2005; NCT00423475 on 16 January 2007; and NCT00667069 on 24 April 2008).