Current challenges and future needs of clinical and endoscopic training in gastroenterology: a European survey.

Background and study aims A universal European training program in gastroenterology and hepatology is currently not available. The European Board of Gastroenterology and Hepatology (EBGH) has produced guidance regarding expected competencies for European gastroenterology trainees but it is unclear whether these have been incorporated in national curricula. The aim of this study was to provide an in-depth assessment of training and research opportunities, professional activities and of socioeconomic aspects of gastroenterology training across Europe through a web-based 90-point questionnaire. Materials and methods Physicians in their last year or who had recently finished their training, from 16 European countries, were invited to answer the questionnaire. Results A total of 144 physicians answered the survey. A minimum number of procedures is required before completing training in nine of 16 countries (56 %). Overall, European trainees dedicate a median of 12 months (IQR 6-25) of their training period to endoscopy and a median of 3 months (IQR 0-6) to ultrasound. Training in interventional endoscopy was not always exhaustive, as about 50 % of participants performed fewer of several interventional procedures than was recommended by EBGH, most participants did not perform endoscopic hemostasis or endoscopic mucosal resection, and nearly a half of participants had no access to pancreatobiliary endoscopy training. Finally, up to 13 % of residents complete their training without the supervision of a mentor. Conclusion In this large European survey, deep gaps and considerable differences in several gastroenterology training activities were found both among and within 16 European countries. Homogenization of educational programs and training opportunities across Europe is therefore necessary.

Endoscopic training: A nationwide survey of French fellows in gastroenterology.

BACKGROUND: During their 4 years of training, French fellows in gastroenterology should acquire theoretical and practical competency in gastrointestinal (GI) endoscopy. AIMS: To evaluate the delivery of endoscopy training to French GI fellows and perception of learning. METHODS: A nationwide electronic survey was carried out of French GI fellows using an anonymous, 17-item electronic questionnaire. RESULTS: A total of 291 out of 484 (60%) GI fellows responded to the survey. Only 40% of subjects had access to theoretical training and/or virtual simulators. Only 49% and 35% of fourth year fellows had reached the threshold numbers of EGD and colonoscopies recommended by the European section and Board of gastroenterology and hepatology. Sixty-two percent and 57% of trainees reported having insufficient knowledge in interpreting gastric and colic lesions. Access to dedicated endoscopy activity for at least 8 weeks during the year was the only independent factor associated with the achievement of the recommended annual threshold number of procedures. CONCLUSION: The access of fellows to theoretical training and to preclinical virtual simulators is still insufficient. Personalized support and regular assessment of cognitive and technical acquisition over the 4 years of training seems to be necessary.

Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma.

BACKGROUND: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients. METHODS: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test. FINDINGS: We included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900-0.970, p<0.0001) in the initial study (replication: 0.930 [0.862-0.971, p<0.0001]; meta-analysis: AUROC=0.940 [0.910-0.970, p<0.0001], no heterogeneity: I2=0%, p=0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR=6.30, for each mSEPT9 positive triplicate [2.92-13.61, p<0.0001]; replication: OR=6.07 [3.25-11.35, p<0.0001]; meta-analysis: OR=6.15 [2.93-9.38, p<0.0001], no heterogeneity: I2=0%, p=0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930-0.989) and 0.942 (0.878-0.978), respectively, with a pooled AUROC of 0.962 ([0.937-0.987, p<0.0001], no heterogeneity: I2=0%, p=0.36; and no publication bias). INTERPRETATION: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC.

The prognostic value of inflammation-based scores in advanced hepatocellular carcinoma patients prior to treatment with sorafenib.

BACKGROUND AND AIMS: The multikinase inhibitor sorafenib is the only currently approved drug for the indication of advanced hepatocellular carcinoma (HCC). It provides a limited gain in survival time but is frequently associated with adverse events. We currently lack simple prognostic factors in sorafenib-treated HCC patients. Various inflammation-based scores (IBSs) have been evaluated as predictors of tumor recurrence and survival in various malignancies (including HCC). The objective of the present study was to determine the prognostic value of IBSs for overall survival (OS) in advanced HCC patients prior to the initiation of sorafenib therapy. METHODS: Patients with Barcelona Clinic Liver Cancer stage C HCC were enrolled retrospectively between October 2007 and September 2015. To identify prognostic factors for OS, bivariate and multivariate analysis were performed using a Cox proportional hazards regression model. RESULTS: 161 patients (87.0% males; median age: 67; median OS: 9.1 months) were enrolled. A multivariate analysis identified a body mass index <25kg/m2 (hazard ratio (HR)=1.55, p<0.017), macroscopic vascular invasion (HR=1.63, p< 0.001), an AST level >38 U/L (HR=2.65, p<0.001), Child Pugh B stage (HR=2.59, p<0.001) and a systemic immune-inflammation index (SII) ≥600 × 109 (HR 1.72, p=0.002) as independent risk factors for OS in advanced HCC. CONCLUSION: IBSs (such as the SII) are novel, simple, low-cost prognostic indices in patients with advanced HCC. They may be of value in determining whether these patients may benefit from sorafenib therapy.

Azathioprine for refractory ulcerative proctitis: A retrospective multicenter study.

BACKGROUND: Efficacy of azathioprine (AZA) in refractory ulcerative proctitis (UP) is unknown. METHODS: All patients treated with AZA for refractory UP in three referral centers between 2002 and 2012 were included. "Treatment success" in the long-term was defined as the absence of colectomy during follow-up, no need for anti-TNF during follow-up, no ongoing systemic steroids use, no adverse event leading to AZA withdrawal, and clinically quiescent disease at last follow-up. RESULTS: Of the 1279 adult patients with ulcerative colitis, 25 patients were treated with AZA for refractory UP (median disease duration 4.9 years). Of these, 4 had no short-term clinical assessment. Of the remaining 21, 4 were primary non responders to AZA, 7 discontinued AZA for adverse events and 10 showed clinical improvement. At the long-term assessment at last follow up after a median of 46 months, 5 patients had treatment success and were still on AZA treatment, the remaining 20 were treatment failures. Of these, 5 discontinued AZA for adverse events and 15 were treated with infliximab (clinical response in 11 patients, primary non-response in one patient, and 3 underwent colectomy). CONCLUSION: AZA may be efficacious in maintaining clinical response in one-fifth of patients with refractory UP in a real-life setting.

25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients.

BACKGROUND AND AIM: The impact of 25-OH vitamin D on sustained viral response (SVR) to antiviral therapy and on fibrosis progression in hepatitis C is debated. We assessed the impact of 25-OH vitamin D concentration on the efficacy of antiviral therapy in naïve genotype 1 hepatitis C virus (HCV)-infected patients. METHODS: The study population consisted of treatment-naïve genotype 1 patients enrolled in a randomised controlled trial. A total of 516 patients received peginterferon α-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks. There were 349 patients with undetectable HCV RNA (<50 IU/ml) at week 24 (W24) who were randomised to continue dual therapy (n = 173) or to continue peginterferon alone (n = 176) until week 48. 25-OH vitamin D concentration was measured at baseline in frozen serum. RESULTS: A total of 461 patients could be analysed for virologic response at W24, and 285 (119 non-responders at W24 + 166 responders who continued dual therapy until W48) for the impact of SVR. There were 487 patients who could be analysed for fibrosis progression. Metavir fibrosis scores (centralised analysis) were: F1 30%, F2 34%, F3 27% and F4 9%. Median 25-OH vitamin D concentrations were similar in virologic responders (13.5 ng/ml) and in non-responders at W24 (12.6 ng/ml), as well as in patients with SVR (12.8 ng/ml) and without SVR (12.8 ng/ml, 3.99) at W72. Median 25-OH vitamin D concentrations were: F1: 14.30 ng/ml, F2: 13.50 ng/ml, F3: 13.30 ng/ml and F4: 12.80 ng/ml. CONCLUSION: In this study, 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients.

Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet.

Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1ß, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet.

Prognosis of advanced hepatocellular carcinoma: a new stratification of Barcelona Clinic Liver Cancer stage C: results from a French multicenter study.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) includes a wide spectrum of tumors and patients' prognosis after treatment is highly variable. Moreover, therapeutic options based on the Barcelona Clinic Liver Cancer (BCLC) staging system algorithm are restricted to one systemic therapy. AIM OF THE STUDY: To refine the stratification among BCLC C HCC patients by establishing a new simple prognostic score. PATIENTS AND METHODS: A regression model based on a BCLC stage C population and validated with an external cohort of BCLC C HCC patients defined the score. It was therefore validated among three external cohorts of BCLC C HCC patients treated with sorafenib. RESULTS: Five variables had independent prognostic values: the number of nodules, the infiltrating nature of the HCC, α-fetoprotein serum level, Child-Pugh score, and Eastern Cooperative Oncology Group Performance Status grade. They were integrated into a new score named NIACE ranging from 0 to 7, well correlated with survival. With the use of one threshold value, this score enables defining of two populations with different survivals among BCLC C patients and specifically among those treated with sorafenib. CONCLUSION: The NIACE score defines different prognostic subgroups after palliative treatment of HCC. It could be an additional tool for BCLC C HCC before inclusion in clinical trials or for the management of patients. These results must be validated in a prospective study.

Keratoconus in Inflammatory Bowel Disease Patients: A Cross-sectional Study.

BACKGROUND AND AIMS: Increasing evidence suggests that keratoconus may have an inflammatory component. The possible association of keratoconus with inflammatory bowel disease (IBD) has yet to be determined. The aim of this study was to determine the prevalence of keratoconus and suspect keratoconus in patients with IBD. METHODS: All consecutive adult IBD patients seen in the Department of Gastroenterology, Nancy, University Hospital, France, between March 2014 and June 2014 were included. Pregnant women, rigid lens wearers, patients with a family history of keratoconus and patients with a history of refractive surgery were excluded. A control group of healthy subjects was included. All included patients underwent a corneal topography (OPD-Scan III, Nidek) to detect keratoconus or suspect keratoconus. Rabinowitz videokeratographic indices were the basis of corneal topography interpretation. RESULTS: Two hundred and one IBD patients were included, 150 with Crohn's disease and 51 with ulcerative colitis. Mean age was 38.7 years and 121 were women. Mean disease duration was 10.8 years. Two IBD patients were diagnosed with keratoconus (1%) and 38 with suspect keratoconus (18.9%). Overall prevalence of keratoconus and suspect keratoconus was 19.9% (95% confidence interval [CI] 17.5-22.0). None of the 100 healthy subjects had keratoconus, while three were diagnosed with suspect keratoconus (p = 0.0002 versus IBD patients). Only smoking was identified as a risk factor (p = 0.029), especially in Crohn's disease. CONCLUSION: Inflammatory bowel disease patients may carry an increased risk of keratoconus and suspect keratoconus, smoking further increasing this risk. This supports the hypothesis of an inflammatory origin of keratoconus.