The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.

[New methods for exploration of the small intestine]. / Nouvelles méthodes d'exploration de l'intestin grêle.

For ten years, a lot of advances have been achieved for the morphological exploration of the small intestine as well as with CT and MR enterography than with wireless capsule endoscopy. These investigations have renewed the approaches of different diseases that can affect the small intestine: tumors, especially sub-mucosal tumors (CT enterography), iron-deficiency anemia (capsule endoscopy) and follow-up of patients with Crohn's disease of the small intestine (MR enterography). Balloon enteroscopy may then allow therapeutic approach when needed (treatment of bleeding angiodysplasia).

Increased Risk of Cancer and Mortality in a Large French Population-Based Paediatric-Onset Inflammatory Bowel Disease Retrospective Cohort.

BACKGROUND AND AIMS: Paediatric-onset IBD [pIBD] is associated with an increased risk of cancer and mortality in adulthood. The aims of this study were to measure the incidence of cancer and mortality in patients with pIBD and identify factors associated with mortality and cancer. METHODS: All patients diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] before the age of 17 years between 1988 and 2011 in the EPIMAD registry were retrospectively followed until 2013 for cancer and 2015 for mortality. Standardized incidence [SIR] and mortality ratios [SMR] were estimated compared to the general population. Cox regression was used to compare the effect of exposures on cancer and mortality among IBD patients. RESULTS: We included 1344 patients [52% males, 75% CD], totalling 12 957 patient-years for cancer incidence and 18 817 patient-years for mortality. There were 14 cases of cancer [median age 27.8 years] and 15 deaths [median age 28.8 years]. The incidence of cancer and of mortality were increased compared to the general population: all-cancer SIR = 2.7 (95% confidence interval [CI]: 1.5-4.8), SMR = 1.7 [95% CI: 1.0-2.8]. Colorectal cancer had the highest SIR and SMR: SIR = 41.2 [95% CI: 17.2-99.0], SMR = 70.4 [95% CI 22.7-218.2]. Cancer was associated with (hazard ratio [HR], 95% CI): active smoking at diagnosis [5.5, 1.8-16.5], p = 0.002; any exposure to anti-tumour necrosis factor [6.1, 1.7-22.3], p = 0.0065; and exposure to combination therapy [7.4, 1.8-29.7], p = 0.0047. Mortality was associated with extraintestinal manifestations (HR 4.9 [95% CI: 1.7-13.8], p = 0.003). CONCLUSIONS: In this large population-based cohort, patients with pIBD had an increased risk of both cancer [2.7-fold] and mortality [1.7-fold], particularly for colorectal cancer.

Gene expression profiling of systems involved in the metabolism and the disposition of xenobiotics: comparison between human intestinal biopsy samples and colon cell lines.

Intestinal cell lines are used as in vitro models for pharmacological and toxicological studies. However, a general report of the gene expression spectrum of proteins that are involved in the metabolism and the disposition of xenobiotics in these in vitro systems is not currently available. To fill this information gap, we systematically characterized the expression profile of 377 genes encoding xenobiotic-metabolizing enzymes, transporters, and nuclear receptors and transcription factors in intestinal mucosa (ileum, ascending colon, transverse colon, descending colon, and rectum) from five healthy subjects and in five commonly used intestinal cell lines (Caco-2, C2BBe1, HT29, T84, and FHC). For this, we performed a quantitative real-time reverse transcription-polymerase chain reaction analysis using TaqMan low-density arrays and analyzed the results by different statistical approaches: Spearman correlation coefficients, hierarchical clustering, and principal component analysis (PCA). A large variation in gene expression spectra was observed between intestinal cell lines and intestinal tissues. Both hierarchical clustering and PCA showed that two distinct clusters are visible, of which one corresponds to all cultured cell lines and the other to all intestinal biopsies. The best agreement between human tissue and the representative cell line was observed for human colonic tissues and HT29 and T84 cell lines. Altogether, these data demonstrated that gene expression profiling represents a new valuable tool for investigating in vitro and in vivo expression level correlation. This study has pointed out interesting expression profiles for various colon cell lines, which will be useful for choosing the appropriate in vitro model for pharmacological and toxicological studies.

Value of wireless capsule endoscopy in patients with indeterminate colitis (inflammatory bowel disease type unclassified).

BACKGROUND: Wireless capsule endoscopy (WCE) can identify small bowel mucosal lesions not seen with other imaging modalities. This technique can therefore play an important diagnostic role in the evaluation of patients with inflammatory bowel disease type unclassified (IBDU). We report on a multicentric study whose objective was to evaluate the value of WCE to increase diagnostic accuracy in categorizing IBDU. METHODS: Thirty patients with IBDU and negative serology were included. WCE was performed with a standard Pillcam capsule. Outcome measures were classified as suggestive of Crohn's disease (CD) when -3 ulcerations were present. RESULTS: WCE displayed endoscopic features suggestive for CD in 5 patients. In 6 other patients, WCE was negative, but repeated ileocolonoscopy with biopsies performed during follow-up evaluation revealed CD in 5 and ulcerative colitis (UC) in 1 patient. UC was found in a seventh case at colectomy performed just after WCE. Eighteen patients remained with a diagnosis of IBDU 16 months on average after WCE. CONCLUSIONS: WCE is a potentially clinically useful technique for categorizing a subgroup of patients with IBDU, although negative WCE does not exclude further diagnosis of CD. Patients with negative WCE who remain IBDU at follow-up evaluation may belong to an original subgroup of IBD.

[International consensus in Paris, 2006, on the indications and use of the endoscopic videocapsule test. Report of the SFED Capsule Commission]. / Consensus international de Paris 2006 sur les indications et les modalités de l'examen par capsule vidéoendoscopique. Rapport de la commission capsule de la Sfed.

Following the 4th International Conference on Capsule Endoscopy (ICCE, Miami 2005), the main indications for videocapsule endoscopy (VCE) were reviewed. The consensus guidelines were published in Endoscopy in 2005. These propositions for VCE were based on an analysis of evidence reported in the literature published through 2005. A small working group of experts examined each methodology and presented their report at the plenary session. The final conclusions were then published. At the ICCE 2006 held in Paris, this first version of the consensus guidelines was improved and completed.

[Gastric or duodenal metastases from clear cell renal cell carcinoma. Report of two cases and review of the literature]. / Métastases gastriques et duodénales de cancer du rein à cellules conventionnelles.

INTRODUCTION: Gastric or duodenal metastases from clear cell renal cell carcinoma are exceptional. According to autopsy series, the incidence of gastrointestinal metastases is 0.06 to 4% for all cancers and 0.2 and 0.7% for renal cancers. OBJECTIVE: To define the diagnostic and therapeutic management of these rare sites in the light of 2 cases of gastric metastases from renal cancer seen in our institution and a review of the literature. RESULTS: These two patients with gastric or duodenal metastases from renal cancer can be added to the 15 cases found in the literature. These 17 cases consisted of 5 cases of duodenal metastases and 12 cases of gastric metastases and were described in 14 articles (2 articles comprised 2 and 3 cases, respectively). Metastases were the presenting sign of the cancer in 3 cases or occurred during follow-up after nephrectomy in 14 cases after a mean of 6.6 years (range: 2 years-14 years). The mean number of metastatic sites was 2.5 (range: 1-5). Presenting symptoms were mainly upper or lower gastrointestinal bleeding (14 out of 17 cases) or anaemia (2 cases). Gastroscopy established the diagnosis and allowed biopsies and control of acute bleeding. For patients with a solitary metastasis and in good general condition, gastrectomy was performed as complementary treatment. For patients with multiple or inoperable metastases, treatment consisted of either endoscopic resection, embolization of the metastasis, or immunotherapy. The benefit of surgery in terms of survival could not be demonstrated due to the short follow-up (mean: 8.6 months; range: 1 to 36 months). The median overall survival of this group has not been reached, but is greater than 6 months. CONCLUSION: Surgical resection of the metastasis is the preferred treatment in the case of a solitary metastasis and absence of contraindication related to the general state. In the other cases, endoscopic resection or embolization of the metastasis can be proposed, with or without systemic immunotherapy. None of these treatments has been shown to be superior in terms of survival in this indication. The place of targeted anti-tumour treatments such as anti-angiogenic drugs has not been evaluated

Adalimumab dose escalation is effective and well tolerated in Crohn's disease patients with secondary loss of response to adalimumab.

BACKGROUND: Although adalimumab is effective in Crohn's disease, most patients experience a loss of response over time. The aim of the present study was to evaluate efficacy and safety of adalimumab dose escalation and identify predictors of a clinical response in Crohn's disease patients with a secondary loss of response. METHODS: We performed a retrospective and observational study including all Crohn's disease patients who underwent dose escalation of adalimumab after a secondary loss of response from 2007 to 2015. RESULTS: A clinical response was observed in 99/124 (79%) patients at 3 months and in 62/107 (61%) patients at 12 months. The predictive factors of response to ADA dose escalation at 12 months on multivariate analysis were: maintenance therapy of 40mg every week rather than 80mg every other week (OR 3.64, 95% CI: 1.28-10.37) and a CRP level≤5mg/L at adalimumab dose escalation (OR 6.64, 95% CI: 1.40-27.53). Adalimumab was withdrawn in 4 patients due to side effects. CONCLUSIONS: Adalimumab dose escalation is an effective and well-tolerated therapeutic option in patients with secondary loss of response. A 40mg every week optimized regimen was predictive of a response to ADA dose escalation.

Patients with Crohn's Disease with High Body Mass Index Present More Frequent and Rapid Loss of Response to Infliximab.

BACKGROUND: Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD. METHODS: All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m), overweight patients (BMI of 25.0-30 kg/m), and obese patients (BMI > 30.0 kg/m). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients. RESULTS: One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m was significantly associated with IFX optimization within 12 months on multivariate analysis. CONCLUSION: This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients.

Using white light during photodynamic therapy: visualization only or treatment?

BACKGROUND: Photodynamic therapy (PDT) involves selective uptake and retention of a photosensitizer in a tumor, followed by irradiation with light (usually a 630 nm diode laser), initiating tumor necrosis through formation of oxidized products or singlet oxygen. Successful PDT of early cancers of the esophagus and of Barrett's esophagus with severe dysplasia has been reported. However, side effects (edema, stricture, etc.) and treatment failure have been observed. This study aims to evaluate the possible photodynamic effect induced by illumination from the endoscope on the PDT effect, since a photon emitted to see the lesion can potentially be a photon to treat it! MATERIALS AND METHODS: Two fiber endoscopes (Olympus GIFPQ20 and Pentax FG34X) and one videoendoscope (Olympus GIFQ140) were evaluated. Output power, irradiance and emission spectrum were measured. Using the molar extinction coefficient of Photofrin and optical coefficients of the esophagus, the relative photodynamic reaction yield, determined as a function of depth, was compared with that obtained with a 630 nm diode laser. RESULTS: The irradiance at 1 and 2 cm was, respectively, 18.4 and 4.6 mW/cm (Pentax FG34X), 10.6 and 2.65 mW/cm (Olympus GIFPQ20), and 2.7 and 3.2 mW/cm (Olympus GIFQ140). The highest irradiance could lead to a relative photodynamic reaction yield at the surface of the esophagus similar to (Olympus GIFPQ20) or greater than (Pentax FG34X) that obtained using a diode laser alone. CONCLUSIONS: Our results could explain side effects sometimes observed when performing PDT. 'Endoscopic' illumination, however, could also represent an interesting alternative to the 630 nm diode laser. When using white light, superficial efficacy of PDT could be reinforced and transmural necrosis leading to perforation or stenoses reduced, since there is less red light in depth compared with a diode laser.

Prevalence of risk factors of prion-related disease according to the French circular 138 (DGS/DH/5C/DHOS/E2/2001/138) among patients referred for gastrointestinal endoscopy.

AIM OF THE STUDY: To assess the prevalence of risk factors of prion-related disease transmission in a gastrointestinal endoscopy unit. METHODS: Clinical evaluation of the risk of transmission of prion-related diseases using the criteria defined by the French circular 138 in patients referred for digestive endoscopy without anesthesia. RESULTS: 1017 patients were included in this study. According to circular 138, 7 patients (0.68%) were at high risk of transmitting prion-related disease. According to these criteria, a high index of suspicion of prion-related disease was detected in 26 patients (2.55%). Clinical evaluation of risk was not possible for 56 patients (5.51%), due to coma or sedation (38 patients) or communication impairment (18 patients). CONCLUSIONS: Application of circular 138 led us to consider that 2.55% of patients in this study had a high risk of prion-related disease. The circular criteria cannot be assessed in patients with sedation for mechanical ventilation, coma or communication impairment.

Impact of Small Bowel Exploration Using Video-Capsule Endoscopy in the Management of Acute Gastrointestinal Graft-versus-Host Disease.

BACKGROUND: The purpose of this study was to evaluate the impact of the global diagnostic approach on the outcome of patients suspected of having acute (a) gastrointestinal (GI) graft-versus-host disease (GVHD). METHODS: Ten consecutive patients with suspected aGI-GVHD were prospectively explored with an exhaustive approach including video-capsule endoscopy (VCE). Images observed with VCE were compared with results obtained with other GI investigations including duodenal biopsies. RESULTS.: Five patients had a normal VCE examination: four were successfully treated symptomatically, but one died as a result of toxoplasmosis. VCE disclosed aGI-GVHD lesions in all five remaining patients, and two of the five were considered normal by upper GI endoscopy. All of these patients experienced improvement in their GI symptoms within 2 weeks of adjustments to their immunosuppressive treatment. CONCLUSIONS: This approach has enhanced the authors' ability to adapt immunosuppressive treatments in patients suffering from suspected aGI-GVHD. Further investigation of the apparently high negative predictive value of VCE will be of great interest, particularly with a view to avoiding unnecessary immunosuppressive treatment.

[Value of endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas. Experience of 54 cases]. / Valeurs de l'échoendoscopie et de la scintigraphie des récepteurs de la somatostatine dans la localisation pré-opératoire des insulinomes et gastrinomes.

AIM: The classic morphological techniques for the localization of insulinomas and gastrinomas are of limited value. Endoscopic ultrasonography and somatostatin receptor scintigraphy have shown high sensitivity for the detection of gastroenteropancreatic endocrine tumors. The aim of the study was to evaluate the sensitivity of endoscopic ultrasonography and that of somatostatin receptor scintigraphy in the localization of insulinomas and gastrinomas. PATIENTS AND METHODS: This retrospective study concerned 54 patients with insulinoma (n=29) or gastrinoma (n=26) operated on between March 1991 and March 2000 and who had at least one among the two tested examinations. Forty-two patients had scintigraphy (17 with insulinoma, 25 with gastrinoma), 47 had endoscopic ultrasonography (28 with insulinoma, 17 with gastrinoma). One of the ten patients with MEN 1 had both tumors. All diagnosis were confirmed by histologic examination. RESULTS: The sensitivity of scintigraphy for the localization of insulinomas was 47%. There was one false positive. Sensitivity of endoscopic ultrasonography for insulinomas was 85%. The sensitivity of scintigraphy in the detection of gastrinomas was 65% for the tumors in the duodenopancreatic area, 20% for the tumors in the pancreatic tail and 71% for metastasis. The sensitivity of endoscopic ultrasonography was 46% for duodenal tumors, 75% for pancreatic tumors and 57% for lymph node metastasis. The combination of both localization studies increased sensitivity to 94%. CONCLUSION: Endoscopic ultrasonography and somatostatin receptor scintigraphy are the gold standard for localization of gastrinomas. Association of both examinations increases the sensitivity. Scintigraphy for the detection of insulinomas should be performed when endoscopic ultrasonography is negative.

Pancreatic head carcinoma and right hepatic artery: embolization management-A case report.

A replaced right hepatic artery (RHA) is the most common anatomical variation in pancreatic surgery. The RHA is frequently encountered and can be problematic in pancreatic carcinoma. The preservation of the RHA is necessary to avoid ischemic complications but can impact margins resection in pancreaticoduodenectomy (PD). We report a case of a 53-year-old man with a head pancreatic carcinoma. There was a close contact between the tumor and the RHA arising from superior mesenteric artery (SMA). Preoperative embolization of the RHA was performed prior to PD.

Small bowel capsule endoscopy for management of Crohn's disease: a retrospective tertiary care centre experience.

BACKGROUND: The role of small bowel capsule endoscopy in the management of established Crohn's disease is uncertain. METHODS: A retrospective study of small bowel capsule endoscopy tests performed in a referral centre from 2008 to 2011; 77 tests were performed in patients with known Crohn's disease. Six patients were excluded due to capsule test retention. Patients were classified into 4 indication groups: unexplained anaemia (G1, n = 6); discrepancy between clinical symptoms and morphology (G2, n = 25), full assessment of Crohn's disease location (G3, n = 37) and evaluation of mucosal healing (G4, n = 3). RESULTS: Twenty-seven (38%) patients had no lesions, 32 (45%) moderate and 12 (17%) severe lesions. Endoscopic lesions were found in 4/6 (67%) G1 patients, 11/25 (44%) G2 and 28/37 (76%) G3 (p < 0.03). Three months after endoscopy was performed, 38/71 patients experienced a change in their treatment that was significantly associated with the severity of endoscopic lesions and with test indications; in 60%, 20% and 58% of patients from G1, G2 and G3, respectively (p < 0.01). CONCLUSION: Small bowel capsule endoscopy resulted in management changes in the majority of patients with established Crohn's disease.

Safety and efficacy of extractible self-expandable metal stents in the treatment of Crohn's disease intestinal strictures: a prospective pilot study.

BACKGROUND: Endoscopic management of Crohn's disease (CD) intestinal strictures with balloon dilation is effective; however, recurrences are frequent and require further dilations or surgery. The use of extractible metallic stents may be as effective as balloon dilation with fewer recurrences. The aim was to investigate in a prospective pilot study the feasibility and clinical effectiveness of the use of extractible stents in the treatment of CD intestinal strictures. METHODS: In two tertiary referral centers, quiescent CD patients except for obstructive symptoms associated with intestinal stenosis of less than 50 mm length on enterography were eligible for transitory stent placement, initially planned to be retrieved after 8 weeks, which was secondarily reduced to 4 weeks after patient 3. RESULTS: Eleven patients (six males, five females, median age 34 years [range 18-66]) were prospectively included. The sites of intestinal stenosis were an ileocolonic anastomosis, an ileosigmoidic anastomosis, and the surgically untreated terminal ileum in eight, one, and two patients, respectively. Stent placement was technically successful in 10 patients. Obstructive symptoms were relieved in 6 out of 10 patients. Two patients needed surgery related to the procedure. Six downstream migrations were observed. Only one patient could have the stent extracted as scheduled on day 28 and remains symptom-free after 73 months of follow-up. CONCLUSIONS: Even if stenting appears an effective technique in treating symptomatic CD intestinal strictures, the procedure is associated with a prohibitively high rate of spontaneous migrations and complications.