Double-Balloon Enteroscopy in Detecting Small-Bowel Neuroendocrine Neoplasms: A Single-Center Prospective Study.

BACKGROUND AND AIM: Small-bowel neuroendocrine neoplasm (sbNEN) diagnosis has improved with double-balloon enteroscopy (DBE). DBE efficacy in the detection of sbNENs is unknown. We aimed to report the experience at a single referral center for NENs. METHODS: All consecutive patients with a suspected sbNEN selected for diagnostic DBE were enrolled. RESULTS: Between 2011 and 2016, 25 patients were referred for a suspected sbNEN. In 15/25 patients, a primary NEN was detected outside the small bowel; in 4, NEN was excluded. After extensive workup, 6 patients (4 males, median age 50 years) underwent DBE (3 anterograde, 2 retrograde, and 1 both; median time: 60 min; median insertion 200 cm). DBE was positive in 3 patients: one had an ileal 2-cm NEN G1, one had an ileal 1.3-cm NEN G1, and one had an ileal 1-cm NEN G2, all surgically removed. Of the 3 other patients, one had a metastatic NEN of unknown primary, the other two had small intestinal NENs, both surgically removed (1.6-cm G1 and G2 NEN). DBE showed a sensitivity of 60% and, in absence of false-positive results, a specificity of 100%. Accuracy resulted 67%. No complications were observed. CONCLUSIONS: In line with data from the literature, the present series showed that DBE is a safe and effective procedure in the diagnosis of sbNENs. Further studies are needed to better clarify the diagnostic role of DBE in the neuroendocrine tumor setting and its relationship with other techniques.

Blue-light imaging compared with high-definition white light for real-time histology prediction of colorectal polyps less than 1 centimeter: a prospective randomized study.

BACKGROUND AND AIMS: Blue-light imaging (BLI) is a new chromoendoscopy technique, potentially useful for differentiating neoplastic from nonneoplastic lesions. The present study was aimed at comparing BLI with high-definition white light (HDWL) in the real-time histology prediction of colon polyps <10 mm. METHODS: Consecutive outpatients undergoing colonoscopy with the ELUXEO 7000 endoscopy platform and 760 series video colonoscopes (Fujifilm Co, Tokyo, Japan) who had at least 1 polyp <10 mm were randomized to BLI or HDWL for polyp characterization. The accuracy of high-confidence real-time histology prediction (adenoma vs not adenoma) by either BLI or HDWL for polyps <10 mm (primary end-point) and diminutive (≤5 mm) polyps was calculated, along with sensitivity, specificity, and positive and negative predictive values, with histopathology as the reference standard. RESULTS: A total of 483 polyps were detected in 245 randomized patients (125 and 120 in the BLI and HDWL arms, respectively). A total of 358 were diminutive, and 283 were adenomas. Overall, 222 (85.7%) and 193 (86.1%) polyps were characterized with high confidence by BLI and HDWL, respectively (P = .887), with an overall accuracy of 92% and 84%, respectively (P = .011). The accuracy was significantly higher by BLI than HDWL, also for diminutive polyps (92% vs 83%; P = .008). When BLI was used, the negative predictive value for diminutive rectosigmoid polyps was 88%, and the post-polypectomy surveillance interval was correctly attributed in 85.7% and 93.7% of patients, respectively, according to U.S. and European guidelines. CONCLUSION: BLI was superior to HDWL for the real-time prediction of histology in polyps <10 mm. A BLI-dedicated classification might further improve the endoscopist performance. (Clinical trial registration number: NCT03274115.).

Effects of low-dose aspirin on clinical outcome and disease progression in patients with gastroenteropancreatic neuroendocrine neoplasm.

Objective: The chemopreventive effect of aspirin (ASA) has been observed in the setting of colorectal cancer and other solid neoplasms. Recently, ASA has demonstrated a promising anti-proliferative effect on GEP-NENs in vitro. However, the direct anti-neoplastic impact of ASA on GEP-NEN clinical outcome is yet to be clarified. Materials and methods: All the GEP-NEN patients followed up in three European Centers from January 2005 to September 2016 were retrospectively enrolled. Patients taking ASA in doses of 75-100 mg daily for cardiovascular prevention for at least six months were evaluated. The possible association between ASA and disease grading, staging, primary site, OS and PFS were evaluated. Results: Two hundred fifty one patients were included (117 males, median age 63 years). Of these, 64 patients were prescribed with ASA. No clear impact on OS or PFS was observed in GEP-NEN patients taking ASA compared to those not taking it. ASA intake was related with the patients' older age. At Cox multivariate analysis, stage IV and Ki-67 resulted independent predictors for OS and PFS. In the setting of intestinal NENs, a suggestive, but not statistically significant, protective role of ASA on PFS was observed [HR 0.41 (95% CI: 0.13-1.29)]. Conclusions: Despite ASA showed promising anti-proliferative effects in vitro and a chemopreventive action in NENs has been reported, a clear impact of ASA on survival in NENs has not emerged from the present study. However, in the subgroup of patients with small-intestine NENs, ASA showed a trend toward a protective role.

Heterogeneity of Duodenal Neuroendocrine Tumors: An Italian Multi-center Experience.

BACKGROUND: The optimal management of duodenal neuroendocrine neoplasms (dNENs) is unclear, and endoscopic resection is increasingly performed instead of surgery. METHODS: This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. RESULTS: From 2000 to 2017, 108 patients (69 males, 39 females, median age 59.5 years) were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox's multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. CONCLUSIONS: dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.

Endoscopic ultrasound appearance of pancreatic serotonin-staining neuroendocrine neoplasms.

BACKGROUND/OBJECTIVES: The pancreatic localization of serotonin-staining neuroendocrine neoplasms is extremely rare. This is a retrospective study aimed at analyzing the endoscopic ultrasound appearance of pancreatic serotoninoma. METHODS: Between 2010 and 2016, all consecutive patients with histologically proven pancreatic serotoninoma who had undergone endoscopic ultrasound were enrolled. RESULTS: Eight patients (six F, median age 68.5 years) had a diagnosis of pancreatic serotoninoma and underwent endoscopic ultrasound examinations. Median diameter of the lesion was ten mm. The nodule echotexture was hypoechoic in seven out of eight cases. The most frequent localization was the pancreatic neck (four); in three cases, the tumor was located in the pancreatic head and in one in the body. In seven cases the tumor caused a main pancreatic duct dilation; in three cases also the secondary ducts were dilated. In one case a dilation of the common bile duct was observed. At contrast-enhanced endoscopic ultrasound no one showed the typical contrast-enhancement. Elastography (available in two patients) showed a rigid pattern of the lesion. CONCLUSIONS: From this case series a specific endoscopic ultrasound appearance resulted for pancreatic serotoninoma, different from other types of pancreatic neuroendocrine neoplasm, but it is difficult to differentiate it from a pancreatic adenocarcinoma or an intraductal papillary mucinous neoplasm.

Linked color imaging reduces the miss rate of neoplastic lesions in the right colon: a randomized tandem colonoscopy study.

BACKGROUND: Linked color imaging (LCI) is a newly developed image-enhancing endoscopy technology that provides bright endoscopic images and increases color contrast. We investigated whether LCI improves the detection of neoplastic lesions in the right colon when compared with high definition white-light imaging (WLI). METHODS: Consecutive patients undergoing colonoscopy were randomized (1:1) after cecal intubation into right colon inspection at first pass by LCI or by WLI. At the hepatic flexure, the scope was reintroduced to the cecum under LCI and a second right colon inspection was performed under WLI in previously LCI-scoped patients (LCI-WLI group) and vice versa (WLI-LCI group). Lesions detected on first- and second-pass examinations were used to calculate detection and miss rates, respectively. The primary outcome was the right colon adenoma miss rate. RESULTS: Of the 600 patients enrolled, 142 had at least one adenoma in the right colon, with similar right colon adenoma detection rates (r-ADR) in the two groups (22.7 % in LCI-WLI and 24.7 % in WLI-LCI). At per-polyp analysis, double inspection of the right colon in the LCI-WLI and WLI-LCI groups resulted in an 11.8 % and 30.6 % adenoma miss rate, respectively (P < 0.001). No significant difference in miss rate was found for advanced adenomas or sessile serrated lesions. At per-patient analysis, at least one adenoma was identified in the second pass only (incremental ADR) in 2 of 300 patients (0.7 %) in the LCI - WLI group and in 13 of 300 patients (4.3 %) in the WLI - LCI group (P = 0.01). CONCLUSIONS: LCI could reduce the miss rate of neoplastic lesions in the right colon.

Duodenal neuroendocrine neoplasms: a still poorly recognized clinical entity.

BACKGROUND: Duodenal neuroendocrine neoplasms (dNENs) are rare tumors, which usually show good prognosis. The optimal management of these tumors is still far from being clearly understood because of their rarity and the poor level of knowledge about their natural history. Herein, we have reviewed the literature on dNENs to collect and analyze the current data on epidemiology, diagnosis and management of these rare tumors. METHODS: Bibliographical searches were performed in PubMed, using the following keywords: duodenal neuroendocrine neoplasm; duodenum; gastrinoma; diagnosis; therapy; guidelines. We searched for all relevant articles published over the last 15 years. Non-English language papers were excluded. RESULTS: We reviewed the pertinent articles about dNENs. Upper gastrointestinal endoscopy with biopsy is the cornerstone of the dNENs diagnostic process. Endoscopic ultrasound with fine-needle aspiration/biopsy should be performed in order to locally stage the disease and in all cases of non-diagnostic endoscopy. Endoscopic or complete surgical removal of the primary lesion is the recommended treatment and is generally achievable for the majority of the patients. A less aggressive approach may be suggested for well-differentiated low-stage tumors. After NEN removal, patients should be closely followed-up especially during the first 3 years by endoscopic examination, imaging tests and CgA measurements. CONCLUSIONS: The multi-disciplinary approach and the preservation of the quality of life of the patients play a key role in the therapeutic process for dNENs. Further studies are needed to better define standardized guidelines specific to dNENs, including optimal management approaches and follow-up intervals.

Relevance of vitamin D deficiency in patients with chronic autoimmune atrophic gastritis: a prospective study.

BACKGROUND: Chronic autoimmune atrophic gastritis (CAAG) is an autoimmune disease characterized by hypo/achlorhydria. A role of CAAG in the pathogenesis of nutritional deficiencies has been reported, therefore we hypothesized a possible association between CAAG and 25-OH-Vitamin D [25(OH)D] deficiency. Aim of the present study is to evaluate the prevalence of 25(OH)D deficiency in CAAG patients. METHODS: 87 CAAG patients (71 females; mean age 63.5 ± 12.8 years) followed at our Centre from January 2012 to July 2015 were consecutively evaluated. 25(OH)D, vitamin B12, parathormone, and calcium were measured in all the CAAG patients. The results were compared with a control group of 1232 healthy subjects. RESULTS: In the CAAG group the mean 25(OH)D levels were significantly lower than in the control group (18.8 vs. 27.0 ng/ml, p < 0.0001). 25(OH)D levels < 20 ng/ml was observed in 57 patients, while levels < 12.5 ng/ml in 27 patients. A significant correlation between vitamin B12 values at diagnosis and 25(OH)D levels was observed (rs = 0.25, p = 0.01). Interestingly, the CAAG patients with moderate/severe gastric atrophy had lower 25(OH)D values as compared to those with mild atrophy (11.8 vs. 20 ng/ml; p = 0.0047). Moreover, the 25(OH)D levels were significantly lower in CAAG patients with gastric carcinoid as compared to those without gastric carcinoid (11.8 vs. 19.8 ng/ml; p = 0,0041). CONCLUSION: Data from the present study showed a significant reduction of 25(OH)D levels in CAAG patients and a possible impairment of vitamin D absorption in CAAG may be postulated. Any implication to the genesis of gastric carcinoids remains to be elucidated.

Celiac Disease 30 Years After Diagnosis: Struggling With Gluten-free Adherence or Gaining Gluten Tolerance?

OBJECTIVES: Studies investigating patients with coeliac disease (CD) on very long-term follow-up are limited. We aimed to evaluate the characteristics of patients with CD diagnosed more than 30 years ago. METHODS: Clinical, histologic, genetic, and demographic data of patients with CD diagnosis made before 1985 were collected and their standardised mortality ratio calculated. According to the gluten-free diet (GFD) status, CD patients were divided into 3 groups and a specific questionnaire on GFD awareness and gluten-free products was administered to patients and caregivers. RESULTS: A total of 337 CD patients were included in the study. The standardised mortality ratio was 0.37 (confidence interval 0.10 to 0.94) compared with a matched population. A total of 197 patients were grouped according to GFD compliance, with 35 CD patients reporting chronic voluntary gluten ingestion. No significant differences were found between groups regarding family history of CD, symptoms and histology at diagnosis, autoimmune disorders. Follow-up histology was performed in 63 patients. Twenty patients had normal histology on gluten-containing diet (GCD). Questionnaire scores were lower in patients on GCD. Caregivers scores were not correlated with patients' gluten consumption. CONCLUSIONS: Although poor adherence to GFD is the major predictor of persistence of mucosal lesions at follow-up histology, a proportion of patients did not show a relapse of villous atrophy in spite chronic voluntary gluten ingestion, nor increase in mortality. Moreover, GFD knowledge and adherence could be partly lost during the transition between childhood and adulthood.

Point shear-wave elastography in chronic pancreatitis: A promising tool for staging disease severity.

BACKGROUND: Objectives: ElastPQ®-pSWE is an ultrasound technique developed to stage disease severity in patients with chronic liver diseases. Little data is available about its application to the pancreas. We aimed to assess the feasibility and reproducibility of pancreatic stiffness (PS) measurements in patients with chronic pancreatitis and their relationship with clinical and laboratory data. MATERIAL AND METHODS: 52 consecutive patients with chronic pancreatitis (CP) (40 males; median age 60 years) underwent hepatic and pancreatic pSWE. Liver stiffness was measured by transient elastography, 42 healthy subjects being controls (25 males; median age 54 years). Pancreatic pSWE inter-observer agreement was analyzed by intraclass correlation coefficient (ICC). The effects of clinical, laboratory and US data on PS measurements were evaluated by linear regression. RESULTS: pSWE was feasible in all the CP patients, but one. Pancreatic stiffness was significantly higher in CP patients than healthy controls (4.3 ± SD 2.4 vs. 2.8 ± SD 1.1 kPa, respectively, p = 0.001). Significantly higher values in the CP group were observed in patients with longer disease duration (>10 vs. ≤10 years) (5.8 ± SD 4 vs. 3.9 ± SD 1.5 kPa, respectively, p = 0.01), on chronic analgesic drugs (6.0 vs. 3.5 kPa, p < 0.05) and with lower body weight (p < 0.05, r = -0.38). At multivariate analysis all the three variables resulted independently associated to the pancreatic stiffness value. The ICC for PS was 0.77. CONCLUSIONS: ElastPQ®-pSWE is promising and reproducible in assessing pancreatic stiffness, which mainly reflects disease length and severity. Accordingly, its use is of potential value in stratifying CP patients by identifying those with a more serious degree of disease.

Use of enteroscopy for the detection of malignant and premalignant lesions of the small bowel in complicated celiac disease: a meta-analysis.

BACKGROUND AND AIMS: Enteroscopy (wireless or wired) is the reference standard for small-bowel (SB) diseases, and it has been applied to detect SB malignancies in complicated celiac disease (CD) with heterogeneous results. The aim of this meta-analysis was to obtain a diagnostic yield (DY) by pooling the data of studies that investigated the use of enteroscopy to detect SB adverse events in CD. METHODS: We performed an online search for studies estimating the DY of wireless and wired enteroscopy in predicting the presence of SB premalignant and/or malignant lesions. The DerSimonian and Laird random-effects method was used to pool the arcsine-transformed proportions of patients with the events. Three meta-analyses were performed considering the following events: the presence of a malignancy, premalignant damage (ulcerative jejunoileitis [UJ]), or the presence of a malignancy or UJ. A subgroup analysis was performed after extracting (if possible) patients with refractory CD (RCD). RESULTS: Of the 529 titles initially resulting from the search, 10 studies on capsule enteroscopy (CE) and 3 on double-balloon or push enteroscopy met the inclusion criteria. Overall, 439 and 76 patients were enrolled in these studies using CE and enteroscopy, respectively. Twelve tumors and 47 UJs were found by CE versus 8 tumors and 13 UJs detected by wired enteroscopy. For malignancies the CE yield was 1.9% (95% CI, .5%-3.8%) and wired enteroscopy yield 8.7% (95% CI, 0%-21.2%); similarly, for UJ the DYs were 8.4% (95% CI, 2.1%-17.7%) and 16.7% (95% CI, 8.7%-26.3%); for either UJ or neoplasia the DYs were 13.0% (95% CI, 5.6%-22.5%) and 27.7% (95% CI, 14.8%-42.6%). For RCD the DYs of all enteroscopic techniques were 1.8% (95% CI, 0%-7.7%) for neoplasia, 22.3% (95% CI, 8.2%-39.7%) for UJ, and 27.5% (95% CI, 13.1%-44.2%) for either. CONCLUSIONS: Enteroscopy is a powerful and efficient diagnostic tool for the detection of SB malignancies in complicated CD.

Impact of Vitamin D on the Clinical Outcome of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: Report on a Series from a Single Institute.

BACKGROUND/AIMS: Vitamin D deficiency is hypothesized to represent a risk factor in several neoplasms. The aim of this study was to determine whether serum 25-hydroxyvitamin D (25-OHvitD) deficiency represents a risk factor for neuroendocrine neoplasms (NENs) and can be associated with overall survival (OS) and progression-free survival (PFS). METHODS: From 2010 to 2015, 138 patients with gastro- entero-pancreatic NENs (61 females; median age, 63 years) were included in the study. Serum 25-OHvitD levels, which were measured at baseline, were defined as deficient if ≤20 ng/mL. In such cases, 25-OHvitD supplementation was administered to the patients. The possible associations between 25-OHvitD levels and disease grading, staging, overall OS, and PFS were considered. Furthermore, the possible association between 25-OHvitD supplementation and PFS or OS was evaluated by Cox proportional hazards regression. RESULTS: Median 25-OHvitD levels were 12.9 ng/mL (range 2-32); in detail, 94 patients (68%) had ≤20 ng/mL, with 46 cases (33%) having ≤10 ng/mL. An inverse correlation was observed between 25-OHvitD levels and OS (p = 0.03, rs = -0.18) and PFS (p = 0.01, rs = -0.22). At Cox proportional hazards regression, mortality was not related to 25-OHvitD levels; however, there was an association between 25-OHvitD supplementation and OS (p < 0.002). CONCLUSIONS: Vitamin D deficiency is highly prevalent among NEN patients. 25-OHvitD supplementation potentially plays an important role in the correction of 25-OHvitD values, and has an influence on the clinical outcome. However, further studies are needed to confirm this observation.

Anti-sulfatide reactivity in patients with celiac disease.

OBJECTIVE: To explore a possible significance of the presence of anti-ganglioside and anti-sulfatide antibodies in sera of adult patients with celiac disease (CD) in different clinical scenario. METHODS: We selected 22 adult patients with newly diagnosed CD and 20 age-sex matched non-CD controls. Patients' serum was tested - before and after at least 6 months on a gluten-free diet (GFD) - for anti-GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b and sulfatide IgM, IgG and IgA auto-antibodies, by means of a dot blot technique and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found the presence of auto-antibodies in untreated patients. In particular, anti-sulfatide IgG antibodies were present in 8 (36%) patients independently of the presence of neurological symptoms. Anti-sulfatide IgA antibodies were present in 3 (19%) patients. During GFD, anti-sulfatide IgG disappeared in all the patients, whereas IgA were observed in 2 patients. Anti-sulfatide, anti-GM1 and anti-GM2 IgM antibodies were also observed in 2 patients on a GFD. All the other auto-antibodies were absent and no demographic or clinical parameters were associated. Non-CD controls did not present any auto-antibody. CONCLUSIONS: We found anti-sulfatide IgG antibodies in CD patients on a gluten-containing diet. Anti-sulfatide IgA antibodies persisted during GFD together with the occurrence of other IgM auto-antibodies. These data suggest a possible link between gluten and IgG auto-antibodies.

Coping with celiac disease: how heavy is the burden for caregivers?

BACKGROUND: Celiac disease (CD) is the most common chronic enteropathy demanding a lifelong gluten-free diet. OBJECTIVE: The aim of the study was to identify and estimate the subjective burden of caregivers of celiac patients. METHODS: A cross-sectional observational study was conducted during the regional meeting of the Italian Society for the Celiac Disease in April 2014. A written self-administered anonymous questionnaire enquired into caregivers' demographic profile, natural history of patients' disease and caregivers' self-reported degree of burden at the onset of symptoms (T0), at CD diagnosis (T1) and during follow-up (T2). Fifty-five caregivers completed the questionnaire (69% females, 47 ± 13 years old, 73% first-degree relatives). RESULTS: The presence of warning symptoms, such as abdominal pain, chronic diarrhea and weight loss was responsible for higher levels of concern. A statistically significant reduction of concern in the follow-up was demonstrated by the comparison of visual analogue scales (VAS) values from T0 to T2 and from T1 to T2 (6.8 ± 3.1 vs 4.2 ± 2.9 and 7.0 ± 2.5 vs 4.2 ± 2.9, respectively; p < 0.001), mirroring the reduction of distress among newly diagnosed individuals. A global impact of gluten-free diet and CD on quality of life was reported in VASs (6.7 ± 2.4). Family (5.4 ± 3.1), social (5.6 ± 2.9) and economic (4.5 ± 3.4) domains were the most associated. CONCLUSION: The assessment of caregivers' subjective burden should be considered as an essential step in the evaluation of celiac patients, needing a specific investigation and support.

A new duodenal rendezvous technique for biliary cannulation in patients with T-tube after orthotopic liver transplantation (with video).

BACKGROUND AND AIMS: Because a traditional rendezvous (RV) technique implies stretching of the papilla, possibly leading to post-ERCP pancreatitis, an alternative duodenal RV technique was evaluated. The aim was to assess the effectiveness, safety, and amount of time spent performing duodenal RV versus traditional RV cannulation in orthotopic liver transplantation patients with a T-tube. METHODS: We retrospectively reviewed data from a prospective ERCP database held by our university hospital. Twenty patients with a T-tube who had undergone ERCP for biliary adverse events after orthotopic liver transplantation were included. The successful cannulation rate, the amount of time spent performing cannulation, the post-ERCP pancreatitis rate, and hyperamylasemia 24 hours after the procedure were recorded. RESULTS: Successful cannulation was achieved by the duodenal RV technique in 9 of 10 patients (90%), taking 146 seconds (interquartile range 63-341 seconds) with a short learning curve effect. An unsuccessful duodenal RV procedure occurred because of the angulation of the hydrophilic tip of the guidewire while crossing the papilla, thus preventing cannulation. Successful cannulation was achieved by the traditional RV technique in all cases (N = 11), including the failed duodenal RV technique, taking 374 seconds (interquartile range 320-410 seconds) (P < .05 vs duodenal RV). However, no post-ERCP pancreatitis occurred after using the duodenal RV technique compared with 2 episodes of mild pancreatitis after using the traditional RV technique. Twenty-four hours after the procedure, the median amylasemia level was 84 IU/L (interquartile range 49-105 IU/L) and 265 IU/L (interquartile range 73-2945 IU/L) for the duodenal versus traditional RV techniques, respectively (P = not significant). CONCLUSIONS: In patients with a T-tube after liver transplantation, the duodenal RV technique was not associated with post-ERCP pancreatitis, presumably because of the reduction of stress on the major papilla. Cannulation by using the duodenal RV technique was faster compared with the traditional RV technique. These preliminary data point out the use of the duodenal RV technique as the first option to choose in case of failed cannulation before attempting the traditional RV technique.

Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve?: The Experience of 2 European Tertiary Referral Centers.

BACKGROUND: Indications to double-balloon enteroscopy (DBE) are not standardized in celiac disease (CD). GOALS: To evaluate the clinical usefulness of DBE in complicated CD. STUDY: DBE findings in celiac patients with suspected small bowel (SB) complications were retrospectively evaluated in 2 tertiary referral centers (Milan and Sheffield). Demographic data of the studied cohort were compared with a database of 1000 noncomplicated CD patients. RESULTS: Twenty-four CD cases (12 males, P=0.01 vs. controls) were reviewed. Mean age at CD diagnosis (y±SD) was 37±20 versus 27±18 and at SB evaluation 47±15 versus 38±13 (P<0.01 compared with controls). Indications for DBE were refractory CD (#9), gastrointestinal symptoms (#6), severe iron-deficiency anemia (#6), and long standing poor dietary adherence (#3). Two jejunal adenocarcinomas and an ileal neuroendocrine tumor were detected in presence of iron-deficiency anemia. Three type I and 3 type II refractory CD patients showed jejunal ulcerations; 2 of type II presented small white raised patches. Patchy atrophy was observed in nonadherent patients and in 2 on a gluten-free diet for a short time. Therapy was planned in 33% of patients after DBE. No adverse events were detected at follow-up [21 mo (range, 0 to 60 mo)]. CONCLUSIONS: This is the largest international study on the outcomes of DBE in CD demonstrating its usefulness to exclude/confirm malignant or premalignant conditions, associated with even minor lesions. Studies are needed to understand the clinical relevance of the SB endoscopic features and to optimize DBE indications.

Somatostatin analogues in functioning gastroenteropancreatic neuroendocrine tumours: literature review, clinical recommendations and schedules.

OBJECTIVE: Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms, which include functioning and non-functioning forms. Somatostatin analogues (SSAs) play a key role in the management of these tumours. Herein, we aimed at reviewing the current evidence about the role of SSAs in the treatment of gastro-entero-pancreatic (GEP)-NETs. MATERIAL AND METHODS: An extensive bibliographical search was performed in PubMed using the following keywords: gastro-entero-pancreatic neuroendocrine tumours, somatostatin analogues, octreotide, lanreotide, in order to identify all the pertinent English-written articles published between 1990 and 2015. RESULTS: SSAs have shown to help the symptomatic and biochemical improvement of patients with NETs and to exhibit a good safety profile. Recent studies have also reported a role for SSAs in tumour growth control, although the results are less impressive and the underlying mechanisms are not fully understood. CONCLUSIONS: SSAs are well known as a symptomatic and, to lesser extent, anti-proliferative treatment in GEP-NETs. However, some issues, including optimal dosage, benefits and adverse events of combination with other molecules, and the role of new analogues, remain to be elucidated in further randomised studies.

Celiac Disease and Drug-Based Therapies: Inquiry into Patients Demands.

BACKGROUND/AIM: Medical research is looking for alternative drug-based options to the gluten-free diet (GFD) for celiac disease. We aimed at evaluating the need for alternative therapies perceived by celiac patients. METHODS: During the 2013 meeting of the Lombardy section of the Italian Celiac Patients Association, adult subjects were invited to fill in a questionnaire investigating their clinical profile in relation to compliance to the diet, quality of life (QOL) as well as their opinion on alternative therapies. RESULTS: Three hundred and seventy two patients (76 m, mean age 41.7 ± 13.9 years) completed the questionnaire. Patients reported a significant improvement in health status (HS) and QOL after the diet was started (p < 0.001). The GFD was accepted by 88% patients, but the need for alternative therapies was reported by 65%. Subjects expressing the need for a drug-based therapy showed a lower increase in QOL (p = 0.003) and HS (p = 0.005) on GFD. The preferred option for an alternative therapy was the use of enzymes (145 subjects), followed by a vaccine (111 subjects). CONCLUSION: The GFD is favorably accepted by most celiac patients. Nevertheless, a proportion of patients pronounce themselves in favor of the development of alternative drugs.

Non-steroid anti-inflammatory drugs for biliary colic.

BACKGROUND: Cholelithiasis refers to the presence of gallstones, which are concretions that form in the biliary tract, usually in the gallbladder. Cholelithiasis is one of the most common surgical problems worldwide and is particularly prevalent in most Western countries.Biliary colic is the term used for gallbladder pain experienced by a person with gallstones and without overt infection around the gallbladder. It is the most common manifestation of cholelithiasis, observed in over one-third of people with gallstones over the course of 10 or more years. Non-steroid anti-inflammatory drugs (NSAIDs) have been widely used to relieve biliary colic pain, but their role needs further elucidation. They may decrease the frequency of short-term complications, such as mild form of acute cholecystitis, jaundice, cholangitis, and acute pancreatitis, but they may also increase the occurrence of more severe and possibly life-threatening adverse events such as gastrointestinal bleeding, renal function impairment, cardiovascular events, or milder events such as abdominal pain, drowsiness, headache, dizziness, or cutaneous manifestations. OBJECTIVES: To assess the benefits and harms of NSAIDs in people with biliary colic. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (Ovid SP), Embase (Ovid SP), Science Citation Index Expanded (Web of Science), and ClinicalTrials.gov until July 2016. We applied no language limitation. SELECTION CRITERIA: Randomised clinical trials recruiting participants presenting with biliary colic and comparing NSAIDs versus no intervention, placebo, or other drugs. DATA COLLECTION AND ANALYSIS: Two review authors (MF and AC) independently identified trials for inclusion. We used risk ratios (RR) to express intervention effect estimates, and we analysed the data with both fixed-effect and random-effects model meta-analyses, depending on the amount of heterogeneity. We controlled random errors with Trial Sequential Analysis. We assessed the methodological quality of the evidence using GRADE criteria. MAIN RESULTS: Twelve randomised clinical trials (RCTs) met our predefined review protocol criteria for analysis. We found only one trial to be at low risk of bias, considering the remaining trials to be at high risk of bias. The risk of selection bias in nine studies was unclear due to poor reporting, leading to uncertainty in the pooled effect estimates. Five trials compared NSAIDs versus placebo, four trials compared NSAID versus opioids, and four trials compared NSAID versus spasmolytic drugs (one of the 12 trials was a three-arm study comparing NSAIDs versus both opioids and spasmolytic drugs). There were 828 randomised participants (minimum 30 and maximum 324 per trial), of whom 416 received NSAIDs and 412 received placebo, spasmolytic drugs, or opioids. Twenty-four per cent of the participants were males. The age of the participants in the trials ranged from 18 to 86 years. All people were admitted to emergency departments for acute biliary pain. There was no mortality. When compared with placebo, NSAIDs obtained a significantly lower proportion of participants without complete pain relief (RR 0.27, 95% confidence interval (CI) 0.19 to 0.40; I2 = 0%; 5 trials; moderate-quality evidence), which was confirmed by Trial Sequential Analysis, but not regarding participants with complications (RR 0.66, 95% CI 0.38 to 1.15; I2 = 26%; 3 trials; very low-quality evidence). NSAIDs showed more pain control than spasmolytic drugs (RR 0.51, 95% CI 0.37 to 0.71; I2 = 0%; 4 trials; low-quality evidence), which was not confirmed by Trial Sequential Analysis, and a significantly lower proportion of participants with complications (RR 0.27, 95% CI 0.12 to 0.57; I2 = 0%; 2 trials; low-quality evidence), which was also not confirmed by Trial Sequential Analysis. We found no difference in the proportions of participants without complete pain relief when comparing NSAIDs versus opioids (RR 0.98, 95% CI 0.47 to 2.07; I2 = 52%), suggesting moderate heterogeneity among trials (4 trials; very low-quality evidence). Only one trial comparing NSAIDs versus opioids reported results on complications, finding no significant difference between treatments. None of the included trials reported severe adverse events. Seven out of the 12 trials assessed non-severe adverse events: in two out of the seven trials, adverse events were not observed, and minor events were reported in the remaining five trials.In addition, we found one ongoing RCT assessing the analgesic efficacy of intravenous ibuprofen in biliary colic. AUTHORS' CONCLUSIONS: NSAIDs have been assessed in relatively few trials including a limited number of participants for biliary colic, considering its common occurrence. We found only one trial to be at low risk of bias. There was no mortality. None of the included trials reported quality of life. The generalisability of the review is low as most of the RCTs included neither elderly people nor participants with comorbidities, who are more prone to complications as compared to others with biliary colic.The beneficial effect of NSAIDs compared with placebo on pain relief was confirmed when we applied Trial Sequential Analysis.The quality of evidence according to GRADE criteria was moderate for the comparison of NSAIDs versus placebo regarding the outcome lack of pain relief and low or very low for the other outcomes and comparisons.We found only one trial at low risk of bias, following the predefined 'Risk of bias' domains. We found the risk of selection bias to be unclear in nine studies due to poor reporting, leading to uncertainty in the pooled effect estimates.

The architecture of diagnostic research: from bench to bedside--research guidelines using liver stiffness as an example.

UNLABELLED: The diagnostic research process can be divided into five phases, designed to establish the clinical utility of a new diagnostic test--the index test. The aim of the present review is to illustrate the study designs that are appropriate for each diagnostic phase, using clinical examples regarding liver fibrosis diagnosed with transient elastography, when possible. Phase 0 is the preclinical pilot phase during which the validity, reliability, and reproducibility of the index test are assessed in healthy and diseased people. Phase I is designed to describe the distribution of the index test results in healthy people and its normal values. Phase IIA comprises studies designed to estimate the accuracy (sensitivity and specificity) of the index test in discriminating between diseased and nondiseased people in a clinically relevant population. Phase IIB studies allow the comparison of the accuracy of different index tests; Phase IIC studies aim to evaluate the possible harms of incorporating the index test in a diagnostic-therapeutic strategy. In phase III, diagnostic test-therapeutic randomized clinical trials aim to assess the benefits and harms of the new diagnostic-therapeutic strategy versus the present strategy. Phase IV comprises large surveillance cohort studies that aim to assess the effectiveness of the new diagnostic-therapeutic strategy in clinical practice. CONCLUSION: As common in clinical research, giving excessive weight to the results of single studies and trials is likely to divert from the totality of evidence obtained through the systematic reviews of these studies, conducted with rigorous methodology and statistical methods. (Hepatology 2014;60:408-418).