Germline variant testing in serrated polyposis syndrome.

BACKGROUND AND AIM: Serrated polyposis syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 British Society of Gastroenterology (BSG) guidelines advise gene panel testing if the patient is under 50 years, there are multiple affected individuals within a family, or there is dysplasia within any of the polyps. METHODS: A database of SPS patients was established at the Oxford University Hospitals NHS Foundation Trust. Patients were referred for genetic assessment based on personal and family history and patient preference. The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40-kb duplication), PMS2, and Lynch syndrome mismatch repair genes. RESULTS: One hundred and seventy-three patients were diagnosed with SPS based on World Health Organization 2019 criteria between February 2010 and December 2020. The mean age of diagnosis was 54.2 ± 16.8 years. Seventy-three patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n = 1). Only 60% (9/15) of these patients would have been recommended for gene panel testing according to current BSG guidelines. CONCLUSIONS: A total of 20.5% of SPS patients tested were affected by heterozygous germline variants, including previously unreported associations with CHEK2 and POLD1. This led to a change in management in seven patients (9.6%). Current recommendations may miss SPS associated with germline variants, which is more common than previously anticipated.

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial.

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

Endoscopic mucosal resection of early oesophageal neoplasia in patients requiring anticoagulation: is it safe?

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) has become the standard treatment for early oesophageal neoplasia. The mucosal defect caused by EMR usually takes several weeks to heal. Despite guidelines on high-risk endoscopic procedures in patients on anticoagulation, evidence is lacking whether EMR is safe in such patients. We investigated the immediate and delayed bleeding risk in patients undergoing diagnostic or therapeutic oesophageal EMR comparing patients requiring warfarin anticoagulation with a control group. METHODS: Warfarin was stopped 5 days before the planned EMR and restarted on the evening following the procedure. Patients with high-risk conditions, such as recent pulmonary thromboemboli, received bridging with low molecular weight heparin. All EMRs were performed when the INR was <1.5. Bleeding events on the day of the EMR and within 3 months post-procedure were documented. RESULTS: One hundred and seventeen consecutive patients with early oesophageal neoplasia were included. Sixty-eight EMRs were performed in 15 patients requiring anticoagulation. One patient on warfarin was readmitted 10 days after EMR with haematemesis and melaena. Out of 400 EMRs in 102 controls, 26 immediate bleeding events occurred requiring endoscopic intervention. One delayed bleeding event (melaena) occurred in the control group. The number of bleeding events did not differ between groups [p = 0.99; odds ratio 1.01 (0.30-3.44)], neither for acute (p = 0.76) nor delayed bleeding (p = 0.24). CONCLUSION: EMR of early oesophageal neoplasia can be safely performed in patients requiring anticoagulation when warfarin is discontinued 5 days before the endoscopic intervention and reinstituted on the evening of the procedure day.

Extracorporeal shock wave lithotripsy with a transportable mini-lithotripter and subsequent endoscopic treatment improves clinical outcome in obstructive calcific chronic pancreatitis.

BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) of pancreatic duct stones followed by ERCP with mechanical clearance of the pancreatic duct and subsequent stenting is an established treatment option for chronic calcific pancreatitis. OBJECTIVE: To test the efficacy of a modified transportable mini-lithotripter for ESWL of pancreatic duct stones. DESIGN: Prospective single-center study. SETTING: University hospital. PATIENTS: This study involved 32 patients with obstructive chronic calcific pancreatitis and pain in whom previous endoscopic stone removal and pancreatic duct decompression had failed. INTERVENTIONS: ESWL followed by ERCP for stone clearance of the pancreatic duct and mechanical removal of stones or stenting. MAIN OUTCOME MEASUREMENTS: Endoscopic duct clearance and/or stent insertion, pain and quality-of-life scores. RESULTS: A median of 4 ESWL sessions (interquartile range 2.75-8.5) with a median of 6800 shock waves (4225-15,425) were required. Pain relief after ESWL only was noted in 24 patients (75.0%), whereas no change in the intensity of pain was reported by 7 patients (21.9%), and pain was worse in 1 patient. All patients underwent ERCP and stent placement, resulting in complete resolution of pain in 17 patients (53.1%) and pain improvement in 28 patients (87.5%). The quality-of-life score was significantly improved after ESWL and endoscopic clearance or stenting in all patients. LIMITATIONS: Uncontrolled study. CONCLUSIONS: ESWL with the mini-lithotripter results in fragmentation of pancreatic duct calculi. ESWL in conjunction with endoscopic clearance of the pancreatic duct and stenting is associated with significant improvement in clinical outcome and quality of life in patients with obstructive calcific chronic pancreatitis.

Severity of initial stent angulation predicts reintervention after successful palliative enteral stenting for malignant luminal obstruction.

BACKGROUND AND AIM: Recurrent stent obstruction necessitating reintervention is problematic and incompletely understood. The aim of the present study was to identify factor(s) predisposing to reintervention. METHODS: Retrospective review of patients (n = 117) referred to a single major endoscopic referral centre for palliative enteral stenting from 1999 to 2006. Twelve were excluded due to inadequate follow-up data (n = 7) or initial radiographic documentation (n = 5). A total of 105 patients (gastroduodenal n = 57, colonic n = 48) were therefore analyzed. The primary outcome of interest was recurrent obstruction necessitating reintervention. Kaplan-Meier analysis of potential factors predisposing to reintervention, including stent angulation (mild [<15°], moderate [15°-90°], severe [>90°]) was completed for 98 patients (technically successful enteral stenting). RESULTS: Technical and clinical success were achieved in 98 of 105 (93.3%) and 92 of 98 (93.9%) cases, respectively. Post-stenting median survival was 97.5 days (range 3-1054). Eighteen patients (18.4%) required reintervention for stent obstruction at a median time to reintervention of 85 days (range 7-481). Increased stent angulation (severe vs mild hazard ratio 6.73 (95% confidence interval 1.59-27.59), P = 0.009) was the only statistically significant factor in multivariate analysis predicting reintervention. CONCLUSIONS: Despite its limitation as a retrospective review, this study found that reintervention for stent obstruction is necessary in almost one in five cases, and increasing severity of stent angulation is the most important risk factor.

Endoscopic resection for Barrett's high-grade dysplasia and early esophageal adenocarcinoma: an essential staging procedure with long-term therapeutic benefit.

OBJECTIVES: Patients with Barrett's high-grade dysplasia (HGD) or early esophageal adenocarcinoma (EAC) that is shown on biopsy alone continue to undergo esophagectomy without more definitive histological staging. Endoscopic resection (ER) may provide more accurate histological grading and local tumor (T) staging, definitive therapy, and complete Barrett's excision (CBE); however, long-term outcome data are limited. Our objective was to demonstrate the effect on histological grade or local T stage, efficacy, safety and long-term outcome of ER for Barrett's HGD/EAC and of CBE in suitable patients. METHODS: This prospective study at two Australian academic hospitals involved 75 consecutive patients over 7 years undergoing ER for biopsy-proven HGD or EAC, using multiband mucosectomy or cap technique. In addition, CBE by 2-3-stage radical mucosectomy was attempted for all Barrett's segments

Needle-knife sphincterotomy: factors predicting its use and the relationship with post-ERCP pancreatitis (with video).

BACKGROUND: In the absence of precut needle-knife sphincterotomy (NKS), failure of biliary cannulation may occur in up to 10% of cases. There are few prospective evaluations of the safety and efficacy of NKS, and studies of its early use in difficult cannulation have been inconclusive. Whether precut NKS after failure of primary biliary cannulation is independently associated with post-ERCP pancreatitis (PEP) remains controversial. OBJECTIVE: To examine the relationship between NKS and PEP. DESIGN: Analysis of prospectively collected data from two randomized trials of ERCP techniques, with PEP as the primary endpoint measure. SETTING: Tertiary-care academic medical center. PATIENTS: This study involved 732 patients from two successive, prospective, randomized trials of naïve papilla cannulation between November 2001 and April 2006. Patients with pancreatic or ampullary cancer were excluded. INTERVENTION: Naïve papilla cannulation, NKS, primary guidewire versus contrast-assisted cannulation, and glyceryl trinitrate patch versus placebo. MAIN OUTCOME MEASUREMENTS: PEP and procedure-related complications. RESULTS: NKS was performed in 94 of 732 patients (12.8%) and was successful in achieving bile duct access in 80 of 94 patients (85%). Cannulation success in the entire group was 717 of 732 patients (97.7%). The overall frequency of PEP following NKS was 14.9% (14 of 94 patients) compared with 6.1% (39 of 638 patients) without NKS (P < .001). The incidence of PEP increased with an increasing number of attempts at cannulating the papilla. Pancreatic stents were inserted in 22 patients, 5 of whom developed pancreatitis. In multivariate analysis, independent predictors of PEP were as follow: female sex (odds ratio [OR] = 3.5, P = .028), suspected sphincter of Oddi dysfunction (SOD) (OR = 9.7, P < .001), partial pancreatic drainage (OR = 4.8, P = .011), 10 to 14 attempts at papilla cannulation (OR = 4.4, P = .031), and >/=15 attempts at papilla cannulation (OR = 9.4, P = .013). NKS was not an independent predictor of PEP. There were no perforations, no major bleeding, and no cases of severe pancreatitis in the NKS group. LIMITATIONS: Nonrandomized for NKS intervention. CONCLUSIONS: The number of attempts at cannulating the papilla is independently associated with PEP, and the risk increases with an increasing number of attempts. NKS is not an independent predictor of PEP.

Non-radical, stepwise complete endoscopic resection of Barrett's epithelium in short segment Barrett's esophagus has a low stricture rate.

Background and aims: Radical endoscopic excision of Barrett's epithelium performing 4 - 6 endoscopic resections during the same endoscopic session results in complete Barrett's eradication but has a high stricture rate (40 - 80 %). Therefore radiofrequency ablation is preferred after endoscopic mucosal resection (EMR) of visible nodules. We investigated the clinical outcome of non-radical, stepwise endoscopic mucosal resection with a maximum of two endoscopic resections per endoscopic session. Methods: We analysed our prospectively maintained database of patients undergoing esophageal EMR for early neoplasia in Barrett's esophagus from 2009 to 2014. EMR was performed using a maximum of two band ligation mucosectomies per endoscopic session; thereafter, follow-up was 3-monthly and EMR was repeated as required for Barrett's eradication. Results: In total, 118 patients underwent staging EMR for early Barrett's neoplasia. Subsequently, 27 patients underwent surgery/chemotherapy due to deep submucosal or more advanced tumor stages or were managed conservatively. The remaining 91 patients with high grade dysplasia (48), intramucosal (38) or submucosal cancer (5) in the resected nodule underwent further endoscopic therapy with a mean follow-up of 24 months. Remission of dysplasia/neoplasia was achieved in 95.6 % after 12 months treatment. Stepwise endoscopic Barrett's resection resulted in complete Barrett's eradication in 36/91 patients (39.6 %) in a mean of four sessions; 40/91 patients (44.0 %) had a short circumferential Barrett's segment (< 3 cm). In this group, repeated EMR achieved complete Barrett's excision in 85.0 %. One patient developed a stricture (1.1 %), one a delayed bleeding, and there were no perforations. Conclusion: In patients with a short Barrett's segment, non-radical endoscopic Barrett's resection at the time of scheduled endoscopy follow-up allows complete Barrett's eradication with very low stricture rate.

Postpolypectomy haemorrhage following removal of large polyps using mechanical haemostasis or epinephrine: a meta-analysis.

BACKGROUND AND AIM: Postpolypectomy haemorrhage (PPH) is a known adverse event that can occur following polypectomy, occurring in 0.3-6.1% of cases. Previous meta-analysis has included small polyps, which are less likely to bleed, and less amenable to some methods of mechanical haemostasis. No comprehensive cost-benefit analysis of this topic is available. The aim of this study was to perform a meta-analysis of randomized trials and a cost-benefit analysis of prophylactic haemostasis in PPH. METHODS: A total of 3092 abstracts from prospective trials conducted in human colonoscopic polypectomy were screened. Outpatients undergoing polypectomy in seven suitable studies (1426 episodes), without polyposis syndromes or bleeding diathesis, were identified. The interventions of prophylactic haemostatic measures (clips, loops, and/or adrenaline injection) to prevent PPH were assessed. The main outcome measurements were PPH measured by haematochezia or drop in haematocrit >10% or haemoglobin >1 g/dl. Risk ratio and number needed to treat (NNT) were generated using meta-analysis. RESULTS: Comparing any prophylactic haemostasis to none, the pooled risk ratio for PPH was 0.35 (0.21-0.57; p < 0.0001), NNT was 13.6, and cost to prevent one PPH was USD652. Using adrenaline alone vs. no prophylactic haemostasis revealed a pooled risk ratio of 0.37 (0.20-0.66; p = 0.001), NNT 14.0, cost to prevent one PPH USD382. Any prophylactic mechanical haemostasis compared to adrenaline produced a RR for PPH of 0.28 (0.14-0.57; p < 0.0001), NNT 12.3, and cost to prevent one PPH USD1368. CONCLUSIONS: Adrenaline injection or mechanical haemostasis reduces the risk of PPH. Routine prophylactic measures to reduce PPH for polyps larger than 10 mm are potentially cost effective, although more thorough cost-benefit modelling is required.

Narrow band imaging facilitates detection of inlet patches in the cervical oesophagus.

BACKGROUND: Proximal esophageal heterotopic gastric mucosa or so-called inlet patch in the cervical oesophagus is easily missed on endoscopic examination because of its localisation, usually just below the upper oesophageal sphincter. We evaluated the clinical use of narrow band imaging for detection of inlet patches. METHODS: In this prospective, controlled observational study, 1407 subsequent patients underwent oesophagogastroduodenoscopy with or without narrow band imaging on withdrawal of the endoscope in the cervical oesophagus. RESULTS: One endoscopist who was not aware of the prospective observation documented 6 (1.17%) cases of inlet patches in 515 oesophagogastroduodenoscopies compared to 4 cases out of 382 (1.05%) performed by the endoscopist who paid special attention to the presence of inlet patches but did not routinely apply narrow band imaging (OR 0.89, CI 95% 0.25-3.20, p=0.85). In comparison, 17 cases of inlet patches out of 510 (3.33%) were detected by the endoscopist who routinely applied narrow band imaging. The detection rate of proximal oesophageal heterotopic gastric mucosa using narrow band imaging was significantly higher compared to white light endoscopy only (OR 3.06, CI 95% 1.39-6.73, p=0.005). CONCLUSIONS: Withdrawal of the endoscope from the cervical oesophagus using narrow band imaging increased the detection of inlet patches about three-fold compared to standard white light endoscopy.

Repeat endoscopic retrograde cholangiopancreaticography after failed initial precut sphincterotomy for biliary cannulation.

AIM: To investigate the outcome of repeating endoscopic retrograde cholangiopancreaticography (ERCP) after initially failed precut sphincterotomy to achieve biliary cannulation. METHODS: In this retrospective study, consecutive ERCPs performed between January 2009 and September 2012 were included. Data from our endoscopy and radiology reporting databases were analysed for use of precut sphincterotomy, biliary access rate, repeat ERCP rate and complications. Patients with initially failed precut sphincterotomy were identified. RESULTS: From 1839 consecutive ERCPs, 187 (10%) patients underwent a precut sphincterotomy during the initial ERCP in attempts to cannulate a native papilla. The initial precut was successful in 79/187 (42%). ERCP was repeated in 89/108 (82%) of patients with failed initial precut sphincterotomy after a median interval of 4 d, leading to successful biliary cannulation in 69/89 (78%). In 5 patients a third ERCP was attempted (successful in 4 cases). Overall, repeat ERCP after failed precut at the index ERCP was successful in 73/89 patients (82%). Complications after precut-sphincterotomy were observed in 32/187 (17%) patients including pancreatitis (13%), retroperitoneal perforations (1%), biliary sepsis (0.5%) and haemorrhage (3%). CONCLUSION: The high success rate of biliary cannulation in a second attempt ERCP justifies repeating ERCP within 2-7 d after unsuccessful precut sphincterotomy before more invasive approaches should be considered.

Restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: rationale and protocol for a cluster randomized feasibility trial.

Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is <8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is <10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial.

Diagnosis and outcome of small bowel tumors found by capsule endoscopy: a three-center Australian experience.

OBJECTIVE: The objective of the study was to examine diagnosis and outcome in a series of patients with small bowel tumors detected by capsule endoscopy (CE) in three Australian centers. METHODS: Review of prospectively collected data from 416 CEs identified 27 tumors in 26 patients. Clinical parameters, tumor histology, and follow-up are reported. RESULTS: Twenty-seven tumors were identified in 26 patients (mean age 61 +/- 13.7 yr). Indications for CE were obscure gastrointestinal (GI) bleeding (21), suspected tumor (3), abdominal pain (1), diarrhea (1). Prior radiology found a possible lesion in 8 of 23 (35%). Nine tumors were proven benign: hamartoma (4), cystic lymphangioma (1), primary amyloid (1), lipoma (1). Two lesions were non-neoplastic: heterotopic gastric mucosa and inflammatory fibroid polyp. Seventeen tumors were malignant: five adenocarcinomas, six carcinoids, two melanoma metastases, two gastrointestinal stromal tumors (GIST), one colon carcinoma metastasis, one non-Hodgkin's lymphoma. Tumors were surgically resected in 23 patients. Resection was considered curative in 12 (52%). Mean duration of follow-up was 26 +/- 13.7 months. Of the five patients with primary adenocarcinoma only one remains disease free. Three of the six with carcinoid tumors have had no recurrence up to 51 months postresection. Both patients with GIST are disease free. Anemia resolved after surgery in the patients with melanoma. CONCLUSIONS: Small bowel tumors are a significant finding at CE and are often missed by other methods of investigation. In many patients, detection of a tumor alters management and improves outcome. Even in malignant lesions, treatment is potentially curative in the absence of metastatic disease.