Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis.

IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. OBJECTIVE: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. DESIGN, SETTING AND PARTICIPANTS: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. EXPOSURES: Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. MAIN OUTCOMES AND MEASURES: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). RESULTS: Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. CONCLUSION: In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. TRIAL REGISTRATION NUMBER: NCT02961374.

A novel blood-sensing capsule for rapid detection of upper GI bleeding: a prospective clinical trial.

BACKGROUND AND AIMS: Upper GI bleeding (UGIB) is a common medical emergency associated with high resource utilization, morbidity, and mortality. Timely EGD can be challenging from personnel, resource, and access perspectives. PillSense (EnteraSense Ltd, Galway, Ireland) is a novel swallowed bleeding sensor for the detection of UGIB, anticipated to aid in patient triage and guide clinical decision-making for individuals with suspected UGIB. METHODS: This prospective, open-label, single-arm comparative clinical trial of a novel bleeding sensor for patients with suspected UGIB was performed at a tertiary care center. The PillSense system consists of an optical sensor and an external receiver that processes and displays data from the capsule as "Blood Detected" or "No Blood Detected." Patients underwent EGD within 4 hours of capsule administration; participants were followed up for 21 days to confirm capsule passage. RESULTS: A total of 126 patients were accrued to the study (59.5% male; mean age, 62.4 ± 14.3 years). Sensitivity and specificity for detecting the presence of blood were 92.9% (P = .02) and 90.6% (P < .001), respectively. The capsule's positive and negative predictive values were 74.3% and 97.8%, and positive and negative likelihood ratios were 9.9 and .08. No adverse events or deaths occurred related to the PillSense system, and all capsules were excreted from patients on follow-up. CONCLUSIONS: The PillSense system is safe and effective for detecting the presence of blood in patients evaluated for UGIB before upper GI endoscopy. It is a rapidly deployed tool, with easy-to-interpret results that will affect the diagnosis and triage of patients with suspected UGIB. (Clinical trial registration number: NCT05385224.).

Retained Food During Esophagogastroduodenoscopy Is a Risk Factor for Gastric-to-Pulmonary Aspiration.

BACKGROUND: Residual food (RF) during esophagogastroduodenoscopy (EGD) is thought, but not proven, to be a risk factor for gastric-to-pulmonary aspiration. AIMS: The aims of this study were to determine the prevalence of RF during EGD, to investigate whether RF was associated with an increased risk of aspiration, especially when monitored anesthesia care (MAC) or general anesthesia (GA) were administered, and to determine whether aspiration associated with RF led to a more severe clinical outcome. METHODS: Patients undergoing EGD between October 2012 and September 2018 were identified. Patient age, sex, aspiration events, RF, sedation type, structural foregut abnormalities, and diagnoses associated with impaired esophageal or gastric motility were noted. The clinical course after an aspiration event was evaluated. RESULTS: RF was identified during 4% of 81,367 EGDs. Aspiration events occurred during 41 (5/10,000) procedures. Aspiration was more likely to occur in patients with RF (odds ratio [OR] 15.1) or those receiving MAC or GA (OR 9.6 and 16.8 relative to conscious sedation, respectively). RF and MAC/GA were synergistically associated with increased odds of aspiration. In a multivariate nominal logistic regression model, older age (OR 2.6), MAC (OR 3.8), GA (OR 4.4), vagotomy (OR 5.2), achalasia (OR 3.8), and RF (OR 10.0) were risk factors for aspiration. Aspiration events in the presence or absence of RF led to similar clinical outcomes. CONCLUSIONS: While aspiration events are rare in patients undergoing EGD, RF and the use of MAC or GA were associated with substantially increased odds of aspiration.

Lumen-apposing metal stents for the treatment of benign gastrointestinal tract strictures: a single-center experience and proposed treatment algorithm.

BACKGROUND: Lumen-apposing metal stents (LAMS) are an alternative therapeutic option for benign gastrointestinal (GI) tract strictures. Our study aimed to evaluate the safety and efficacy of LAMS for the management of benign GI strictures. METHODS: Consecutive patients who underwent a LAMS placement for benign luminal GI strictures at a tertiary care center between January 2014 and July 2021 were reviewed. Primary outcomes included technical success, early clinical success, and adverse events (AEs). Other outcomes included rates of stent migration and re-intervention after LAMS removal. RESULTS: One hundred and nine patients who underwent 128 LAMS placements (67.9% female, mean age of 54.3 ± 14.2 years) were included, and 70.6% of the patients had failed prior endoscopic treatments. The majority of strictures (83.5%) were anastomotic, and the most common stricture site was the gastrojejunal anastomosis (65.9%). Technical success was achieved in 100% of procedures, while early clinical success was achieved in 98.4%. The overall stent-related AE rate was 25%. The migration rate was 27.3% (35/128). Of these, five stents were successfully repositioned endoscopically. The median stent dwell time was 119 days [interquartile range (IQR) 68-189 days], and the median follow-up duration was 668.5 days [IQR: 285.5-1441.5 days]. The re-intervention rate after LAMS removal was 58.3%. CONCLUSIONS: LAMS is an effective therapeutic option for benign GI strictures, offering high technical and early clinical success. However, the re-intervention rate after LAMS removal was high. In select cases, using LAMS placement as destination therapy with close surveillance is a reasonable option.

Neoplasia Diagnosis After Multi-target Stool DNA Is Enhanced Among Lowest Baseline Detectors.

BACKGROUND AND AIMS: Variation in colorectal neoplasia detection limits the effectiveness of screening colonoscopy. By evaluating neoplasia detection rates of individual colonoscopists, we aimed to quantify the effects of pre-procedural knowledge of a positive (+) multi-target stool DNA (mt-sDNA) on colonoscopy quality metrics. METHODS: We retrospectively identified physicians who performed a high volume of + mt-sDNA colonoscopies; colorectal neoplasia at post-mt-sDNA colonoscopy was recorded. These colonoscopists were stratified into quartiles based on baseline adenoma detection rates. Baseline colonoscopy adenoma detection rates and sessile serrated lesion detection rates were compared to post-mt-sDNA colonoscopy neoplasia diagnosis rates among each quartile. Withdrawal times were measured from negative exams. RESULTS: During the study period (2014-17) the highest quartile of physicians by volume of post-mt-sDNA colonoscopies were evaluated. Among thirty-five gastroenterologists, their median screening colonoscopy adenoma detection rate was 32% (IQR, 28-39%) and serrated lesion detection rate was 13% (8-15%). After + mt-sDNA, adenoma diagnosis increased to 47% (36-56%) and serrated lesion diagnosis increased to 31% (17-42%) (both p < 0.0001). Median withdrawal time increased from 10 (7-13) to 12 (10-17) minutes (p < 0.0001) and was proportionate across quartiles. After + mt-sDNA, lower baseline detectors had disproportionately higher rates of adenoma diagnosis in female versus male patients (p = 0.048) and higher serrated neoplasia diagnosis rates among all patients (p = 0.0092). CONCLUSIONS: Knowledge of + mt-sDNA enriches neoplasia diagnosis compared to average risk screening exams. Adenomatous and serrated lesion diagnosis was magnified among those with lower adenoma detection rates. Awareness of the mt-sDNA result may increase physician attention during colonoscopy. Pre-procedure knowledge of a positive mt-sDNA test improves neoplasia diagnosis rates among colonoscopists with lower baseline adenoma detection rates, independent of withdrawal time.

Inhibition of the BMP pathway prevents development of Barrett's-associated adenocarcinoma in a surgical rat model.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

Performance and Predictors of Migration of Partially and Fully Covered Esophageal Self-Expanding Metal Stents for Malignant Dysphagia.

BACKGROUND & AIMS: Self-expanding metal stents (SEMS) are routinely used to palliate malignant dysphagia. However esophageal SEMS can migrate or obstruct due to epithelial hyperplasia. The aim of this study was to evaluate the rates and factors predicting migration and obstruction, and the nutritional outcomes in partially covered (pc) vs. fully covered (fc) SEMS vs. fcSEMS with antimigration fins (AF) placed for malignant dysphagia. METHODS: A retrospective review of consecutive patients undergoing SEMS placement for malignant dysphagia at three academic medical centers. RESULTS: Among 357 patients, there were 55 (15.4%) stent migrations, 45 (12.6%) obstructions from epithelial hyperplasia, and 20 (5.6%) food impactions. Median overall survival was 79 days (IQR 41,199). The percent weight change/change in albumin at 30 and 60 days after SEMS placement were -2.24%/-0.544 g/dL and -2.98%/-0.55 g/dL, respectively. Stent migration occurred significantly more often with fcSEMS than pcSEMS (25.3% vs 10.9%; P < .003), but there was no difference when either group was compared to fcSEMS-AF (19.3%). The overall rate of epithelial hyperplasia resulting in stent obstruction was low (12.6%) and not different between stent types. Factors associated with increased risk of SEMS migration on multivariable logistic regression included stricture traversability with a diagnostic endoscope (OR, 2.37; 95% CI, 1.29-4.35) and use of fcSEMS (OR, 2.56; 1.31-5.00) or fcSEMS-AF (OR, 2.30, 1.03-5.14). CONCLUSIONS: Traversability of a malignant esophageal stenosis predicts SEMS migration. In these patients with a limited overall survival, pcSEMS are associated with lower rates of stent migration and similar rates of obstruction compared to fcSEMS.

Endoscopic management of refractory leaks and fistulas after bariatric surgery with long-term follow-up.

BACKGROUND: In selected cases of post-bariatric leaks and fistulas, endoscopy is an initial treatment modality. Management can be complex and require multiple endoscopic sessions with varying degrees of success. Our aim was to describe our tertiary care experience on endoscopy management of refractory post-bariatric leaks and fistulas. METHODS: Patients with post-bariatric leaks and/or fistulas who failed an initial endoscopic intervention were included. Endoscopic treatments were classified into four strategies: (1) closure management, (2) active drainage, (3) passive drainage, and (4) plugging. Clinical success and adverse events were assessed. RESULTS: A total of 25 patients (mean age = 45.3 ± 11.8 years and 56% female) were included. Clinical success was achieved in 20 patients (80%) with a mean of 3.0 ± 1.5 procedures and a median time to healing of 114.5 (53-210.3) days. Closure and plugging were the main successful strategies used for early and acute leaks/fistulas, while drainage was for late and chronic leaks/fistulas. Adverse events were observed in 13 patients (52%) with one serious adverse event. Patients with fistulas had a lower success rate (72.2% vs. 100%, P = 0.052). Of those with clinical failure (n = 5), four underwent reconstructive surgery, eventually led to success in 3 patients. The other one died of septic shock related to a complicated fistula. CONCLUSIONS: Complex multi-modality endoscopic management ultimately achieved clinical success in most cases of refractory leaks/fistulas post-bariatric with an acceptable safety profile. However, a close follow-up to detect the development of long-term failure is warranted. These patients should be referred to a specialized bariatric center with expertise in bariatric endoscopy and surgery.

Barrett Esophagus Length, Nodularity, and Low-grade Dysplasia are Predictive of Progression to Esophageal Adenocarcinoma.

GOALS: To investigate factors predictive of progression from nondysplastic Barrett esophagus (NDBE) or low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) using a large, prospective cohort of patients, wherein all esophageal biopsies undergo expert gastrointestinal pathologist review. BACKGROUND: Efficacy and cost-effectiveness of endoscopic surveillance to detect incident EAC in the setting of Barrett esophagus (BE), particularly in NDBE patients, is questioned. Previous studies have reported factors predictive of progression to EAC to guide surveillance intervals, but their strength is limited by small sample size and absence of expert gastrointestinal pathologist involvement in esophageal biopsy review. STUDY: NDBE and LGD subjects were identified from a prospective registry in a tertiary care center. "Progressors" were BE subjects who developed HGD/EAC>12 months after the initial NDBE or LGD diagnosis. Cox proportional hazards model were used to identify predictors of progression. RESULTS: In total, 318 with NDBE and 301 with BE-LGD (mean age, 62.6 y, 85% male) were included. The mean follow-up was 5.3 years. The 7 NDBE and 21 LGD subjects progressed to HGD/EAC. BE length [hazards ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.29], presence of nodularity (HR, 4.98; 95% CI, 1.80-11.7), and baseline LGD (HR, 2.57; 95% CI, 1.13-6.57) were significant predictors of progression on multivariate analysis. CONCLUSIONS: In this well-defined cohort of NDBE and BE-LGD subjects, BE length, presence of LGD, and nodularity were independent predictors of progression to HGD/EAC. These factors may aid in identifying high-risk patients who may benefit from closer endoscopic surveillance/therapy.

Efficacy of Over-the-Scope Clips in Management of High-Risk Gastrointestinal Bleeding.

BACKGROUND & AIMS: Standard endoscopic therapies do not control bleeding or produce complications in as many as 20% of patients with nonvariceal gastrointestinal bleeding. Most bleeding comes from ulcers with characteristics such as high-risk vascular territories and/or large vessels. We evaluated the efficacy of using over-the-scope clips (OTSCs) as primary or rescue therapy for patients with bleeding from lesions that have a high risk for adverse outcomes. METHODS: We performed a retrospective analysis of data from 67 patients with gastrointestinal bleeding from high-risk lesions who were treated with OTSCs as primary (n = 49) or rescue therapy (n = 18) at a quaternary center, from December 2011 through February 2015. The definition of high-risk lesions was lesions that were situated in the area of a major artery and larger than 2 mm in diameter and/or a deep penetrating, excavated, fibrotic ulcer with high-risk stigmata, in which a perforation could not be ruled out or thermal therapy would cause perforation, or lesions that could not be treated by standard endoscopy. Clinical severity was determined based on the Rockall score and a modified Blatchford score. Our primary outcome was the incidence of rebleeding within 30 days after OTSC placement. We assessed risk factors for rebleeding using univariate hazard models followed by multivariable analysis. RESULTS: Of the 67 patients, 47 (70.1%) remained free of rebleeding at 30 days after OTSC placement. We found no difference in the proportion of patients with rebleeding who received primary or rescue therapy (hazard ratio, 0.639; 95% confidence interval, 0.084-4.860; P = .6653). Only 9 rebleeding events were linked clearly to OTSCs and required intervention, indicating an OTSC success rate of 81.3%. We found no significant associations between rebleeding and clinical scores. However, on multivariable analysis, patients with coronary artery disease had a higher risk of rebleeding after OTSC independent of international normalized ratio and antiplatelet use (hazard ratio, 7.30; P = .0002). CONCLUSIONS: In a retrospective analysis of 67 patients with bleeding from high-risk gastrointestinal lesions, we found OTSCs to prevent rebleeding in more than 80% of cases. In the past, these lesions were treated with surgical or radiologic interventions. Patients with coronary artery disease have an increased risk of rebleeding after OTSCs, suggesting the need for escalated therapies.

Outcomes of endoscopic intervention for overt GI bleeding in severe thrombocytopenia.

BACKGROUND AND AIMS: Gastrointestinal bleeding (GIB) in the setting of thrombocytopenia raises concerns about endoscopic procedure risk. We aimed to assess the safety and outcomes of endoscopy for overt GIB in the setting of severe thrombocytopenia in liver cirrhosis (LC) and non-liver cirrhosis (NLC). METHODS: This is a retrospective study on inpatients who underwent endoscopy within 24 hours of presentation for overt GIB with a platelet count (PC) of 20 to <50 × 103/mL. Outcomes included diagnostic and therapeutic yields, procedural adverse events, packed red blood cell (pRBC) and platelet transfusions, recurrent bleeding rate, and all-cause and GIB-related mortality. RESULTS: One hundred forty-four patients were identified. The median PC was 41 × 103/mL and 61% had LC. The diagnostic yield was 68% (LC = 61%, NLC = 79%, P = .04). Therapeutic yield was 60% (59% vs 60%, P = 1.00). The initial hemostasis rate was 94% with one adverse event. The median number of pRBC and platelet transfusions decreased after intervention in the entire cohort. Recurrent bleeding rates were 22% at 1 month and 30% at 1 year, with no differences between groups. An increased international normalized ratio (INR) >2 was a predictor of recurrent bleeding. All-cause mortality was 19% at 1 month and 37% at 1 year, whereas GIB-associated mortality in our cohort was only 3% at 1 month and 4% at 1 year, with no significant difference between LC and NLC. Predictors of mortality were INR >2, activated partial thromboplastin time >38 seconds, hypotension, intensive care unit admission, and pulmonary comorbidities. CONCLUSION: In this study cohort, we observed that endoscopy for overt GIB in the setting of severe thrombocytopenia in patients with LC and NLC appears safe, has moderate diagnostic and therapeutic yields with high initial hemostasis rate, and is associated with a significant decrease in pRBC and platelet transfusions. Recurrent bleeding and all-cause mortality rates remain high.

Esophagorespiratory Fistulas: Survival and Outcomes of Treatment.

GOAL: The purpose of this study was to characterize outcomes of esophagorespiratory fistulas (ERF) by etiology and initial treatment strategy. BACKGROUND: ERF is a morbid condition for which optimal treatment strategies and outcomes are still in evolution. STUDY: Medical records and images were reviewed for all patients diagnosed with ERF at Mayo Clinic in Rochester, MN, between September 1, 2001 and January 1, 2012. Fistulas were classified as malignant or benign. Treatment strategies were classified as surgical or nonsurgical (typically esophageal stent placement). Technical and clinical success, survival, and survival free of second intervention were assessed. RESULTS: A total of 123 patients with acquired ERF were identified, of whom 65 (53%) were malignant and 58 (47%) benign. Initial treatment strategy was nonsurgical in 88 (72%) patients and surgical in 35 (28%); lower Charlson comorbidity scores were associated with increased likelihood of surgery. Technical and clinical success was seen in a majority of patients treated both surgically and nonsurgically. Patients with malignant ERF treated surgically survived longer than patients undergoing nonsurgical treatment (hazard ratio=5.6, P=0.005). In contrast, those with benign ERF had similar overall survival regardless of whether they received initial surgical or nonsurgical treatment; reintervention was more common in those who underwent nonsurgical treatment (hazard ratio=2.3, P=0.03). CONCLUSIONS: We conclude that survival in malignant ERF is better with surgical intervention in selected patients. Surgical and nonsurgical techniques achieve similar survival in benign ERF, but reintervention is more common in those treated endoscopically.

Predictors of Progression in Barrett's Esophagus with Low-Grade Dysplasia: Results from a Multicenter Prospective BE Registry.

OBJECTIVES: Low-grade dysplasia (LGD) is a risk factor for progression in Barrett's esophagus (BE). Progression estimates however vary and predictors of progression are not well established. We aimed to assess predictors of progression in a multicenter BE-LGD cohort. METHODS: All subjects with LGD (diagnosed by a GI pathologist) in a prospective BE registry were identified. Progression was defined development of HGD/EAC more than 12 months after index date of LGD diagnosis. Clinical, endoscopic factors and impact of histologic review by an independent panel of two GI pathologists were assessed as predictors of progression. Cox proportional hazard models were used to assess their association with risk of progression. RESULTS: 244 BE-LGD subjects met inclusion criteria. Their mean age was 63.2 years. 205 (84%) were males. The median follow up was 4.8 years. Fifty six patients were diagnosed with HGD/EAC in less than 12 months, while 14 progressed to HGD/EAC after 12 months, with an overall annual risk of progression of 1.2%. 29% of LGD subjects were downgraded to non-dysplastic and the remaining re-confirmed as LGD or indefinite dysplasia. The risk of progression in the reconfirmed LGD group was eight fold higher (hazards ratio: 7.6, 95% CI: 1.5-139.4) in a propensity score stratified model. CONCLUSIONS: In this large BE-LGD cohort, progression risk increased substantially when an additional panel of two expert GI pathologists re-confirmed a LGD diagnosis. These BE subjects may be candidates for endoscopic therapy. LGD was a marker of prevalent HGD/EAC in 18% of patients.

Quality indicators for the management of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma: international consensus recommendations from the American Gastroenterological Association Symposium.

The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barrett's esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barrett's esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barrett's esophagus.

Outcomes and Predictors of Rebleeding After 2-Octyl Cyanoacrylate Injection in Acute Gastric Variceal Hemorrhage.

BACKGROUND AND AIM: Endoscopic injection of 2-octyl cyanoacrylate (2-OCA) is used on an off-label basis for gastric variceal hemorrhage (GVH) in the United States. We assessed the efficacy, safety, and predictors of rebleeding after gastric variceal obturation (GVO) with 2-OCA in patients with acute GVH. MATERIALS AND METHODS: A retrospective analysis was performed of patients with GVH who underwent 2-OCA injection for GVO over a 15-year period. Rates of acute hemostasis, predictors of rebleeding, and cyanoacrylate-related adverse events were assessed. RESULTS: A total of 95 patients (63 males, median age 59±14 y) were analyzed. Gastric varices were categorized as GOV-1 (3%), GOV-2 (61%), and isolated gastric varices type 1 (36%) per Sarin classification. Initial hemostasis was achieved in all patients. Successful GVO, defined as sustained hemostasis within a month after injection, was achieved in 87 (92%) patients. Failed GVO with in-hospital rebleeding was observed in 8 (8%) patients. On univariate analysis, only the model for end-stage liver disease score was associated with an increased risk of rebleeding (odds ratio 1.2; 95% confidence interval, 1.1-1.4; P<0.01). Glue-related adverse events consisted of pulmonary emboli in 2 patients (2.1%), resulting in death in 1 patient. All cause in-hospital mortality was 13% due to uncontrolled gastric variceal rebleeding (n=3), renal failure (n=6), metastatic hepatocellular carcinoma (n=1), hemorrhagic stroke (n=1), and pulmonary embolism (n=1). CONCLUSIONS: Injection of 2-OCA was effective at achieving hemostasis in a high proportion of patients (92%) admitted for acute GVH. The risk of glue-related pulmonary embolism approximated 2% in our patient cohort, including 1 fatality.

Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.

BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. METHODS: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. RESULTS: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). CONCLUSIONS: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.