Malondialdehyde-Acetaldehyde Extracellular Matrix Protein Adducts Attenuate Unfolded Protein Response During Alcohol and Smoking-Induced Pancreatitis.

BACKGROUND & AIMS: Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized. METHODS: Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 µg/mL) for the mechanistic studies. RESULTS: A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P < .001) and attenuated unfolded protein response (P < .04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers. CONCLUSIONS: The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.

Adenoma and polyp detection rates during insertion versus withdrawal phase of colonoscopy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colonoscopy is the preferred modality for colorectal cancer screening because it has both diagnostic and therapeutic capabilities. Current consensus states that colonoscopy should be performed with initial rapid passage of the instrument to the cecum, followed by thorough evaluation for and removal of all polyps during a deliberate slow withdrawal. Reports have suggested that polyps that are seen but not removed during insertion are sometimes quite difficult to find during withdrawal. METHODS: We performed a comprehensive literature search of several major databases (from inception to March 2020) to identify randomized controlled trials comparing inspection and polypectomy during the insertion phase as opposed to the traditional practice of inspection and polypectomy performed entirely during the withdrawal phase. We examined differences in terms of adenoma detection rate (ADR), polyps detected per patient (PDPP), cecal intubation time (CIT), withdrawal time, and total procedure time. RESULTS: Seven randomized controlled trials, including 3834 patients, were included in our final analysis. The insertion/withdrawal cohort had 1951 patients and the withdrawal-only cohort 1883 patients. Pooled odds of adenoma detection in the insertion/withdrawal cohort was .99 (P = .8). ADR was 47.2% in the insertion/withdrawal cohort and 48.6% in the withdrawal-only cohort. Although total procedure and withdrawal times were shorter in the insertion/withdrawal cohort, PDPP in both cohorts were not statistically significant (1.4 vs 1.5, P = .7). CONCLUSIONS: Additional inspection and polypectomy during the insertion and withdrawal phases of colonoscopy offer no additional benefit in terms of ADR or PDPP.

Lumen-apposing Metal Stents, Fully Covered Self-expanding Metal Stents, and Biodegradable Stents in the Management of Benign of GI Strictures: A Systematic Review and Meta-Analysis.

BACKGROUND: Refractory benign gastrointestinal (GI) strictures are difficult to treat and placement of a stent is a commonly sought resort. Stents used for this purpose are fully covered self-expanding metal stent (FCSEMS), a biodegradable stent (BDS) and recently, a lumen-apposing metal stent (LAMS). There is no data comparing these stents to this end. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings (from inception through October 2018) to identify studies that reported on the performance of FCSEMS, BDS, and LAMS in the treatment of refractory benign GI strictures. Our goals were to evaluate the pooled rate of technical success, clinical success, and adverse events with these stents and compare the outcomes between them. RESULTS: A total of 31 studies were analyzed. In total, 14 (342 patients), 11 (226 patients), and 8 studies (192 patients) reported the use of FCSEMS, BDS, and LAMS, respectively. The pooled rate of technical success was 96.5% [95% confidence interval (CI): 93.5-98.1], 91.9% (95% CI: 85.6-95.6), and 97.6% (95% CI: 94.0-99.0) with FCSEMS, BDS, and LAMS respectively. No statistical significance to the difference was noted. The pooled rate of clinical success was 48.4% (95% CI: 37.1-59.8), 34.9% (95% CI: 23.6-48.1), and 78.8% (95% CI: 65.8-87.8) with FCSEMS, BDS, and LAMS, respectively. Statistical significance was noted in LAMS versus FCSEMS (P=0.001) and LAMS versus BDS (P=0.001). LAMS demonstrated statistically better outcomes in regards to stent migration and postprocedure pain when compared with FCSEMS and BDS. CONCLUSION: Our study demonstrates that LAMS gives better clinical outcomes in the treatment of refractory benign GI strictures when compared with FCSEMS and BDS. Variability in the site, as well as the length of stricture, indirect comparison, and heterogeneity, were the limitations of our study.

Periampullary Diverticula and ERCP Outcomes: A Systematic Review and Meta-Analysis.

INTRODUCTION: Periampullary diverticulum (PAD) is most often asymptomatically found in elderly population. ERCP in the presence of PAD is technically challenging since the location and orientation of the ampulla could be altered. Various studies have reported differing results on the technical success and safety outcomes of ERCP in the presence of PAD. We aimed at a meta-analysis of such studies to assess the technical success and the occurrence of complications during ERCP in patients with PAD. METHODS: We conducted a comprehensive search of several databases and conference proceedings including PubMed, EMBASE, and Web of Science databases (earliest inception to October 2017). The search was done in accordance with PRISMA guidelines to identify studies. Studies that reported on the ERCP outcomes based on the presence of PAD were included. Both prospective and retrospective studies, manuscripts and abstracts were included. Only articles in English literature were included. The primary analysis focused on the overall technical success of ERCP in the presence of PAD, and the secondary analysis was to estimate the risk of occurrence of complications. RESULTS: Our search resulted in 16 studies that were included for final analysis. These 16 studies reported on 2794 patients, who had PAD, and the control group included 13,032 patients, who did not have a PAD during ERCP. Our meta-analysis of this data showed an Odd's ratio estimate of having a successful ERCP procedure in patients with PAD to be 0.51 [95% C.I. (0.35-0.72)] when compared to patients without it. This was statistically significant, with a p value 0.00. Considerable heterogeneity was noted among the studies. The heterogeneity proportion was quantified at 74.6% based on I2 statistic. The secondary outcomes measured were complications. We analyzed the pooled Post-ERCP Pancreatitis (PEP), cholangitis, perforation, and bleeding. Only those studies that had the data for these complications in both the study and the control groups were selected. PEP: The pooled Odd's estimate of having PEP was 1.28, [95% C.I (0.88-1.87)] from 12 studies reporting on 1863 patients with PAD in comparison with 7803 patients without it. The risk of PEP occurrence tended to be more in the group without PAD, though it was not statistically significant, with a p value 0.20. There was some heterogeneity observed between the studies, with the quantification I2 statistic being 28.6%. Our analysis shows that having PAD does not put a patient at increased risk for PEP. Bleeding: The pooled Odds estimate was 1.69, 95% C.I. 0.88-3.25 from nine studies reporting on 1816 patients with PAD in comparison with 5327 patients without it. This was not statistically significant, p value 0.11. Considerable heterogeneity was noted, with I2 being 55.7%. The risk of having a bleed was noted to be more in control group, and having PAD did not put patients at increased risk for bleeding during an ERCP procedure. Perforation: Patients with PAD undergoing ERCP were not at increased risk for perforation. Seven studies reported on this complication. This was noted in seven patients out of 1245 in study group, and 19 patients out of 4912 in control group. The pooled Odd's estimate was 1.24, 95% C.I. 0.54-2.87. There was no statistical significance, p value 0.61. No heterogeneity was noted among the studies included in this analysis. Cholangitis: Only four studies reported on this complication. In a total of 778 patients in study group, four had cholangitis and eight had this complication out of 3886 patients in the control group. The pooled Odd's was 2.12, 95% C.I. 0.61-7.33. There was no statistical significance, p value 0.24. No heterogeneity was noted. CONCLUSION: ERCP is technically feasible and increasingly successful when performed by experts in the presence of PAD. The risk of complications such as PEP, bleeding, perforation and cholangitis does not differ between ERCP done in patients with and without PAD.

Efficacy of EUS-guided needle-based confocal laser endomicroscopy in the diagnosis of pancreatic lesions: A systematic review and meta-analysis.

Background and Objectives: Needle-based confocal laser endomicroscopy (nCLE) is a procedure in which an AQ-Flex nCLE mini-probe is passed through an EUS-FNA needle into a pancreatic lesion to enable subsurface in vivo tissue analysis. In this study, we conducted a systematic review and meta-analysis of nCLE for the diagnosis of pancreatic lesions. Materials and Methods: We conducted a comprehensive search of several databases and conference proceedings, including PubMed, EMBASE, Google-Scholar, MEDLINE, SCOPUS, and Web of Science databases (earliest inception to March 2020). The primary outcomes assessed the pooled rate of diagnostic accuracy for nCLE and the secondary outcomes assessed the pooled rate of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events (AE) of nCLE to diagnose premalignant/malignant pancreatic lesions. Results: Eleven studies on 443 patients were included in our analysis. The pooled rate of diagnostic accuracy of EUS nCLE was 83% (95 confidence interval [CI] = 79-87; I 2 = 0). The pooled rate of sensitivity, specificity, PPV and NPV of EUS nCLE was 85.29% (95% CI = 76.9-93.68; I 2 = 85%), 90.49% (95% CI = 82.24-98.74; I 2 = 64%), 94.15% (95% CI = 88.55-99.76; I 2 = 68%), and 73.44% (95% CI = 60.16-86.72; I 2 = 93%), respectively. The total AE rate was 5.41% (±5.92) with postprocedure pancreatitis being the most common AE at 2.28% (±3.73). Conclusion: In summary, this study highlights the rate of diagnostic accuracy, sensitivity, specificity, and PPV for distinguishing premalignant/malignant lesions. Pancreatic lesions need to be further defined with more validation studies to characterize CLE diagnosis criteria and to evaluate its use as an adjunct to EUS-FNA.

Safety and efficacy of EUS-guided ablation of pancreatic lesions with ethanol versus ethanol with paclitaxel: A systematic review and meta-analysis.

Background and Objectives: EUS-guided ethanol ablation has emerged as an alternative method for pancreatic lesions. Recently, paclitaxel was added to ethanol to assess ablative effects in pancreatic lesions. We performed a systematic review and meta-analysis on EUS-guided ethanol ablation (EUS E) versus EUS-guided ethanol with paclitaxel (EUS EP) ablation for the management of pancreatic lesions. Methods: Comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Google Scholar, and Web of Science databases (from inception to May 2020). The primary outcome evaluated complete ablation of the lesions radiologically and the secondary outcome evaluated adverse events (AEs). Results: Fifteen studies on 524 patients were included in our analysis. The pooled complete ablation rate was 58.89% (95% confidence interval (CI) = 38.72-77.80, I2 = 91.76%) and 55.99% (95% CI = 44.66-67.05, I2 = 0) in the EUS E and EUS EP groups (P = 0.796), respectively. The pooled AE rates were 13.92% (95% CI = 4.71-26.01, I2 = 83.43%) and 31.62% (95% CI = 3.36-68.95, I2 = 87.9%) in the EUS E and EUS EP groups (P = 0.299), respectively. The most common AE was abdominal pain at 7.27% (95% CI = 1.97-14.6, I2 = 68.2%) and 12.44% (95% CI = 0.00-39.24, I2 = 81.1%) in the EUS E and EUS EP groups (P = 0.583), respectively. Correlation coefficient (r) was ‒0.719 (P = 0.008) between complete ablation and lesion size. Conclusion: Complete ablation rates were comparable among both groups. AE rates were higher in the EUS EP group. Further randomized controlled trials are needed to validate our findings.

Endoscopic cryotherapy: Indications, techniques, and outcomes involving the gastrointestinal tract.

Endoscopic cryotherapy is a technique utilized for the ablation of target tissue within the gastrointestinal tract. A cryotherapy system utilizes the endoscopic application of cryogen such as liquid nitrogen, carbon dioxide or liquid nitrous oxide. This leads to disruption of cell membranes, apoptosis, and thrombosis of local blood vessels within the target tissue. Several trials utilizing cryotherapy for Barrett's esophagus (BE) with variable dysplasia, gastric antral vascular ectasia (GAVE), esophageal carcinoma, radiation proctitis, and metastatic esophageal carcinomas have shown safety and efficacy. More recently, liquid nitrogen cryotherapy (cryodilation) was shown to be safe and effective for the treatment of a benign esophageal stricture which was refractory to dilations, steroid injections, and stenting. Moreover, liquid nitrogen cryotherapy is associated with less post procedure pain as compared to radiofrequency ablation in BE with comparable ablation rates. In patients with GAVE, cryotherapy was found to be less tedious as compared to argon plasma coagulation. Adverse events from cryotherapy most commonly include chest pain, esophageal strictures, and bleeding. Gastric perforations did occur as well, but less often. In summary, endoscopic cryotherapy is a promising and growing field, which was first demonstrated in BE, but the use now spans for several other disease processes. Larger randomized controlled trials are needed before its role can be established for these different diseases.

Efficacy of pancreatoscopy for pancreatic duct stones: A systematic review and meta-analysis.

BACKGROUND: Pancreatic duct stones can lead to significant abdominal pain for patients. Per oral pancreatoscopy (POP)-guided intracorporal lithotripsy is being increasingly used for the management of main pancreatic duct calculi (PDC) in chronic pancreatitis. POP uses two techniques: Electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). Data on the safety and efficacy are limited for this procedure. We performed a systematic review and meta-analysis with a primary aim to calculate the pooled technical and clinical success rates of POP. The secondary aim was to assess pooled rates of technical success, clinical success for the two individual techniques, and adverse event rates. AIM: To perform a systematic review and meta-analysis of POP, EHL and LL for management of PDC in chronic pancreatitis. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Cochrane, Google Scholar and Web of Science databases (from 1999 to October 2019) to identify studies with patient age greater than 17 and any gender that reported on outcomes of POP, EHL and LL. The primary outcome assessed involved the pooled technical success and clinical success rate of POP. The secondary outcome included the pooled technical success and clinical success rate for EHL and LL. We also assessed the pooled rate of adverse events for POP, EHL and LL including a subgroup analysis for the rate of adverse event subtypes for POP: Hemorrhage, post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), perforation, abdominal pain, fever and infections. Technical success was defined as the rate of clearing pancreatic duct stones and clinical success as the improvement in pain. Random-effects model was used for analysis. Heterogeneity between study-specific estimates was calculated using the Cochran Q statistical test and I 2 statistics. Publication bias was ascertained, qualitatively by visual inspection of funnel plot and quantitatively by the Egger test. RESULTS: A total of 16 studies including 383 patients met the inclusion criteria. The technical success rate of POP was 76.4% (95%CI: 65.9-84.5; I 2 = 64%) and clinical success rate was 76.8% (95%CI: 65.2-85.4; I 2 = 66%). The technical success rate of EHL was 70.3% (95%CI: 57.8-80.3; I 2 = 36%) and clinical success rate of EHL was 66.5% (95%CI: 55.2-76.2; I 2 = 19%). The technical success rate of LL was 89.3% (95%CI: 70.5-96.7; I 2 = 70%) and clinical success rate of LL was 88.2% (95%CI: 66.4-96.6; I 2 = 77%). The incidence of pooled adverse events for POP was 14.9% (95%CI: 9.2-23.2; I 2 = 49%), for EHL was 11.2% (95%CI: 5.9-20.3; I 2 = 15%) and for LL was 13.1% (95%CI: 6.3-25.4; I 2 = 31%). Subgroup analysis of adverse events showed rates of PEP at 7% (95%CI: 3.5-13.6; I 2 = 38%), fever at 3.7% (95%CI: 2-6.9; I 2 = 0), abdominal pain at 4.7% (95%CI: 2.7-7.8; I 2 = 0), perforation at 4.3% (95%CI: 2.1-8.4; I 2 = 0), hemorrhage at 3.4% (95%CI: 1.7-6.6; I 2 = 0) and no mortality. There was evidence of publication bias based on funnel plot analysis and Egger's test. CONCLUSION: Our study highlights the high technical and clinical success rates for POP, EHL and LL. POP-guided lithotripsy could be a viable option for management of chronic pancreatitis with PDC.

Clinical efficacy and safety of palliative esophageal stenting without fluoroscopy: a systematic review and meta-analysis.

Background and study aims Despite advances in curative treatments for esophageal cancer, many patients often present with advanced disease. Dysphagia resulting in significant weight loss and malnutrition leads to poor quality of life. Palliative esophageal stenting with self-expanding metal stents (SEMS) helps alleviate symptoms and prolongs survival. However, access to fluoroscopy may be limited at certain centers causing delay in patient care. Methods We searched multiple databases from inception to November 2019 to identify studies evaluating the efficacy and safety of endoscopic palliative esophageal stenting and selected only those studies where fluoroscopic guidance was not used. Our primary aim was to calculate the overall technical as well as clinical success. Using meta-regression analysis, we also evaluated the effect of tumor location and obstruction length on overall technical and clinical success. Results A total of 1778 patients from 17 studies were analyzed. A total of 2036 stents were placed without the aid of fluoroscopy. The pooled rate of technical success was 94.7 % (CI 89.9-97.3, PI 55-99; I 2  = 85) and clinical success was 82.1 % (CI 67.1-91.2, PI 24-99; I 2  = 87). Based on meta-regression analysis both the length of obstruction and tumor location did not have any statistically significant effect on technical and clinical success. The pooled rate of adverse events was 4.1 % (CI 2.4-7.2; I 2  = 72) for stent migration, 8.1 % (CI 4.1-15.4; I 2  = 89) for tumor overgrowth and 1.2 % (CI 0.7-2; I 2  = 0) for perforation. The most frequent clinical adverse event was retro-sternal chest pain. Conclusion Palliative esophageal stenting without fluoroscopy using SEMS is both safe and effective in patients with advanced esophageal cancer.

Comparison of EUS-guided conventional smear and liquid-based cytology in pancreatic lesions: A systematic review and meta-analysis.

Background and study aims Endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) has limitations of inadequate sampling and false-negative results for malignancy. It has been performed using conventional smear (CS) cytology with rapid on-site evaluation (ROSE) with reasonable diagnostic accuracy. An alternative to ROSE is liquid-based cytology (LBC). Commonly used LBC techniques include precipitation-based (SurePath™) and filtration-based (ThinPrep ® , CellPrep ® ). Data regarding the diagnostic efficacy of LBC compared with CS are limited. Methods Multiple databases were searched through March 2020 to identify studies reporting diagnostic yield of EUS-guided CS and LBC in pancreatic lesions. Pooled diagnostic odds and rates of performance for the cytologic diagnoses of benign, suspicious, and malignant lesions were calculated. Diagnostic efficacy was evaluated by pooled rates of accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results Nine studies with a total of 1308 patients were included in our final analysis. Pooled diagnostic odds of CS cytology were 1.69 (CI 1.02-2.79) and 0.39 (CI 0.19-0.8) for malignant lesions when compared to filtration-based and precipitation-based LBC techniques, respectively. For CS, precipitation-based and filtration-based LBC, pooled diagnostic accuracy was 79.7 %, 85.2 %, 77.3 %, sensitivity was 79.2 %, 83.6 %, 68.3 %, and specificity was 99.4 %, 99.5 %, 99.5 %, respectively. Conclusions The precipitation-based LBC technique (SurePath™) had superior diagnostic odds for malignant pancreatic lesions compared with CS cytology in the absence of ROSE. It showed superior accuracy and sensitivity, but comparable specificity and PPV. Diagnostic odds of CS cytology in the absence of ROSE were superior to the filtration-based LBC technique (ThinPrep ® , Cellprep ® ) for diagnosing malignant pancreatic lesions.