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.

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 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.

Endo-sponge in management of anastomotic colorectal leaks: a systematic review and meta-analysis.

Background and study aims Following colorectal surgery, anastomotic dehiscence and leak formation has an incidence of 2 % to 7 %. Endo-SPONGE has been applied in the management of anastomatic leaks (ALs) after colorectal surgery. This is the first systematic review and meta analysis to evaluate the efficacy and safety of Endo-SPONGE in the management of colorectal ALs. Patients and methods The primary outcomes assessed were the technical and clinical success of Endo-SPONGE placement in colorectal ALs. The secondary outcomes assessed were the overall adverse events (AEs) and the AE subtypes. Pooled estimates were calculated using random-effects models with 95 % confidence interval (C. I.). The statistical analysis was done using STATA v16.1 software (StataCorp, LLC College Station, Texas, United States). Results The analysis included 17 independent cohort studies with a total of 384 patients. The rate of technical success was 99.86 % (95 % CI: 99.2 %, 100 %; P  = 0.00; I 2  = 70.69 %) and the calculated pooled rate of clinical success was 84.99 % (95 % CI: 77.4 %, 91.41 %; P  = 0.00; I 2  = 68.02 %). The calculated pooled rate of adverse events was 7.6 % (95 % CI: 3.99 %, 12.21 %; P  = 0.03; I 2  = 42.5 %) with recurrent abscess formation and bleeding being the most common AEs. Moderate to substantial heterogeneity was noted in our meta-analysis. Conclusions Endoscopic vacuum therapy appears to be a minimally invasive, safe, and effective treatment modality for patients with a significant colorectal leak without any generalized peritonitis with high clinical and technical success rates and a low rate of adverse events. Further prospective or randomized controlled trials are needed to validate our findings.

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.

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.

Efficacy of EUS-RFA in pancreatic tumors: Is it ready for prime time? A systematic review and meta-analysis.

Background and study aims Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) can be used in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). We performed a systematic review and meta-analysis to evaluate the efficacy of EUS-RFA in treatment of locally advanced unresectable PDAC and other pancreatic tumors. Patients and methods A comprehensive search was done of multiple electronic databases and conference proceedings including PubMed, EMBASE, Web of Science databases, Google Scholar and manual search of references (from inception through May 2019) to identify the studies reporting use of EUS-RFA for pancreatic lesions. The primary outcome was to evaluate technical and clinical success of the procedure. The secondary outcome was to study overall adverse events (AEs). Results Thirteen studies reporting 165 EUS-RFA procedures on 134 patients were included. Of 134 patients, 27.94 % (38) had unresectable locally advanced PDAC, 40 % (53) had PNETs, 3 % (4) had metastasis to the pancreas and 30 % (41) had other lesions. The pooled technical success rate calculated out of the total number of procedures was 100 % (95 % CI [99.18 - 100], I2 = 0 %). The pooled clinical success rate calculated out of the total number of patients was 91.58 % (95 % CI [82.5 - 98.08], I2 = 21.5 %). The pooled overall AE rates were 14.67 % (95 % CI [4.77 - 27.46], I2 = 56.19 %) out of which abdominal pain was the most common with 9.82 % (95 % CI [3.34 - 18.24], I2 = 23.76 %). Low to moderate heterogeneity was noted. Conclusion EUS-RFA has high technical (100 %) and clinical success (91.5 %) rates. Further multicenter trials are needed to further validate our findings.

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.

Reversal of anti-drug antibodies against tumor necrosis factor inhibitors with addition of immunomodulators: A systematic review and meta-analysis.

BACKGROUND: The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD). AIMS: We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients. METHODS: We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model. RESULTS: Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5 months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36-94.38, I2 = 60.77%). CONCLUSION: In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.

Diagnostic yield of deep biopsy via endoscopic submucosal dissection for the diagnosis of upper gastrointestinal subepithelial tumors: a systematic review and meta-analysis.

BACKGROUND: Conventionally, endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNA)/EUS-FNB) has been used for tissue diagnosis of upper gastrointestinal (GI) subepithelial tumors (SETs). However, deep biopsy (DB) via endoscopic submucosal dissection (ESD) is emerging as an alternative technique, given the inadequate tissue sampling with EUS-FNA/EUS-FNB. Our aim was to conduct a systematic review and meta-analysis to report the overall diagnostic yield of DB via ESD for upper GI SETs. METHODS: PubMed, Cochrane Library and Web of Science databases were searched to identify studies (from commencement to Oct 2017) that reported the DB via ESD technique for diagnosis of upper GI SETs. The primary outcome of interest was the method's overall diagnostic yield and the secondary outcome was to the occurrence of complications. The meta-analysis was performed using the DerSimonian and Laird random-effects model. RESULTS: A total of 7 studies, comprising 209 patients with a mean age of 57.3 years, were included in the final meta-analysis. The overall pooled diagnostic yield of DB via ESD for upper GI SETs was 95% (95% confidence interval [CI] 84.91-99.98, I2=78.2%). Overall, pooled outcomes of major bleeding and perforation in our meta-analysis was noted in 0.07% (95%CI 0.00-2.32, I2=0%) and 0% (95%CI 0.00-1.70, I2=0%) respectively. Data regarding major bleeding and perforation rates were not reported in 2 studies. Substantial heterogeneity was observed in our meta-analysis. CONCLUSION: DB via ESD is an effective and safe procedure for diagnosing upper GI SETs. Further multicenter randomized controlled trials are needed to validate these findings.

Clinical efficacy of per-oral endoscopic myotomy (POEM) for spastic esophageal disorders: a systematic review and meta-analysis.

BACKGROUND: POEM has been successfully performed in patients with spastic esophageal disorders (SED), such as diffuse esophageal spasm, jackhammer esophagus, and type 3 achalasia. We performed a systematic review and meta-analysis to evaluate its efficacy in these patients and if total average myotomy length and prior medical or endoscopic treatments affected clinical success. METHODS: PubMed, EMBASE, Google-Scholar, Scopus, and Cochrane Review were searched for studies on POEM in SED from 2008 to September 2018. Clinical success was determined by Eckardt score (≤ 3) at follow-up. Sub-group analysis was performed based on myotomy length and evaluates the effect of prior treatments on clinical success. RESULTS: 9 studies with 210 patients were included in the final analysis. We found that the pooled rate of clinical success for POEM was 89.6% (95% CI 83.5-93.1, 95% PI 83.4-93.7, I2 = 0%). In three studies (50 patients), where total myotomy length was < 10 cm, the pooled rate of clinical success was 91.1% (95% CI 79.5-96.4, I2 = 0%). In six studies (160 patients), the length was > 10 cms and the pooled rate of clinical success was 89.1% (95% CI 83.0-93.2, I2 = 0%). The difference between these results was not statistically significant (p = 0.69). Additionally, a meta-regression analysis showed that prior treatment status did not significantly affect the primary outcome (p = 0.43). CONCLUSIONS: While it is well known that POEM is a safe and effective treatment for spastic esophageal disorders, we conclude that variation in total myotomy length and prior endoscopic or medical treatments did not have a significant effect on clinical success.

Safety and efficacy of combined antegrade and retrograde endoscopic dilation for complete esophageal obstruction: a systematic review and meta-analysis.

BACKGROUND: Complete esophageal obstruction (CEO) due to occlusive proximal stricture occurs after chemoradiation for head and neck cancers. A combined antegrade and retrograde endoscopic technique with controlled recanalization and dilation (CARD) has been shown to be an effective and safe method for regaining and maintaining esophageal luminal patency in the short term. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings, including PubMed, EMBASE, and Web of Science databases (from inception through November 2018), to identify studies that reported the outcomes of CARD. The primary outcomes were the pooled rates of technical and clinical success, specifically improvement in dysphagia and independence from percutaneous endoscopic gastrostomy (PEG)-tube feeds. The secondary outcomes were the need for repeat dilations and the risks of complications, such as pneumomediastinum, perforation, and death. RESULTS: From a total of 19 studies (229 cases and 251 procedures) the calculated technical success rate was 88.9% (95% confidence interval [CI] 83.9-92.5, I 2=0). The rates of improvement in dysphagia and being PEG-tube free were 58.4% (95%CI 50-66.3, I 2=12.6) and 43.5% (95%CI 34.1-53.4, I 2=30.6), respectively. The pooled rate of repeat dilatations was 78.9% (95%CI 69.7-85.8, I 2=15.2). The risks of pneumomediastinum, perforation and death were 9.9% (95%CI 6.2-15.6, I 2=0), 8% (95%CI 4.8-13, I 2=0), and 6.8% (95%CI 3.4-13.1, I 2=0), respectively. Minimal heterogeneity was noted in the analysis. CONCLUSIONS: The CARD procedure for CEO has a high technical success rate, but also a high rate of repeat dilations. Given its complexity and associated adverse events, this procedure should be restricted to centers with a high level of expertise.