Topazian, Mark

Abstract Background Abdominal pain is a debilitating symptom affecting ∼80% of pancreatic cancer (PC) patients. Pancreatic duct (PD) decompression has been reported to alleviate this pain, although this practice has not been widely adopted. We aimed to evaluate the role, efficacy, and safety of endoscopic PD decompression for palliation of PC post-prandial obstructive-type pain. Methods A systematic review until 7 October 2020 was performed. Two independent reviewers selected studies, extracted data, and assessed the methodological quality. Results We identified 12 publications with a total of 192 patients with PC presenting with abdominal pain, in whom PD decompression was attempted, and was successful in 167 patients (mean age 62.5 years, 58.7% males). The use of plastic stents was reported in 159 patients (95.2%). All included studies reported partial or complete improvement in pain levels after PD stenting, with an improvement rate of 93% (95% confidence interval, 79%–100%). The mean duration of pain improvement was 94 ± 16 days. Endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events (AEs) were post-sphincterotomy bleeding (1.8%), post-ERCP pancreatitis (0.6%), and hemosuccus pancreaticus (0.6%). AEs were not reported in two patients who underwent endoscopic ultrasound-guided PD decompression. In the 167 patients with technical success, the stent-migration and stent-occlusion rates were 3.6% and 3.0%, respectively. No AE-related mortality was reported. The methodological quality assessment showed the majority of the studies having low or unclear quality. Conclusion In this exploratory analysis, endoscopic PD drainage may be an effective and safe option in selected patients for the management of obstructive-type PC pain. However, a randomized–controlled trial is needed to delineate the role of this invasive practice.

Abstract Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Performance of endoscopic procedures is associated with a risk of infection from COVID-19. This risk can be reduced by the use of personal protective equipment (PPE). However, shortage of PPE has emerged as an important issue in managing the pandemic in both traditionally high and low-resource areas. A group of clinicians and researchers from thirteen countries representing low, middle, and high-income areas has developed recommendations for optimal utilization of PPE before, during, and after gastrointestinal endoscopy with particular reference to low-resource situations. We determined that there is limited flexibility with regard to the utilization of PPE between ideal and low-resource settings. Some compromises are possible, especially with regard to PPE use, during endoscopic procedures. We have, therefore, also stressed the need to prevent transmission of COVID-19 by measures other than PPE and to conserve PPE by reduction of patient volume, limiting procedures to urgent or emergent, and reducing the number of staff and trainees involved in procedures. This guidance aims to optimize utilization of PPE and protection of health care providers.

Abstract Background Endoscopic intervention for pancreatic fluid collections (PFCs) with disconnected pancreatic duct syndrome (DPDS) has been associated with failures and increased need for additional endoscopic and non-endoscopic interventions. The primary aim of this study was to determine the outcomes of endoscopic ultrasound (EUS)-guided transmural drainage of PFCs in patients with DPDS. Methods In patients undergoing EUS-guided drainage of PFCs from January 2013 to January 2018, demographic profiles, procedural indications and details, adverse events, outcomes, and subsequent interventions were retrospectively collected. Overall treatment success was determined by PFC resolution on follow-up imaging or stent removal without recurrence. Results EUS-guided drainage of PFCs was performed in 141 patients. DPDS was present in 57 of them (40 %) and walled-off necrosis was the most frequent type of PFC (55 %). DPDS was not associated with lower clinical success, increased number of repeat interventions, or increased time to PFC resolution. Patients with DPDS were more likely to be treated with permanent transmural plastic double-pigtail stents (odds ratio [OR] 6.4; 95 % confidence interval [CI] 2.5 – 16.5; P < 0.001). However, when stents were removed, DPDS was associated with increased PFC recurrence after stent removal (OR 8.0; 95 %CI 1.2 – 381.8; P = 0.04). Conclusions DPDS frequently occurs in patients with PFCs but does not negatively impact successful resolution. DPDS is associated with increased PFC recurrence after stent removal.

Background and Aims Presence of malignant regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). Limited data support the utility of endoscopic ultrasound (EUS)/fine needle aspiration (FNA) for detection of MRLNs in extrahepatic CCA, but there are no data for its role in intrahepatic CCA (iCCA). The aim of this study is to evaluate the staging impact of EUS for CCA, including analysis by subtype. Approach and Results We identified consecutive patients with CCA who underwent EUS staging at a single tertiary care center from October 2014 to April 2018. Among this cohort, we abstracted clinical demographic, radiographical, procedural, cytopathological, and surgical data. STATA 15 software was used for comparative analysis calculations (StataCorp LP, College Station, TX). The study cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross‐sectional imaging (86% vs. 47%; P < 0.001). FNA was performed in 133 (98.5%) patients with RLNs, with a median of three passes per node. EUS‐FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross‐sectional imaging (83% vs. 50%; P = 0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050 days; P < 0.001) and increased risk of death (hazard ratio = 4.1; P < 0.001). Conclusions EUS‐FNA is effective for identifying MRLN in patients with CCA, and should be routinely incorporated into staging of all CCA subtypes given the impact of MRLN on prognosis and management decisions.

INTRODUCTION: Early endoscopic intervention of pancreatitis with acute necrotic collection is conflicting with standard practice except in extenuating circumstances. The Atlanta criteria define necrotic collections based on the age from onset of disease as either acute necrotic collections (ANC ≤ 4 weeks) or walled-off necrosis (WON > 4 weeks). Some patients with ANCs will have clinically apparent infection of necrosis potentially necessitating infectious source control via endoscopic intervention where percutaneous drainage is technically challenging or inadequate. At present, data regarding early endoscopic intervention for acute necrotic collections is lacking. METHODS: A retrospective review of patients undergoing endoscopic intervention for pancreatic necrosis between 2008 and 2018 was performed. Included patients had definitive pancreatic/peri-pancreatic necrosis on contrast-enhanced computed tomography, signs/symptoms and laboratory evidence of pancreatitis in relation to hospital presentation, and endoscopic intervention within 28 days of symptom onset. Patients with prior percutaneous or surgical intervention were excluded. ANC cases were matched and compared to WON controls for analyzed parameters via conditional logistic regression. RESULTS: Twenty four patients were identified to have attempted drainage within 28 days of symptom onset, three of which were excluded (imaging limitations, spontaneous drainage/fistulization, unclear date of symptom onset). Demographic and clinical characteristic data are summarized in Table 1, with procedure and outcome characteristics shown in Table 2 for the 21 ANC cases in comparison to WON controls. Overall, ANC cases had slightly larger collections, with statistically significantly longer hospital stays as compared to matched WON controls ( P < 0.01); otherwise measured variables were not statistically significant between the groups. CONCLUSION: There is a paucity of data regarding the safety and efficacy of intervention of ANCs complication pancreatitis. We found in this study that there was reasonable success in clinically indicated endoscopic drainage of ANCs without significant sequelae from the procedures undertaken as compared to matched WON controls. This study demonstrates the safety of intervening on ANCs as early as 15 days if clinically indicated. Further research in regards to efficacy/safety of intervention and prognostic indicators of early intervention is required to further discern whether this applies to general practice of ANC management.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis which is recognized as a major risk factor for cholangiocarcinoma (CCA). We aimed to investigate the roles of the biliary and intestinal microflora in the inflammatory process of PSC and to determine if the microflora is associated with progression to CCA. METHODS: We studied the bile and stool microbiomes in samples obtained from patients with PSC (31 stool and 35 bile samples), sporadic CCA (11 stool and 26 bile samples), and PSC coexisting with CCA (16 stool and bile 17 samples). Control bile was obtained from patients with cholelithiasis or choledocholithiasis (n = 17). DNA extraction was followed by amplification and high-throughput next generation sequencing (MiSeq) of the 16S rDNA (V3-V5) region to identify the microbiota present. We performed: 1. analysis of the stool microbiome between PSC and CCA patients; 2. analysis of the biliary microbiome in PSC and CCA patients; 3. comparison of the biliary microbiome collected before and after biliary stent placement. RESULTS: Although bile samples from study patients had significantly lower sequencing depths than stool, their sequencing depths were much higher than bile from negative controls. The microbiomes of stool and bile samples from the same patients were significantly correlated ( P = 0.022). CCA bile samples had significant difference of alpha diversity from control bile samples with less Streptococcaceae and Desulfovibrionaceae (FDR < 10%) than PSC whereas no significant change of stool microbiome was identified between CCA and PSC. Fusobacterium and Gemella were correlated to PSC duration. An increased abundance of Fusobacteria after stent placement was revealed. Fusobacteria, which is inflammation-promoting, was also increased with the number of stents in the bile duct. CONCLUSION: Our study suggests that the bile microbiome is potentially a more distinctive biomarker than the stool microbiome for PSC and CCA development. There is increased inhabitance of inflammation-promoting bacteria in the bile of CCA patients and after biliary stent placement. Increased PSC duration also increases the microbial burden in the bile, which may also promote CCA development. We further detected specific bile microbes statistically associated with CCA or stent presence in the bile ducts, which raises the possibility of their role in the CCA progression or stent obstruction. Additional analyses with more samples are needed.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs ( TBX15 , BMP3 ) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86–0.99), 0.71 (0.57–0.85), and 0.72 (0.60–0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77–0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Abstract Background and study aim The role of esophageal overtubes in upper gastrointestinal endoscopic suturing is unknown. This study aimed to determine whether overtube use was associated with technical success or adverse events. Patients and methods A retrospective review of consecutive patients who underwent endoscopic suturing for various indications was performed. Results A total of 719 patients underwent endoscopic suturing for various indications, including endoscopic bariatric procedures in 262, stent fixation in 258, defect closure in 190, and hemostasis in nine. An overtube was used in 186 procedures (25.9 %). Technical success was achieved in all cases. Minor mucosal trauma occurred in 15 cases (8.1 %) with use of an overtube, and none without an overtube (P < 0.0001). No full-thickness esophageal perforation or hemorrhage related to overtube use or the suturing device occurred. Conclusions Endoscopic suturing can be performed safely for a variety of indications, including endoscopic bariatric procedures, defect repair, and stent fixation without an esophageal overtube. Minor esophageal mucosal trauma and equipment cost are increased when an overtube is used.

OBJECTIVES: Expression of prostaglandin biosynthetic pathway enzymes in mucinous pancreatic cysts is unknown. Cyclooxygenase-2 (COX-2) inhibition is a potential cancer chemoprevention strategy for these lesions. We evaluated the expression of COX-2, cytosolic phospholipase A2 (cPLA2), and protein kinase B (AKT) in the epithelium of pancreatic cysts and correlated enzyme expression with aspirin (ASA) use and cyst fluid prostaglandin E 2 (PGE 2 ) concentration. METHODS: Pathology of 80 resected pancreatic cysts was reviewed. Expression of COX-2, cPLA2, and AKT was quantified by tissue immunohistochemistry immunoreactivity scores (IRSs). IRS values were compared between cyst types and (in 30 cases) with matched cyst fluid PGE 2 concentrations. RESULTS: The mean IRS was higher in the epithelium of mucinous vs nonmucinous cysts for COX-2 (6.1 ± 4.7 vs 3.2 ± 2.8, P = 0.01) and cPLA2 (6.9 ± 3.0 vs 2.9 ± 2.9, P < 0.001). Cyst epithelial COX-2 expression was higher in mucinous cysts with low-grade dysplasia vs those with high-grade dysplasia or invasive carcinoma (IRS 8.0 ± 3.9 vs 1.5 ± 2.9, P < 0.001), whereas the opposite was found for cPLA2 (6.2 ± 3.0 vs 8.6 ± 2.3, P = 0.005). Cyst fluid PGE 2 concentrations did not correlate with either the IRS or a history of low- to moderate-dose ASA use. CONCLUSIONS: COX-2 and cPLA2 are overexpressed in the epithelium of mucinous pancreatic cysts. COX-2 and/or cPLA2 inhibition might prevent the emergence or progression of mucinous pancreatic cysts, but higher doses of ASA or nonsteroidal anti-inflammatory drugs may be necessary to substantially inhibit cyst epithelial COX-2 activity.