Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Endoscopic submucosal dissection with versus without traction for pathologically staged T1B esophageal cancer: a multicenter retrospective study.

BACKGROUND AND AIMS: Positive vertical margins (VMs) are common after endoscopic submucosal dissection (ESD) of T1b esophageal cancer (EC) and are associated with an increased risk of recurrence. Traction during ESD provides better exposure of the submucosa and may allow deeper dissection, potentially reducing the risk of positive VMs. We conducted a retrospective multicenter study to compare the proportion of resections with positive VMs in ESD performed with versus without traction in pathologically staged T1b EC. METHODS: Patients who underwent ESD revealing T1b EC (squamous or adenocarcinoma) at 10 academic tertiary referral centers in the United States (n = 9) and Brazil (n = 1) were included. Demographic and clinical data were abstracted. ESD using either traction techniques (tunneling, pocket) or traction devices (clip line, traction wire) were classified as ESD with traction (Tr-ESD) and those without were classified as conventional ESD without traction. The primary outcome was a negative VM. Multivariable logistic regression was used to assess associations with negative VMs. RESULTS: A total of 166 patients with pathologically staged T1b EC underwent Tr-ESD (n = 63; 38%) or conventional ESD without traction (n = 103; 62%). Baseline factors were comparable between both groups. On multivariable analysis, Tr-ESD was found to be independently associated with negative VMs (odds ratio, 2.25; 95% confidence interval, 1.06-4.91; P = .037) and R0 resection (odds ratio, 2.83; 95% confidence interval, 1.33-6.23; P = .008). CONCLUSION: Tr-ESD seems to be associated with higher odds of negative VMs than ESD without traction for pathologically staged T1b EC, and future well-conducted prospective studies are warranted to establish the findings of the current study.

Endoscopic transesophageal retrograde drainage tandem with endoscopic closure for management of esophageal leak after peroral endoscopic myotomy for Zenker diverticulum.

Video 1Endoscopic transesophageal retrograde drainage tandem with endoscopic closure for management of esophageal leak after peroral endoscopic myotomy for Zenker diverticulum.

Successful Design and Implementation of a POEM Program for Achalasia in an Integrated Healthcare System.

BACKGROUND: Per Oral Endoscopic Myotomy (POEM) is a minimally invasive treatment for achalasia with results comparable to laparoscopic Heller myotomy (LHM). Studies have described the development of proficiency for endoscopists learning to perform POEM, and societies have defined educational and technical objectives for advanced endoscopy fellows in training. However, there is limited guidance on the organizational strategy and educational plan necessary to develop an achalasia service with POEM expertise. AIMS: We aim to outline the steps for design and implementation of a successful POEM program. METHODS: We reported our experience developing a multi-disciplinary clinical program for POEM and the steps taken to achieve procedural proficiency. We also reported our technical success (successful tunneling into the gastric cardia and myotomy of LES muscle fibers) and clinical success (post-procedure Eckardt score ≤ 3) at 3-6 months and 12 months post-procedure. Adverse events were classified per the ASGE lexicon for endoscopic adverse events. RESULTS: After creating a multi-disciplinary clinical program for achalasia and completing procedural proficiency for POEM, our technical success rate was 100% and clinical success rate 90% for the first 41 patients. One adverse event (2.4%) occurred, moderate in severity per the American Society of Gastrointestinal Endoscopy (ASGE) lexicon for adverse endoscopic events. CONCLUSION: In this study, we outlined the steps involved to establish a POEM service in a large integrated healthcare system. Prior competency in interventional endoscopy, procedural training models, POEM observation and education, proctorship, and interdisciplinary patient care are recommended.

Outcomes of endoscopic retrograde cholangiography and percutaneous transhepatic biliary drainage in liver transplant recipients with a Roux-en-Y biliary-enteric anastomosis.

Backgrounds/Aims: Data regarding outcomes of endoscopic retrograde cholangiography (ERC) in liver transplant (LT) recipients with biliary-enteric (BE) anastomosis are limited. We report outcomes of ERC and percutaneous transhepatic biliary drainage (PTBD) as first-line therapies in LT recipients with BE anastomosis. Methods: All LT recipients with Roux-BE anastomosis from 2001 to 2020 were divided into ERC and PTBD subgroups. Technical success was defined as the ability to cannulate the bile duct. Clinical success was defined as the ability to perform cholangiography and therapeutic interventions. Results: A total of 36 LT recipients (25 males, age 53.5 ± 13 years) with Roux-BE anastomosis who underwent biliary intervention were identified. The most common indications for a BE anastomosis were primary sclerosing cholangitis (n = 14) and duct size mismatch (n = 10). Among the 29 patients who initially underwent ERC, technical success and clinical success were achieved in 24 (82.8%) and 22 (75.9%) patients, respectively. The initial endoscope used for the ERC was a single balloon enteroscope in 16 patients, a double balloon enteroscope in 7 patients, a pediatric colonoscope in 5 patients, and a conventional reusable duodenoscope in 1 patient. Among the 7 patients who underwent PTBD as the initial therapy, six (85.7%) achieved technical and clinical success (p = 0.57). Conclusions: In LT patients with Roux-BE anastomosis requiring biliary intervention, ERC with a balloon-assisted enteroscope is safe with a success rate comparable to PTBD. Both ERC and PTBD can be considered as first-line therapies for LT recipients with a BE anastomosis.

Endoscopic Submucosal Dissection in the Esophagus: Indications, Techniques, and Outcomes.

Endoscopic submucosal dissection (ESD) is well-accepted endoscopic resection modality for esophageal lesions with benefits in certain situations. ESD offers potential cure for early esophageal cancer and detailed pathologic information for risk stratification. Techniques are mostly standardized, and the use of traction method is encouraged. Indication and proper techniques of ESD in esophageal disease and clinical outcomes will be discussed in this article with pearls for care planning and management during periprocedural period.

EUS-guided choledochoduodenostomy using a lumen-apposing metal stent in a patient with preexisting duodenal stent and ascites.

Video 1EUS-guided choledochoduodenostomy using a lumen-apposing metal stent in a patient with preexisting duodenal stent and ascites.

Follow-up outcomes of mucosal defect closures after endoscopic resection using a helix tacking system and endoclips.

Background and Aims: The X-Tack endoscopic HeliX tacking system (Apollo Endosurgery, Austin, Tex, USA) has recently been approved by the Food and Drug Administration and is slowly gaining popularity for the closure of large tissue defects. Despite its increasing use, outcome data of using the X-Tack system for mucosal defect closure after endoscopic resection (ER) are limited. Here, we report the follow-up outcomes of a series of cases that underwent ER and mucosal closure aided by the HeliX tacking system. Methods: We identified a total of 5 cases in which the X-Tack system and endoclips were used for mucosal defect closure after ER. The cases involved ER of large and/or flat polyps in the duodenum and colon. The patients were followed up at 4, 6, and 9 months after ER. Results: In all cases, X-Tacks with endoclips achieved complete closure of the large mucosal defects. None of the patients experienced any adverse events, such as abdominal pain or bleeding. At follow-up, the X-Tacks either fell off or were seen grouped or situated as a single piece (tack) in the mucosa where initially placed. None of the endoclips were found during the follow-up endoscopic examinations. Conclusions: The X-Tack system together with endoclips facilitated complete closure of large mucosal defects, especially for lesions located in difficult locations. At follow-up, several retained X-Tacks were found either in groups or as a single piece. The X-Tacks seen in groups will likely fall off with repetitive pulling forces with food or feces. However, the single tacks that were secured in the wall may stay indefinitely. The novel HeliX tacking system seems to be a promising aid for the effective closure of large mucosal defects; however, further studies are needed to assess the long-term outcome of this novel system.

Outcomes for endoscopic submucosal dissection of pathologically staged T1b esophageal cancer: a multicenter study.

BACKGROUND AND AIMS: The outcomes of endoscopic submucosal dissection (ESD) for T1b esophageal cancer (EC) and its recurrence rates remain unclear in the West. Using a multicenter cohort, we evaluated technical outcomes and recurrence rates of ESD in the treatment of pathologically staged T1b EC. METHODS: We included patients who underwent ESD of T1b EC at 7 academic tertiary referral centers in the United States (n = 6) and Brazil (n = 1). We analyzed demographic, procedural, and histopathologic characteristics and follow-up data. Time-to-event analysis was performed to evaluate recurrence rates. RESULTS: Sixty-six patients with pathologically staged T1b EC after ESD were included in the study. A preprocedure staging EUS was available in 54 patients and was Tis/T1a in 27 patients (50%) and T1b in 27 patients (50%). En-bloc resection rate was 92.4% (61/66) and R0 resection rate was 54.5% (36/66). Forty-nine of 66 patients (74.2%) did not undergo surgery immediately after resection and went on to surveillance. Ten patients had ESD resection within the curative criteria, and no recurrences were seen in a 13-month (range, 3-18.5) follow-up period in these patients. Ten of 39 patients (25.6%) with noncurative resections had residual/recurrent disease. Of the 10 patients with noncurative resection, local recurrence alone was seen in 5 patients (12.8%) and metastatic recurrence in 5 patients (12.8%). On univariate analysis, R1 resection had a higher risk of recurrent disease (hazard ratio, 6.25; 95% confidence interval, 1.29-30.36; P = .023). CONCLUSIONS: EUS staging of T1b EC has poor accuracy, and a staging ESD should be considered in these patients. ESD R0 resection rates were low in T1b EC, and R1 resection was associated with recurrent disease. Patients with noncurative ESD resection of T1b EC who cannot undergo surgery should be surveyed closely, because recurrent disease was seen in 25% of these patients.

Initial multicenter experience using a novel endoscopic tack and suture system for challenging GI defect closure and stent fixation (with video).

BACKGROUND AND AIMS: Closure of endoscopic resection defects can be achieved with through-the-scope clips, over-the-scope clips, or endoscopic suturing. However, these devices are often limited by their inability to close large, irregular, and difficult-to-reach defects. Thus, we aimed to assess the feasibility and safety of a novel through-the-scope, suture-based closure system developed to overcome these limitations. METHODS: This was a retrospective multicenter study involving 8 centers in the United States. Primary outcomes were feasibility and safety of early use of the device. Secondary outcomes were assessment of need for additional closure devices, prolonged procedure time, and technical feasibility of performing the procedure with an alternative device(s). RESULTS: Ninety-three patients (48.4% women) with mean age 63.6 ± 13.1 years were included. Technical success was achieved in 83 patients (89.2%), and supplemental closure was required in 24.7% of patients (n = 23) with a mean defect size of 41.6 ± 19.4 mm. Closure with an alternative device was determined to be impossible in 24.7% of patients because of location, size, or shape of the defect. The use of the tack and suture device prolonged the procedure in 8.6% of cases but was considered acceptable. Adverse events occurred in 2 patients (2.2%) over a duration of follow-up of 34 days (interquartile range, 13-93.5) and were mild and moderate in severity. No serious adverse events or procedure-related deaths occurred. CONCLUSIONS: The novel endoscopic through-the-scope tack and suture system is safe, efficient, and permits closure of large and irregularly shaped defects that were not possible with established devices.

Endoscopic submucosal dissection vs. endoscopic mucosal resection for early Barrett's neoplasia in the West: a retrospective study.

BACKGROUND: The difference in clinical outcomes after endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for early Barrett's esophagus (BE) neoplasia remains unclear. We compared the recurrence/residual tissue rates, resection outcomes, and adverse events after ESD and EMR for early BE neoplasia. METHODS: We included patients who underwent EMR or ESD for BE-associated high grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC) at eight academic hospitals. We compared demographic, procedural, and histologic characteristics, and follow-up data. A time-to-event analysis was performed to evaluate recurrence/residual disease and a Kaplan-Meier curve was used to compare the groups. RESULTS: 243 patients (150 EMR; 93 ESD) were included. EMR had lower en bloc (43 % vs. 89 %; P < 0.001) and R0 (56 % vs. 73 %; P = 0.01) rates than ESD. There was no difference in the rates of perforation (0.7 % vs. 0; P > 0.99), early bleeding (0.7 % vs. 1 %; P > 0.99), delayed bleeding (3.3 % vs. 2.1 %; P = 0.71), and stricture (10 % vs. 16 %; P = 0.16) between EMR and ESD. Patients with non-curative resections who underwent further therapy were excluded from the recurrence analysis. Recurrent/residual disease was 31.4 % [44/140] for EMR and 3.5 % [3/85] for ESD during a median (interquartile range) follow-up of 15.5 (6.75-30) and 8 (2-18) months, respectively. Recurrence-/residual disease-free survival was significantly higher in the ESD group. More patients required additional endoscopic resection procedures to treat recurrent/residual disease after EMR (EMR 24.2 % vs. ESD 3.5 %; P < 0.001). CONCLUSIONS: ESD is safe and results in more definitive treatment of early BE neoplasia, with significantly lower recurrence/residual disease rates and less need for repeat endoscopic treatments than with EMR.

Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. PREVENTION RELEVANCE: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

Clinical Impact of Pathogenic Germline Variants in Pancreatic Cancer: Results From a Multicenter, Prospective, Universal Genetic Testing Study.

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach. METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers. RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14-5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25-1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, and RAD51C. DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

Interobserver Agreement for Classifying Post-liver Transplant Biliary Strictures in Donation After Circulatory Death Donors.

INTRODUCTION: Biliary strictures are a common complication of donation after circulatory death (DCD) liver transplantation (LT) and require multiple endoscopic retrograde cholangiopancreatography (ERCP) procedures. Three classification systems, based on cholangiograms, have been proposed for categorizing post-LT biliary strictures. We examined the interobserver agreement for each of the three classifications. METHODS: DCD LT recipients from 2012 through March 2017 undergoing ERCP for biliary strictures were included in the study. Initial cholangiograms delineating the entire biliary tree prior to endoscopic intervention were selected. One representative cholangiogram was selected from each ERCP. Five interventional endoscopists independently viewed each anonymized cholangiogram and classified the post-LT stricture according to each of the three classification systems. The Ling classification proposes four types of post-LT strictures based on their location. The Lee classification proposes four classes based on location and number of intrahepatic strictures. The binary system classifies strictures into anastomotic or non-anastomotic types. The Krippendorff's alpha reliability estimate was used to grade the strength of agreement as "poor," "fair," "moderate," "good," or "excellent" for values between 0-0.20, 0.21-0.4, 0.41-0.6, 0.61-0.08, and 0.81-1, respectively. RESULTS: One hundred DCD LT recipients (age 57.07 ± 8.8 years; 71 males) were initially evaluated. Of these, 49 patients who underwent 206 ERCP procedures for biliary strictures were included in the analysis. One hundred thirty-nine cholangiograms were selected and subsequently classified by five endoscopists. Interobserver agreement for post-LT biliary strictures was 0.354 for Ling classification (fair agreement), 0.405 for Lee classification (fair agreement), and 0.421 for the binary classification (moderate agreement). The binary classification provided the least amount of detail regarding the location and number of biliary strictures. DISCUSSION: The currently available classification systems for assessing post-LT biliary strictures have sub-optimal interobserver agreement. A better-designed classification system is needed for categorizing post-LT biliary strictures.

Efficacy of Endoscopic Submucosal Dissection for Superficial Gastric Neoplasia in a Large Cohort in North America.

BACKGROUND & AIMS: Endoscopic submucosal dissection (ESD) is a widely accepted treatment option for superficial gastric neoplasia in Asia, but there are few data on outcomes of gastric ESD from North America. We aimed to evaluate the safety and efficacy of gastric ESD in North America. METHODS: We analyzed data from 347 patients who underwent gastric ESD at 25 centers, from 2010 through 2019. We collected data on patient demographics, lesion characteristics, procedure details and related adverse events, treatment outcomes, local recurrence, and vital status at the last follow up. For the 277 patients with available follow-up data, the median interval between initial ESD and last clinical or endoscopic evaluation was 364 days. The primary endpoint was the rate of en bloc and R0 resection. Secondary outcomes included curative resection, rates of adverse events and recurrence, and gastric cancer-related death. RESULTS: Ninety patients (26%) had low-grade adenomas or dysplasia, 82 patients (24%) had high-grade dysplasia, 139 patients (40%) had early gastric cancer, and 36 patients (10%) had neuroendocrine tumors. Proportions of en bloc and R0 resection for all lesions were 92%/82%, for early gastric cancers were 94%/75%, for adenomas and low-grade dysplasia were 93%/ 92%, for high-grade dysplasia were 89%/ 87%, and for neuroendocrine tumors were 92%/75%. Intraprocedural perforation occurred in 6.6% of patients; 82% of these were treated successfully with endoscopic therapy. Delayed bleeding occurred in 2.6% of patients. No delayed perforation or procedure-related deaths were observed. There were local recurrences in 3.9% of cases; all occurred after non-curative ESD resection. Metachronous lesions were identified in 14 patients (6.9%). One of 277 patients with clinical follow up died of metachronous gastric cancer that occurred 2.5 years after the initial ESD. CONCLUSIONS: ESD is a highly effective treatment for superficial gastric neoplasia and should be considered as a viable option for patients in North America. The risk of local recurrence is low and occurs exclusively after non-curative resection. Careful endoscopic surveillance is necessary to identify and treat metachronous lesions.

Full-thickness resection device (FTRD) for treatment of upper gastrointestinal tract lesions: the first international experience.

Background and study aims The Full-Thickness Resection Device (FTRD) provides a novel treatment option for lesions not amenable to conventional endoscopic resection techniques. There are limited data on the efficacy and safety of FTRD for resection of upper gastrointestinal tract (GIT) lesions. Patients and methods This was an international multicenter retrospective study, including patients who had an endoscopic resection of an upper GIT lesion using the FTRD between January 2017 and February 2019. Results Fifty-six patients from 13 centers were included. The most common lesions were mesenchymal neoplasms (n = 23, 41 %), adenomas (n = 7, 13 %), and hamartomas (n = 6, 11 %). Eighty-four percent of lesions were located in the stomach, and 14 % in the duodenum. The average size of lesions was 14 mm (range 3 to 33 mm). Deployment of the FTRD was technically successful in 93 % of patients (n = 52) leading to complete and partial resection in 43 (77 %) and 9 (16 %) patients, respectively. Overall, the FTRD led to negative histological margins (R0 resection) in 38 (68 %) of patients. A total of 12 (21 %) mild or moderate adverse events (AEs) were reported. Follow-up endoscopy was performed in 31 patients (55 %), on average 88 days after the procedure (IQR 68-138 days). Of these, 30 patients (97 %) did not have any residual or recurrent lesion on endoscopic examination and biopsy, with residual adenoma in one patient (3 %). Conclusions Our results suggest a high technical success rate and an acceptable histologically complete resection rate, with a low risk of AEs and early recurrence for FTRD resection of upper GIT lesions.

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation.

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.