Resectability of Small Duodenal Tumors: A Randomized Controlled Trial Comparing Underwater Endoscopic Mucosal Resection and Cold Snare Polypectomy.

INTRODUCTION: Underwater endoscopic mucosal resection (UEMR) and cold snare polypectomy (CSP) are novel endoscopic procedures for superficial nonampullary duodenal epithelial tumors (SNADET). However, consensus on how to use both procedures appropriately has not been established. In this study, we evaluated treatment outcomes of both procedures, including resectability. METHODS: In this single-center randomized controlled study conducted between January 2020 and June 2022, patients with SNADET ≤12 mm were randomly allocated to UEMR and CSP groups. The primary end point was sufficient vertical R0 resection (SVR0), which was defined as R0 resection including a sufficient submucosal layer. We compared treatment outcomes including SVR0 rate between groups. RESULTS: The SVR0 rate was significantly higher in the UEMR group than in the CSP group (65.6% vs 41.5%, P = 0.01). By contrast, the R0 resection rate was not significantly different between study groups (70.3% vs 61.5%, P = 0.29). The submucosal layer thickness was significantly greater in the UEMR group than in the CSP group (median 546 [range, 309-833] µm vs 69 [0-295] µm, P < 0.01). CSP had a shorter total procedure time (median 12 [range, 8-16] min vs 1 [1-3] min, P < 0.01) and fewer total bleeding events (9.4% vs 1.5%, P = 0.06). DISCUSSION: UEMR has superior vertical resectability compared with CSP, but CSP has a shorter procedure time and fewer bleeding events. Although CSP is preferable for most small SNADET, UEMR should be selected for lesions that cannot be definitively diagnosed as mucosal low-grade neoplasias.

Novel perfusion system using continuous liquid-suction catheter attachment in colorectal endoscopic submucosal dissection with water pressure method (with video).

Water pressure method (WPM) is useful for colorectal endoscopic submucosal dissection (ESD), characterized not only by underwater conditions but also by active water pressure via the waterjet function. However, the extension of the colorectum by injecting excess water and contaminating the operative field by stool and bleeding have been issues. This study aimed to evaluate the feasibility of a novel perfusion system using a continuous liquid-suction catheter attachment (CLCA) in colorectal ESD with WPM. We retrospectively reviewed cases in which the perfusion system was used in colorectal ESD with WPM between August 2022 and September 2023. We evaluated clinical characteristics, treatment outcomes, volume of injection by the waterjet function, volume of suction by the endoscope and CLCA, and concentration of floating matter in the operative field over time. Thirty-one cases were enrolled. The median lesion size was 30 (range, 15-100) mm. In all cases, en bloc resection was achieved without perforation. The median injection volume was 2312 (range, 1234-13,866) g. The median suction volumes by the endoscope and CLCA were 918 (range, 141-3162) and 1147 (range, 254-11,222) g, respectively. The median concentration of floating matter in the operative field (measured in 15 cases) was 15.3 (range, 7.3-112) mg/mL when the endoscope arrived at the lesion and 8.0 (range, 3.2-16) mg/mL after endoscopically washing at the beginning of the ESD. It ranged from 7.6 to 13.4 mg/dL every 20 min during ESD. This perfusion system could prevent the extension of the lumen and maintain a good field of view in colorectal ESD with WPM.

Non-interventional Management of Asymptomatic Diminutive Choledocholithiasis Versus Endoscopic Extraction in Consecutive Patients.

BACKGROUND: Current guidelines recommend treating choledocholithiasis, regardless of symptoms or stone size, with endoscopic retrograde cholangiopancreatography (ERCP). However, asymptomatic choledocholithiasis, discovered incidentally on imaging, may carry a higher risk of ERCP-related adverse events, and some asymptomatic and diminutive stones may not cause biliary adverse events during extended follow-up. Therefore, we aimed to clarify the best treatment strategies for asymptomatic choledocholithiasis based on stone size. METHODS: We retrospectively identified patients with incidental imaging-found asymptomatic diminutive (≤ 4 mm) or non-diminutive (> 4 mm) choledocholithiasis and divided them into two groups: those who did not undergo ERCP and were treated when complications arose (on-demand group) and those who underwent ERCP before being symptomatic (intervention group). Adverse events were defined as any biliary or pancreatic complication related to ERCP or arising during observation or after intervention. The primary outcome was the adjusted overall adverse event-free survival using the propensity score-based matching weights method comparing the two groups of stone size. RESULTS: Among 148 patients identified (median follow-up period, 969 days), 68 had diminutive stones and 80 had non-diminutive stones. Of the 68 patients with diminutive stones, 51 were in the on-demand group and 17 in the intervention group. The overall adjusted adverse event-free survival was significantly higher in the on-demand group for diminutive stones (97.4% and 70.1%, respectively, at 3 years; p = 0.01). DISCUSSION: Patients with incidental imaging-detected asymptomatic diminutive choledocholithiasis may benefit from clinical observation, pursuing ERCP when symptoms develop.

Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study.

Environmental and genetic factors play a critical role in the pathogenesis of pancreatic cancer, which is likely to follow a multistep process that includes intraductal papillary mucinous neoplasm. The pathogenesis of familial pancreatic cancer has been reported; however, epidemiological characteristics and causative genes remain unclear. This study aimed to determine the relationship between the family history of pancreatic cancer and tumor malignancy and identify novel susceptible germline variants of pancreatic cancer. We performed an epidemiologic study at our institute on a cohort of 668 patients with intraductal papillary mucinous neoplasm and 242 with pancreatic cancer but without associated intraductal papillary mucinous neoplasm stratified by family history of pancreatic cancer. Whole-exome sequencing was conducted for 10 patients from seven families with familial pancreatic cancer and intraductal papillary mucinous neoplasm. We found that patients who had intraductal papillary mucinous neoplasm with positive family history of pancreatic cancer within first-degree relatives were more likely to develop malignancy in a shorter period than those without family history. Duplicate frameshift variants in TET2 c.3180dupG (p.Pro1061fs) and ASXL1 c.1934dupG (p.Gly646fs) in one family and POLN c.1194dupT (p.Glu399fs) in another were identified as pathogenic truncating germline variants which were previously recognised susceptibility genes. Moreover, PDIA2 c.1403C>T (p.Pro468Leu) and DPYSL4 c.926C>A (p.Pro309Gln) were shared in four and two patients, respectively. In particular, PDIA2 was identified as a novel candidate for one of the deleterious variants of familial pancreatic cancer.

External drainage of bile and pancreatic juice after endoscopic submucosal dissection for duodenal neoplasm: Feasibility study (with video).

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for superficial duodenal epithelial tumors (SDETs) is technically difficult and has a high risk of adverse events. Endoscopic nasobiliary and nasopancreatic duct drainage (ENBPD) may reduce the risk of delayed adverse events by preventing exposure of the post-ESD mucosal defect to bile and pancreatic juice. This study was performed to evaluate the safety and feasibility of ENBPD after duodenal ESD. METHODS: Patients who underwent ESD for SDETs from July 2010 to March 2020 were included. We collected data on the success rate of ENBPD, adverse events due to insertion of a side-viewing endoscope, and pancreatitis after ENBPD. We also collected the clinical outcomes of duodenal ESD, including the incidence rate of delayed adverse events (defined as bleeding or perforation found after the endoscopic procedure). RESULTS: Among 70 patients without complete closure of the post-ESD mucosal defect, ENBPD was successfully performed in all 25 patients including 21 cases inserted immediately after ESD and four cases inserted later. There were no adverse events associated with ENBPD procedure intraoperatively, while pancreatitis after ENBPD occurred in four patients (16.0%). No patients who underwent immediate ENBPD required intervention for an intra-abdominal abscess or delayed perforation, whereas 3 of 49 patients (6.1%) who did not undergo immediate ENBPD required surgery or drainage of an abscess. CONCLUSIONS: Endoscopic nasobiliary and nasopancreatic duct drainage is technically feasible and might provide effective prophylaxis for delayed adverse events, even if a large mucosal defect is present after ESD.

Impact of electrical pulse cut mode during endoscopic papillectomy: Pilot randomized clinical trial.

OBJECTIVE: Endoscopic papillectomy is increasingly being used for ampullary adenoma treatment. However, it remains challenging despite increased safety with treatment advances. The ideal power output and electrosurgical current mode for mucosal resection are not established. We aimed to identify the ideal electrical pulse for use during resection. METHODS: This pilot randomized, single-blind, prospective, multicenter trial, recruited patients with ampullary adenomas and conventional anatomy who were scheduled to undergo endoscopic papillectomy. Endoscopic treatment was performed using a standardized algorithm and patients were randomized for endoscopic papillectomy with Endocut or Autocut. The primary outcome was the incidence of delayed bleeding. Incidence of procedure-related pancreatitis, successful complete resection, pathological findings, and other adverse events were secondary endpoints. RESULTS: Sixty patients were enrolled over a 2-year period. The incidences of delayed bleeding (13.3% vs. 16.7%, P = 1.00) and pancreatitis (27% vs. 30%, P = 0.77) were similar between both groups. The rate of crush artifacts was higher in the Endocut than in the Autocut group (27% vs. 3.3%, P = 0.03). Immediate bleeding when resecting tumors greater than 14 mm in diameter was more common in the Autocut than in the Endocut group (88% vs. 46%, P = 0.04). CONCLUSIONS: The Autocut and Endocut modes have similar efficacy and safety for endoscopic papillectomy. The Endocut mode may prevent immediate bleeding in cases with large tumor sizes, although it causes more frequent crush artifacts. REGISTRY AND THE REGISTRATION NUMBER: The Japanese UMIN Clinical Trials Registry (UMIN-CTR: 000021382).

Multicenter comparative study on the usefulness of the optimal electrosurgical unit setting in endoscopic papillectomy for ampullary neoplasms (with video).

BACKGROUND: Endoscopic papillectomy (EP) is less invasive than surgery but procedure-related adverse events (AEs) still frequently occur. This study compared the benefits of EP using a new optimal endoCUT setting on the VIO (Erbe) electrosurgical unit (VIO-EP) with those using the conventional electrosurgical unit setting (ICC-EP, Erbe). METHODS: This multicenter, retrospective, comparative cohort study included 57 patients who underwent VIO-EP and 91 who underwent ICC-EP. The primary outcome was occurrence of EP-related AEs. Secondary outcomes were pathological findings (the resection margins, the R0 resection, and residual lesions). RESULTS: Pancreatitis tended to be less common in the VIO-EP group (5.3% vs. 9.9%, p = .248). Evaluation of computed tomography images showed that pancreatitis was confined to the pancreatic head in 77.8% of cases in the ICC-EP group and in 33.3% of those in the VIO-EP group. After exclusion of cases of delayed bleeding, pancreatitis tended to be less common in the VIO-EP group; this finding was not statistically significant (2.3% vs. 8.2%, p = .184). In pathological findings, residual lesions were significantly less common in the VIO-EP group. CONCLUSIONS: The risks of pancreatitis and residual lesions after EP may be lower when the VIO electrosurgical unit is used with the optimal setting.

Unique bile acid profiles in the bile ducts of patients with primary sclerosing cholangitis.

BACKGROUND: The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC. METHODS: Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13). RESULTS: The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups. CONCLUSIONS: Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.

Successful radiotherapy for recurrent obstructive pancreatitis secondary to pancreatic metastasis from cervical squamous-cell carcinoma.

Metastatic pancreatic cancer is a rare condition and cases of pancreatic metastasis from cervical cancer are infrequently reported. Furthermore, the incidence rates of pancreatic tumors as the cause of pancreatitis and of pancreatitis in patients with pancreatic tumors are similarly low. Pancreatitis may occur when a tumor obstructs the pancreatic duct. This condition may be difficult to manage and significantly reduces the quality of life because of severe abdominal pain. Here, we present a rare case of obstructive pancreatitis caused by pancreatic metastasis from cervical squamous-cell carcinoma, pathologically confirmed using endoscopic ultrasonography-guided fine-needle biopsy and treated with palliative irradiation to achieve rapid therapeutic relief. It is important to obtain appropriate tissue samples, confirm the pathological diagnosis, and compare the pathological findings with those of the primary tumor to select the appropriate treatment for obstructive pancreatitis caused by a metastatic pancreatic tumor.

Endoscopic Ultrasound-Guided Sampling for Personalized Pancreatic Cancer Treatment.

Pancreatic cancer is the most lethal solid malignancy, and the number of patients with pancreatic cancer is increasing. Systemic chemotherapies are often ineffective for such patients, and there is an urgent need for personalized medicine. Unlike other types of cancer, personalized treatments for pancreatic cancer are still in development. Consequently, pancreatic cancer is less sensitive to anticancer drugs and is often refractory to common treatments. Therefore, advances in personalized medicine for pancreatic cancer are necessary. This review examined advances in personalized medicine for pancreatic cancer, including the use of endoscopic ultrasound (EUS)-guided sampling. EUS-guided sampling is widely used for diagnosing pancreatic tumors and is expected to be applied to sampled tissues. Additionally, there has been an increase in clinical research using EUS-guided sampling. The combination of precision medicine using genomic testing and pharmacological profiles based on high-throughput drug sensitivity testing using patient-derived organoids is expected to revolutionize pancreatic cancer treatment.

Endoscopic Diagnosis of Biliary Stricture Combined with Digital Cholangioscope: A Case Series.

The endoscopic diagnosis of biliary tract lesions is applied as a non-invasive method; however, its diagnostic accuracy is not yet high. Moreover, digital cholangioscopy is used for directly visualizing the inside of the bile duct, resulting in a more precise biopsy. We present the case series of the outcomes of diagnosis using digital cholangioscopy in patients who underwent cholangioscopy for the evaluation of biliary stenosis in our department between January 2014 and March 2021. The controls were those who underwent a biopsy for biliary stenosis with conventional endoscopic retrograde cholangiopancreatography (ERCP). Background data for each case were collected, and the clinical outcomes by biopsy were evaluated, focusing on the accuracy of the diagnosis. Cholangioscopy was performed in 15 cases, while a conventional biopsy by ERCP was performed in 172 cases. Nine of 15 cases (60.0%) were diagnosed with cholangiocarcinoma. The number of specimens obtained through conventional ERCP and cholangioscopy was 2.5 ± 1.3 and 3.3 ± 1.5, respectively (p = 0.043). The diagnostic accuracy of conventional ERCP and cholangioscopy were 65.7% (113 of 172 cases) and 100%, respectively, which was significantly higher in the group with cholangioscopy. Digital cholangioscopy is useful when the diagnosis of the biliary stricture using the conventional ERCP method is difficult.

New strategy for evaluating pancreatic tissue specimens from endoscopic ultrasound-guided fine needle aspiration and surgery.

BACKGROUND AND AIM: Preoperative histological evaluation of pancreatic neoplasms is important for guiding the resection strategy and preventing postoperative adverse events. However, conventional endoscopic methods have technical limitations that reduce the accuracy of the histopathological examination. Probe electrospray ionization mass spectrometry (PESI-MS) may be a useful technique for rapidly evaluating small specimens. METHODS: This single-center prospective study included patients with pancreatic neoplasms between October 2018 and December 2019. Pancreatic ductal adenocarcinoma (PDAC) specimens were obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and non-neoplastic tissue was obtained via surgery. Specimens were subjected to PESI-MS and the mass spectra were analyzed using partial least squares regression-discriminant analysis. RESULTS: The study included 40 patients with 20 nonneoplastic specimens and 19 PDAC specimens (1 case of neuroendocrine carcinoma was omitted). All nonneoplastic specimens were sufficient for PESI-MS analysis, although only 7 of 19 PDAC specimens were sufficient for PESI-MS analysis because of poor sample quality or insufficient quantity (<1 mg). Among the 27 analyzed cases, the mass spectra clearly differentiated between the PDAC and nonneoplastic specimens. CONCLUSIONS: This study revealed that PESI-MS could differentiate between PDAC and nonneoplastic specimens, even in cases where EUS-FNA produced very small specimens.

Efficacy and safety of immediate oral intake in patients with mild acute pancreatitis: A randomized controlled trial.

OBJECTIVES: Early enteral nutrition is recommended for patients with severe acute pancreatitis (AP); however, nutritional management strategies for patients with mild AP have not been established. The aim of this study was to evaluate the benefits and safety of immediate oral intake of low-fat solid food in patients with mild AP who were allowed to take opioid analgesics. METHODS: In this single-center randomized study, the immediate feeding (IMF) group was permitted immediate oral intake of low-fat (15 g/d) solid food. In the standard food (STF) group, patients received gradually increasing amounts of dietary fat. Twenty-six patients were randomized, with 13 allocated to each group. The primary outcome was the period between diagnosis and recovery from AP. The cost and rate of progression to severe disease were evaluated as secondary outcomes. RESULTS: The IMF group (mean recovery days: 2 ± 1) recovered significantly earlier (mean difference in recovery days: 6.3; 95% confidence interval [CI], 4.8-7.9; P < 0.001) than the STF group (mean recovery days: 8.3 ± 2.3), with a lower overall treatment cost (mean difference in costs: -$460; 95% CI, -$880 to -$40; P = 0.034). The IMF group showed a lower rate of progression to severe AP (IMF, 0%; STF, 15.3%; P = 0.48). CONCLUSION: The initial treatment strategy for mild AP should be altered from the gradual introduction of oral feeding upon the absence of pain to immediate oral nutrition with opioid analgesics, to improve treatment efficacy and reduce treatment cost.

A long (7 cm) prophylactic pancreatic stent decreases incidence of post-endoscopic papillectomy pancreatitis: a retrospective study.

Background and study aims Endoscopic papillectomy (EP) is a minimally invasive treatment for ampullary neoplasms and is recognized as an alternative treatment to surgical resection; however, there are few reports on a suitable pancreatic stent (PS) after EP for preventing pancreatitis. The aim of this study was to evaluate the efficacy of a long PS after EP. Patients and methods In this retrospective single-center study, 39 patients with pathologically proven ampullary neoplasms who underwent EP between March 2012 and August 2018 were enrolled. The study participants were divided into two subgroups according to the PS length: those with a PS shorter than 5 cm (short PS group, n = 17) and those with a PS of 7 cm (long PS group, n = 22). The incidence of adverse events and risk factors for pancreatitis were evaluated. Results The diameter of all PSs was 5 Fr. Post-EP pancreatitis occurred in nine patients (23.1 %), with two cases of severe pancreatitis (5.1 %). Pancreatitis occurred more frequently in the short PS group (7/17, 41.2 %) than in the long PS group (2/22, 9.1 %) ( P  = 0.026). There were no significant differences between the two groups in terms of other adverse events. Univariate and multivariate analyses showed that a long PS was the only factor associated with a decreased incidence of post-EP pancreatitis ( P  = 0.042; odds ratio, 0.16; 95 % confidence interval, 0.027-0.94). Conclusion A long (7 cm) PS significantly decreased incidence of pancreatitis after EP. Prospective randomized studies with a larger number of patients and wider range of PS lengths are required.

Novel mainstream capnometer system is safe and feasible even under CO2 insufflation during ERCP-related procedure: a pilot study.

BACKGROUND AND AIMS: There is a need to safely achieve conscious sedation during endoscopic retrograde cholangiopancreatography (ERCP). We evaluated the safety and feasibility of a mainstream capnometer system to monitor apnoea during ERCP under CO2 insufflation. METHODS: Non-intubated adult patients undergoing ERCP-related procedures with intravenous sedation were enrolled. End-tidal CO2 (EtCO2) was continuously monitored during the procedure under CO2 insufflation using a mainstream capnometer system, comprising a capnometer and a specially designed bite block for upper gastrointestinal endoscopy and ERCP. Oxygen saturation (SpO2) was also monitored continuously during the procedure. In this study, we evaluated the safety and feasibility of the capnometer system. RESULTS: Eleven patients were enrolled. Measurement of EtCO2 concentration was possible from the beginning to the end of the procedure in all 11 cases. There was no measurement failure, dislocation of the bite block, or adverse event related to the bite block. Apnoea linked to hypoxaemia occurred five times (mean duration, 174.4 s). CONCLUSION: This study confirmed that apnoea was detected earlier than when using a percutaneous oxygen monitor. Measurement of EtCO2 concentration using the newly developed mainstream capnometer system was feasible and safe even under CO2 insufflation.

Electric Endocut and Autocut Resection for Endoscopic Papillectomy: A Systematic Review.

Objective Risks of bleeding and pancreatitis after mucosal resection using the purecut/autocut and blendcut/endocut modes for endoscopic papillectomy have not been fully clarified. Thus, a systematic review on electrosurgical cutting modes for endoscopic papillectomy was conducted focusing on the types and incidence of adverse events. Methods We searched the PubMed and Cochrane library for cases of endoscopic papillectomy recorded as of April 2017. Studies reporting the methods of electrically excising a tumor in the duodenal papilla and the number of adverse events were extracted. Studies were collected and examined separately based on the electrosurgical cutting mode, and the incidence rate for each adverse event was summarized. Results A total of 159 relevant articles were found; among them, 20 studies were included and 139 excluded. Five studies analyzed endoscopic papillectomy with the purecut/autocut mode and 16 with the blendcut/endocut mode. Only one study investigated both modes (purecut and endocut). With the purecut/autocut mode, the incidence of bleeding was 2.8-50%, and that of pancreatitis was 0-50% (mean: 12.8%). With the blendcut/endocut mode, the incidence of bleeding was 0-42.3%, and that of pancreatitis was 0%-17.9% (mean: 9.5%). Conclusion Both methods had high adverse event rates for endoscopic papillectomy. Thus, a standard method of endoscopic papillectomy, including the electrosurgical cutting mode, needs to be established.

Successful EUS-guided antegrade stenting for malignant severe biliary obstruction combined with a newly developed plastic stent.

Background and study aims We report the effectiveness of a newly developed plastic stent for preventing bile leakage after endoscopic ultrasonography (EUS)-guided antegrade stenting. This treatment was performed on a 59-year-old woman with malignant obstructive jaundice caused by peritoneal metastasis. First, we attempted transpapillary drainage using short-type single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography, but we could not achieve it. We then attempted EUS-guided antegrade stenting through the intrahepatic bile duct from the esophagojejunal anastomosis. We successfully inserted uncovered metallic stents for common bile duct and a newly plastic stent for hepaticojejunostomy from the antegrade approach. There were no adverse events after the treatment.

Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.