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.

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.

Background and aim: This prospective randomized study was designed to assess the efficacy of 10-day and 14-day rifabutinbased triple therapy as a third-or fourth-line rescue therapy. Methods: Patients who failed first-and second-line eradication therapy were enrolled. H. pylori was isolated from gastric biopsy specimens and the rpoB mutation status, a factor of resistance to rifamycins, and minimum inhibitory concentrations (MICs) of rifabutin and amoxicillin were determined. Enrolled patients were randomly assigned to receive 10-day or 14-day eradication therapy with esomeprazole (20 mg, 4 times a day (q.i.d.)), amoxicillin (500 mg, q.i.d.), and rifabutin (300 mg, once a day (q.d.s.)). Poor compliance was defined as intake of <80% of study drugs. Successful H. pylori eradication was confirmed using a [13C] urea breath test or a stool antigen test, 12 weeks after the end of therapy. Results: Twelve patients were assigned to the 10-day group, and 17, to the 14-day group. Intention-to-treat and per-protocol analyses of eradication rates were 83.3% and 81.8% for the 10-day group and 94.1% and 91.7% for the 14-day group, respectively. All patients with rpoB mutation-positive strains (n ¼ 3) showed successful eradication, irrespective of the regimen received. Therapy was stopped due to adverse events in 8.3% and 29.3% of patients in the 10-day and 14-day groups, respectively. Conclusion: Both the 10-day and 14-day therapies were effective as rescue regimens. In particular, the 14-day therapy resulted in successful eradication in over 90% of patients, but the 10-day treatment may be enough to obtain a successful eradication rate, considering the tolerability of therapy.

There is no significant difference in the eradication rates between EAS and EMS, regardless of the gyrA mutation status of the H. pylori strains. GyrA mutation status was an important factor in predicting successful eradication with sitafloxacin-containing rescue therapies.

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Pancreatic fat content measured by computed tomography was significantly associated with IPMN. These results suggest that IPMN may develop secondary to pancreatic steatosis that could be an overlapping risk factor for PDAC and IPMN.

ObjectiveEndoscopic 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.MethodsThis 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.ResultsSixty 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).ConclusionsThe 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 numberThe Japanese UMIN Clinical Trials Registry (UMIN‐CTR: 000021382).

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.