Bi, Yan

Objectives Pancreatic acinar cell carcinoma (ACC) is a rare pancreatic cancer. The advancement of treatment is hampered because of the limited knowledge of its molecular mechanism. Methods Whole-exome sequencing was performed on DNA extracted from 11 pure ACC surgical samples. Potential germline variants were removed on the basis of polymorphic databases, alternative allele frequency, coverage depth, and Catalogue of Somatic Mutations in Cancer (COSMIC) annotations after variant calling procedure. Mutation profiles and signatures were assessed through the Mutational Patterns package. Results A median of 34 somatic mutations were detected (range, 19–60). Three novel recurrent small deletions were identified. Common pancreatic ductal adenocarcinoma mutations or neuroendocrine tumor mutants were not found. FAT atypical cadherin 4, mucin 5B, titin, and zinc finger homeobox 3 were consistently mutated across 4 independent ACC studies. A high contribution of COSMIC mutational signature 1 was seen in ACC, indicating deamination of 5-methylcytosine. The majority of the patients had COSMIC signatures 6, 15, or 20, relating to defective DNA mismatch repair. Six patients showed COSMIC mutational signature 10 because of the altered activity of DNA polymerase epsilon. Conclusions Distinct mutational signatures pathways were found in ACC and targeting them may improve clinical outcome.

Hyperstimulation of the cholecystokinin 1 receptor (CCK1R), a G protein–coupled receptor (GPCR), in pancreatic acinar cells is commonly used to induce pancreatitis in rodents. Human pancreatic acinar cells lack CCK1R but express cholinergic receptor muscarinic 3 (M3R), another GPCR. To test whether M3R activation is involved in pancreatitis, a mutant M3R was conditionally expressed in pancreatic acinar cells in mice. This mutant receptor loses responsiveness to its native ligand, acetylcholine, but can be activated by an inert small molecule, clozapine- N -oxide (CNO). Intracellular calcium and amylase were elicited by CNO in pancreatic acinar cells isolated from mutant M3R mice but not WT mice. Similarly, acute pancreatitis (AP) could be induced by a single injection of CNO in the transgenic mice but not WT mice. Compared with the cerulein-induced AP, CNO caused more widespread acinar cell death and inflammation. Furthermore, chronic pancreatitis developed at 4 weeks after 3 episodes of CNO-induced AP. In contrast, in mice with 3 recurrent episodes of cerulein-included AP, pancreas histology was restored in 4 weeks. Furthermore, the M3R antagonist ameliorated the severity of cerulein-induced AP in WT mice. We conclude that M3R activation can cause the pathogenesis of pancreatitis. This model may provide an alternative approach for pancreatitis research.

H. pylori is the most common infection in the world and is associated with gastrointestinal and extra-gastrointestinal manifestations, including peptic ulcer disease, gastrointestinal bleeding, and lymphoproliferative disorders. Despite being discovered less than half a century ago, antibiotic resistance, exacerbated by medication non-adherence and inefficacy of proton pump inhibitors, has grown substantially, explaining the rising incidence of refractory H. pylori infection. In this review, we discuss risk factors, treatment options, surveillance and follow-up, as well as emerging therapies for refractory H. pylori.

Abstract Clostridioides difficile infection (CDI) is an issue of great concern due to its rising incidence, recurrence, morbidity and impact on healthcare spending. Treatment guidelines have changed in the last few years, and new therapies are being considered. This is a practical review for the primary care practitioner of the latest guidelines for CDI diagnosis, treatment, and emerging therapies.

Abstract Helicobacter pylori is the most prevalent bacteria infecting humans resulting in a variety of gastrointestinal and extra gastrointestinal complications. Although most of the infected adults are asymptomatic, the prevalence varies in different parts of the world it is higher in Eastern and Southern Europe. Eradication of Helicobacter pylori is necessary to prevent precancerous conditions like gastric atrophy, gastric intestinal metaplasia and gastric dysplasia. This comprehensive review addresses briefly on: whom and how to test and treat including recommended first line therapies, salvage therapies, testing for eradication and strategy to be used in primary care clinics.

Objective Solid organ transplant (SOT) recipients have moderately increased risk of pancreatic adenocarcinoma (PAC). We evaluated the incidence and survival of PAC in 2 cohorts and aimed to identify potential risk factors. Methods This study performed a retrospective cohort analysis. Cohort A was extracted from the United Network of Organ Sharing data set and cohort B from SOT recipients evaluated at 3 Mayo Clinic transplant centers. The primary outcome was age-adjusted annual incidence of PAC. Descriptive statistics, hazard ratios, and survival rates were compared. Results Cohort A and cohort B included 617,042 and 29,472 SOT recipients, respectively. In cohort A, the annual incidence rate was 12.78 per 100,000 in kidney-pancreas, 13.34 in liver, and 21.87 in heart-lung transplant recipients. Receiving heart-lung transplant, 50 years or older, and history of cancer (in either recipient or donor) were independent factors associated with PAC. Fifty-two patients developed PAC in cohort B. Despite earlier diagnosis (21.15% with stage I–II), survival rates were similar to those reported for sporadic (non-SOT) patients. Conclusions We report demographic and clinical risk factors for PAC after SOT, many of which were present before transplant and are common to sporadic pancreatic cancer. Despite the diagnosis at earlier stages, PAC in SOT portends a very poor survival.

Objective The aim of the study was to compare incidence and outcomes of acute pancreatitis among advanced heart failure therapies. Methods Two retrospective cohorts are as follows: A, patients with heart failure presenting to our hospitals and B, the US National Inpatient Sample. Three groups were compared: left ventricular assist device (LVAD) recipients, transplant recipients, and controls who did not qualify for advanced therapies. Primary outcomes were pancreatitis incidence and mortality. Secondary outcomes included kidney failure, multiorgan failure, shock, and health care utilization. Results Cohort A included 1344 heart failure patients, and cohort B included 677,905 patients with acute pancreatitis. In cohort A, annual pancreatitis incidence was 6.7 cases per 1000 LVAD recipients, 4.1 per 1000 LVAD bridge-to-transplant, 2.3 per 1000 transplant recipients, and 3.2 per 1000 heart failure controls ( P = 0.03). Combined, the incidence was 5.6 per 1000 LVAD users and 2.7 in 1000 non-LVAD users (relative risk, 2.1; P = 0.009). In cohort B, increased mortality was seen in LVAD users, but not in transplant recipients. Left ventricular assist device patients had higher odds of kidney failure, multiorgan failure, shock, and intensive care. Conclusions Patients with LVAD have double risk of pancreatitis, worse clinical outcomes, and increased healthcare utilization. Studies elucidating the mechanisms behind pancreatic injury in advanced heart failure are suggested.