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Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF–conditioned medium and RNA sequencing data of acinar cells post–conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs). A close association of acino–ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment–induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation. Results collectively suggest the first evidence for CAF-influenced acino–ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception. [Display omitted] Pancreatic cancer inception and early detection remain elusive. Complex cellular crosstalk transforming normal cells toward tumor development by means of novel cell signaling mechanism has been identified as the potential culprit. [ABSTRACT FROM AUTHOR]

A histologic diagnosis of GI subepithelial tumors (SETs) is important because of the malignant potential of these lesions. The current modalities of choice, including EUS-guided FNA and biopsy (EUS-FNA/FNB) have demonstrated suboptimal diagnostic success. Single-incision with needle-knife (SINK) biopsy has emerged as an alternative diagnostic approach to increase tissue acquisition and diagnostic success. The aim of this study was to perform a systematic review and meta-analysis to evaluate the technical success, diagnostic success, and adverse events of SINK biopsy. We searched multiple databases including PubMed, EMBASE, CINAHL, Cochrane, Web of Science, and Google Scholar from inception to July 2022. The primary outcomes assessed were the technical success and diagnostic success of SINK in GI SETs. The secondary outcomes assessed were adverse events and whether immunohistochemical analysis could be successfully performed on tissue samples obtained via SINK. Seven studies with a total of 219 SINK biopsy procedures were included in this meta-analysis. The technical success rate was 98.1% (95% CI, 94.9%-99.3%; P =.000; I 2 =.0%), and the diagnostic success rate was 87.9% (95% CI, 82.6%-91.7%; P =.000; I 2 =.0%). The immunohistochemical success rate was 88.3% (95% CI, 78.7%-93.9%; P =.000; I 2 = 3.5%). The rate of adverse events was 7.5% (95% CI, 4.3%-12.7%; P =.00; I 2 = 7.2%), and bleeding was the most common adverse event. SINK biopsy is a safe diagnostic procedure with a high technical and diagnostic success in patients with GI SET. Further randomized controlled trials and direct comparison studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized. Tandem mass tag–based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 μg/mL) for the mechanistic studies. A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P <.001) and attenuated unfolded protein response (P <.04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers. The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis. Alcohol and smoking combined generate the stable aldehyde adducts on extracellular matrix proteins leading to impaired unfolded protein response resulting in loss of pancreatic parenchyma and poor regeneration after pancreatic insult. [ABSTRACT FROM AUTHOR]

Background: Vascular invasion (VI) in a patient with pancreatic or periampullary cancers precludes surgery and indicates a poor prognosis. Published data on the accuracy of EUS in diagnosing VI is varied. Objective: The aim of this meta-analysis was to evaluate the accuracy of EUS in diagnosing VI in patients with pancreatic and periampullary cancers. Design: Data from EUS studies were pooled according to the Mantel-Haenszel and DerSimonian Laird methods. Patients: EUS studies in which VI was confirmed by surgery or angiography were selected. Interventions: EUS. Main Outcome Measures: Pooled estimates of sensitivity, specificity, likelihood ratios, and diagnostic odds ratio of EUS. Results: Data were extracted from 29 studies (N = 1308) that met the inclusion criteria. The pooled sensitivity of EUS in diagnosing VI was 73% (95% CI, 68.8-76.9) and the pooled specificity was 90.2% (95% CI, 87.9-92.2). The positive likelihood ratio for diagnosing VI by EUS was 9.1 (95% CI, 4.6-17.9) and the negative likelihood ratio was 0.3 (95% CI, 0.2-0.5). Diagnostic odds ratio, the odds of having VI in positive as compared with negative EUS studies, was 40.1 (95% CI, 16.1-99.9). The P value for χ2 heterogeneity for all the pooled estimates was >.05. Conclusions: Although EUS is the best noninvasive test to diagnose VI in pancreatic and periampullary cancers, this meta-analysis showed that the specificity (90%) is high but the sensitivity (73%) is not as high as suggested. Further refinements in EUS technologies and interpretation may improve the sensitivity for detecting VI. [Copyright &y& Elsevier]

Colonoscopy is the preferred modality for colorectal cancer screening because it has both diagnostic and therapeutic capabilities. Current consensus states that colonoscopy should be performed with initial rapid passage of the instrument to the cecum, followed by thorough evaluation for and removal of all polyps during a deliberate slow withdrawal. Reports have suggested that polyps that are seen but not removed during insertion are sometimes quite difficult to find during withdrawal. We performed a comprehensive literature search of several major databases (from inception to March 2020) to identify randomized controlled trials comparing inspection and polypectomy during the insertion phase as opposed to the traditional practice of inspection and polypectomy performed entirely during the withdrawal phase. We examined differences in terms of adenoma detection rate (ADR), polyps detected per patient (PDPP), cecal intubation time (CIT), withdrawal time, and total procedure time. Seven randomized controlled trials, including 3834 patients, were included in our final analysis. The insertion/withdrawal cohort had 1951 patients and the withdrawal-only cohort 1883 patients. Pooled odds of adenoma detection in the insertion/withdrawal cohort was.99 (P =.8). ADR was 47.2% in the insertion/withdrawal cohort and 48.6% in the withdrawal-only cohort. Although total procedure and withdrawal times were shorter in the insertion/withdrawal cohort, PDPP in both cohorts were not statistically significant (1.4 vs 1.5, P =.7). Additional inspection and polypectomy during the insertion and withdrawal phases of colonoscopy offer no additional benefit in terms of ADR or PDPP. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: There has been compelling evidence for the role of oxidative stress in the pathogenesis of cardiovascular complications in type 2 diabetes mellitus (T2DM). We analyzed the association of C242T and Val762Ala polymorphisms of NADPH oxidase p22phox and poly (ADP-ribose) polymerase-1 (PARP-1) genes respectively with coronary artery disease (CAD) and its severity, myocardial infarction (MI) and cardiovascular risk factors in T2DM patients. Materials and methods: We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with and 89 without MI and 121 T2DM individuals with no evidence of CAD for the two gene polymorphisms. Results: The 242T and 762Ala alleles were significantly more frequent in T2DM subjects without CAD than those with CAD, thereby associating them with a significant protective effect against development of CAD [p=0.002 (C242T); 0.02 (Val762Ala)]. The association was further characterized by a relatively lower frequency of 242T and 762Ala alleles in T2DM patients with multi (MVD)/triple vessel disease respectively [p=0.003 (C242T); 0.02 (Val762Ala)]. Conversely, the genotype and allele frequencies of these polymorphisms were not significantly different in T2DM+CAD patients with or without MI. Stratification of risk by putative risk factors for CAD revealed a significant interaction with these polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of C242T and Val762Ala polymorphisms and other putative risk factors with CAD/MVD in T2DM individuals. Conclusions: Our observations indicate a significant relationship between p22phox C242T and PARP-1 Val762Ala polymorphisms, CAD and its severity, but not with occurrence of MI in T2DM individuals with significant coronary stenoses. [Copyright &y& Elsevier]