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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, with adenosquamous carcinoma of the pancreas (ASCP), a rare variant, representing 1-10% of cases. Standard chemotherapy trials for pancreatic cancer exclude ASCP, leaving its optimal treatment uncertain. This report describes a 68-year-old male with metastatic ASCP and a KRAS G12C mutation, progressing through multiple lines of systemic therapy, including targeted inhibition of KRAS G12C. Notably, the patient exhibited a robust response to single-agent immune checkpoint inhibition (ICI) with pembrolizumab, despite intact mismatch repair proteins. The limited success of traditional therapies in pancreatic cancer, coupled with the rarity of ASCP, presents a challenge in establishing effective treatment strategies. While KRAS G12C inhibitors demonstrated modest benefits, this case highlights the remarkable response to ICI in a patient with squamous histology. The distinct tumor microenvironment of ASCP, characterized by squamous differentiation, may contribute to this exceptional response. This underscores the need for further research and clinical trials focused on ICI in ASCP, with an ongoing multi-center phase 2 trial investigating outcomes in this specific subset.

Adequate sampling is essential to an accurate pathologic evaluation of pancreatectomy specimens resected for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT). However, limited data are available for the association between the sampling and survival in these patients. We examined the association of the entire submission of the tumor (ESOT) and the entire submission of the pancreas (ESOP) with disease-free survival (DFS) and overall survival (OS), as well as their correlations with clinicopathologic features, for 627 patients with PDAC who received NAT and pancreaticoduodenectomy. We demonstrated that both ESOT and ESOP were associated with lower ypT, less frequent perineural invasion, and better tumor response (p < 0.05). ESOP was also associated with a smaller tumor size (p < 0.001), more lymph nodes (p < 0.001), a lower ypN stage (p < 0.001), better differentiation (p = 0.02), and less frequent lymphovascular invasion (p = 0.009). However, since ESOP and ESOT were primarily conducted for cases with no grossly identifiable tumor or minimal residual carcinoma in initial sections, potential bias cannot be excluded. Both ESOT and ESOP were associated with less frequent recurrence/metastasis and better DFS and OS (p < 0.05) in the overall study population. ESOP was associated with better DFS and better OS in patients with ypT0/ypT1 or ypN0 tumors and better OS in patients with complete or near-complete response (p < 0.05). ESOT was associated with better OS in patients with ypT0/ypT1 or ypN0 tumors (p < 0.05). Both ESOT and ESOP were independent prognostic factors for OS according to multivariate survival analyses. Therefore, accurate pathologic evaluation using ESOP and ESOT is associated with the prognosis in PDAC patients with complete or near-complete pathologic response and ypT0/ypT1 tumor after NAT.

Purpose of reviewThe burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a causal factor for PDAC and examined clinical manifestations of PDAC-associated acute pancreatitis.Recent findingsRecent findings detail the timing of acute pancreatitis before and after PDAC occurrence, further solidifying the evidence for PDAC-associated acute pancreatitis and for acute pancreatitis as a causal risk factor for PDAC. The risk of PDAC remains elevated above the general population in patients with distant history of acute pancreatitis. PDAC risk also increases with recurrent acute pancreatitis episodes, independent of smoking and alcohol. Mechanisms linking acute pancreatitis to PDAC include inflammation and neutrophil infiltration, which can be attenuated by suppressing inflammation and/or epigenetic modulation, thus slowing the progression of acinar-to-ductal metaplasia. Clinical presentation and management of acute pancreatitis in the context of PDAC are discussed, including challenges acute pancreatitis poses in the diagnosis and treatment of PDAC, and novel interventions for PDAC-associated acute pancreatitis.SummaryPDAC risk may be reduced with improved acute pancreatitis prevention and treatment, such as antiinflammatories or epigenetic modulators. Increased acute pancreatitis and PDAC burden warrant more research on better diagnosis and management of PDAC-associated acute pancreatitis.

BACKGROUND: Multiagent neoadjuvant chemotherapy (NAT) has been linked with improved survival for locally advanced (LA) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). However, the existence of disparities in its utilization remains to be elucidated. METHODS: All adults with PDAC were tabulated from the 2011-2017 Nationwide Cancer Database. Tumor vascular involvement was determined using the clinical T stage and CS_EXTENSION variables. The significance of temporal trends was calculated using Cuzicks non-parametric test. A Cox proportional hazard model was used to assess the impact of NAT utilization on hazard of two-year mortality. A logistic regression model was developed to determine factors associated with receipt of NAT. RESULTS: Of 3811 patients meeting inclusion criteria, 50.8 % received NAT. NAT utilization significantly increased over the study period, from 31.7 % in 2011 to 81.1 % in 2017 (p

OBJECTIVE: The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression. DESIGN: We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype. RESULTS: In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahigh tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment. CONCLUSIONS: Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of all pancreatic cancer cases. Five-year survival rates have remained below 12% since the 1970s, in part due to the difficulty in detection prior to metastasis (migration and invasion into neighboring organs and glands). Mechanical memory is a concept that has emerged over the past decade that may provide a path toward understanding how invading PDAC cells "remember" the mechanical properties of their diseased ("stiff", elastic modulus, E ≈ 10 kPa) microenvironment even while invading a healthy ("soft", E ≈ 1 kPa) microenvironment. Here, we investigated the role of mechanical priming by culturing a dilute suspension of PDAC (FG) cells within a 3D, rheologically tunable microgel platform from hydrogels with tunable mechanical properties. We conducted a suite of acute (short-term) priming studies where we cultured PDAC cells in either a soft (E ≈ 1 kPa) or stiff (E ≈ 10 kPa) environment for 6 h, then removed and placed them into a new soft or stiff 3D environment for another 18 h. Following these steps, we conducted RNA-seq analyses to quantify gene expression. Initial priming in the 3D culture showed persistent gene expression for the duration of the study, regardless of the subsequent environments (stiff or soft). Stiff 3D culture was associated with the downregulation of tumor suppressors (LATS1, BCAR3, CDKN2C), as well as the upregulation of cancer-associated genes (RAC3). Immunofluorescence staining (BCAR3, RAC3) further supported the persistence of this cellular response, with BCAR3 upregulated in soft culture and RAC3 upregulated in stiff-primed culture. Stiff-primed genes were stratified against patient data found in The Cancer Genome Atlas (TCGA). Upregulated genes in stiff-primed 3D culture were associated with decreased survival in patient data, suggesting a link between patient survival and mechanical priming.

In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole-genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions, and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 foregut endoderm transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each genes role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this review underscores the prognostic significance of specific mutations, such as loss of TP53, and explores some potential targeted therapies tailored to these molecular signatures. The findings highlight the importance of genomic analyses for risk assessment, early detection and the design of personalized treatment approaches in pancreatic cancer. Overall, this review provides a comprehensive analysis of the molecular intricacies of pancreatic tumors, paving the way for more effective and tailored therapeutic interventions.

ObjectivesNo study has explored whether availability of endoscopic retrograde cholangiopancreatography (ERCP) is adequate and equitable across US children's hospitals. We hypothesized that ERCP availability and utilization differs by geography and patient factors.MethodsHealthcare encounter data from 2009 to 2019 on children with pancreatic and biliary diseases from the Pediatric Health Information System were analyzed. ERCP availability was defined as treatment at a hospital that performed pediatric ERCP during the year of service.ResultsFrom 2009 to 2019, 37,946 children (88,420 encounters) had a potential pancreatic or biliary indication for ERCP; 7066 ERCPs were performed. The commonest pancreatic diagnoses leading to ERCP were chronic (47.2%) and acute pancreatitis (43.2%); biliary diagnoses were calculus (68.3%) and obstruction (14.8%). No ERCP was available for 25.0% of pancreatic encounters and 8.1% of biliary encounters. In multivariable analysis, children with public insurance, rural residence, or of Black race were less likely to have pancreatic ERCP availability; those with rural residence or Asian race were less likely to have biliary ERCP availability. Black children or those with public insurance were less likely to undergo pancreatic ERCP where available. Among encounters for calculus or obstruction, those of Black race or admitted to hospitals in the West were less likely to undergo ERCP when available.ConclusionsOne-in-four children with pancreatic disorders and one-in-12 with biliary disorders may have limited access to ERCP. We identified racial and geographic disparities in availability and utilization of ERCP. Further studies are needed to understand these differences to ensure equitable care.

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy's utility in monitoring patients with PDAC with surgically resectable disease.

Bacterial flagella and type IV pili (TFP) are surface appendages that enable motility and mechanosensing through distinct mechanisms. These structures were previously thought to have no components in common. Here, we report that TFP and some flagella share proteins PilO, PilN, and PilM, which we identified as part of the Helicobacter pylori flagellar motor. H. pylori mutants lacking PilO or PilN migrated better than wild type in semisolid agar because they continued swimming rather than aggregated into microcolonies, mimicking the TFP-regulated surface response. Like their TFP homologs, flagellar PilO/PilN heterodimers formed a peripheral cage that encircled the flagellar motor. These results indicate that PilO and PilN act similarly in flagella and TFP by differentially regulating motility and microcolony formation when bacteria encounter surfaces.

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance is a promising precision medicine approach, and its potential to inform clinical decisions is now being tested in several large multiinstitutional clinical trials. PDOs are cultivated in the extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the effect of different sources of BMEs on organoid drug response is unknown. Here, we tested the effect of BME source on proliferation, drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel compared with Cultrex and UltiMatrix. However, we observed no substantial effect on drug response when organoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their classical or basal-like designation. Overall, we found that the BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves or drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.

As the Editor-in-Chief of World Journal of Gastroenterology, every week prior to a new issues online publication, I perform a careful review of all encompassed articles, including the title, clinical and/or research importance, originality, novelty, and ratings by the peer reviewers. Based on this review, I select the papers of choice and suggest pertinent changes (e.g., in the title) to the Company Editors responsible for publication. This process, while time-consuming, is very important for assuring the quality of publications and highlighting important articles that Readers may revisit.

Phosphoinositide-3-kinase γ (PI3Kγ) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3Kγ inhibition, synergizes with α-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3Kγ inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFNγ secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3Kγ showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3Kγ-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3Kγ inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3Kγ in B cell-dependent immunity, suggesting that PI3Kγ depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.

BackgroundPancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC).MethodsWe conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses.ResultsA total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P

Endoscopic ultrasonography (EUS) is pivotal for diagnosing and sampling pancreatic tumor tissues. This study aimed to assess how the histological type and size of tumors influence the adequacy of macroscopic tissue cores acquired using EUS-guided fine needle biopsy (FNB). We conducted a retrospective study involving 180 patients with pathologically confirmed pancreatic malignancies at our hospital, a medical center, between July 2020 and June 2023. Personal and clinical data, EUS findings, and pathological results were extracted from the patient records. The macroscopic tissue core acquisition rate was 86.1%. Patients with tumors larger than 3 cm had a higher sufficiency rate (93.3%) compared to those with tumors 3 cm or smaller (78.9%, p = 0.005). It was more difficult to obtain sufficient tissue cores from neuroendocrine tumors than from adenocarcinomas (67.7% vs. 89.9%, p = 0.001). Interestingly, obtaining a sufficient tissue core only affected the diagnostic rate of adenocarcinoma (93.3% vs. 60%, p < 0.001) but did not significantly influence the diagnostic rate of neuroendocrine tumors. This study highlights that small tumors (< 3 cm) and neuroendocrine tumors pose a challenge in obtaining sufficient tissue cores. However, obtaining sufficient tissue cores significantly influences the pathological diagnosis of FNB in adenocarcinoma but not in neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

Background/Objectives: Autoimmune pancreatitis (AIP) is a diagnosis-challenging disease that often mimics pancreatic malignancy. Pancreatic resection is considered to be a curative treatment for pancreatic ductal adenocarcinoma (PDAC). This meta-analysis aims to study the incidence of AIP in patients who have undergone pancreatic resection for clinical manifestation of cancer. Methods: A comprehensive search was conducted in three databases, PubMed, Embase and the Cochrane Library, using the terms 'autoimmune pancreatitis' and 'pancreatic resection' and supplemented by manual checks of reference lists in all retrieved articles. Results: Ten articles were included in the final analysis. 8917 pancreatic resections were performed because of a clinical suspicion of pancreatic cancer. AIP accounted for 140 cases (1.6%). Type 1 AIP comprised the majority of cases, representing 94% (132 cases), while type 2 AIP made up the remaining 6% (eight cases) after further classification. AIP accounted for almost 26% of all cases of benign diseases involving unnecessary surgery and was overrepresented in males in 70% of cases compared to 30% in females. The mean age for AIP patients was 59 years. Serum CA 19 − 9 levels were elevated in 23 out of 47 (49%) AIP patients, where higher levels were detected more frequently in patients with type 1 AIP (51%, 22 out of 43) than in those with type 2 AIP (25%, 1 out of 4). The sensitivity of IgG4 levels in type 1 AIP was low (43%, 21/49 patients). Conclusion: Even with modern diagnostic methods, distinguishing between AIP and PDAC can still be challenging, thus potentially resulting in unnecessary surgical procedures in some cases. Serum CA 19 − 9 levels are not useful in distinguishing between AIP and PDAC. Work must thus be done to improve diagnostic methods and avoid unnecessary complicated surgery. [ABSTRACT FROM AUTHOR]

Background and aim: Pancreatic cancer is lethal and prevalent among other cancer types. The recurrence of this tumor is high, especially in patients who did not receive adjuvant therapies. Early prediction of PC recurrence has a significant role in enhancing patients' prognosis and survival. So far, machine learning techniques have given us insight into favorable performance efficiency in various medical domains. So, this study aims to establish a prediction model based on machine learning to achieve better prediction on this topic. Materials and methods: In this retrospective research, we used data from 585 PC patient cases from January 2019 to November 2023 from three clinical centers in Tehran City. Ten chosen ensemble and non-ensemble algorithms were used to establish prediction models on this topic. Results: Random forest and support vector machine with an AU-ROC of approximately 0.9 obtained more performance efficiency regarding PC recurrence. Lymph node metastasis, tumor size, tumor grade, radiotherapy, and chemotherapy were the best factors influencing PC recurrence. Conclusion: Random forest and support vector machine algorithms demonstrated high-performance ability and clinical usability to improve doctors' decisions in achieving different therapeutic and diagnostic measures. [ABSTRACT FROM AUTHOR]

Pancreatic cancer exhibits a high degree of malignancy with a poor prognosis, lacking effective prognostic targets. Utilizing histopathological methodologies, this study endeavors to predict the expression of pathological features in pancreatic ductal adenocarcinoma (PAAD) and investigate their underlying molecular mechanisms. Pathological images, transcriptomic, and clinical data from TCGA-PAAD were collected for survival analysis. Image segmentation using unsupervised machine learning was employed to extract features, perform clustering, and establish models. The prognostic value of pathological features and associated clinical risk factors were evaluated; the correlation between pathological features and molecular mechanisms, gene mutations, and immune infiltration was analyzed. By clustering 45 effective pathological features, we divided PAAD patients into two groups: cluster 1 and cluster 2. Significant associations with poor prognosis were found for cluster 2 in both the training group (n = 113) and validation group (n = 75) (p = 0.006), with pathological stages II-IV identified as potential synergistic risk factors (HR = 2.421, 95% CI = 1.263–4.639, p = 0.008). Subsequently, through multi-omics correlation analysis, we further revealed a close association between cluster 2 and the oxidative phosphorylation mechanism. Within the cluster 2 group, 28 oxidative phosphorylation genes exhibited reduced expression, CDKN2A gene mutations were upregulated, and there was significant downregulation of Tregs infiltration and related immune gene expression. The pathomic model constructed using machine learning serves as a valuable prognostic target for PAAD. The histopathological features cluster 2 are closely associated with the downregulation of oxidative phosphorylation levels and Tregs immune infiltration. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non‐metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment‐naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)‐treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry. Differentially abundant metabolites (DAMs) in TN versus NAT groups were identified and their correlation with various clinical parameters was assessed. Metabolomics profiling identified 40 tissue and five serum DAMs in TN versus NAT PDAC. In general, DAMs associated with amino acid and nucleotide metabolism were lower in NAT compared to TN. Four DAMs—3‐hydroxybutyric acid (BHB), 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF), glycochenodeoxycholate and citrulline—were common to both tissue and serum and showed a similar pattern of differential abundance in both groups. A strong positive correlation was observed between serum carbohydrate 19‐9 antigen (CA 19‐9) and tissue carnitines (C12, C18, C18:2) and N8‐acetylspermidine. The reduction in CA 19‐9 following NAT correlated negatively with serum deoxycholate levels, and the latter correlated positively with survival. This study revealed neoadjuvant‐chemotherapy‐induced changes in metabolic pathways in PDAC, mainly amino acid and nucleotide metabolism, and these correlated with reduced CA 19‐9 following neoadjuvant FOLFIRINOX treatment. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion The shared risk profiles for cancer and heart disease suggest many individuals with cancer may have an implantable cardioverter defibrillator (ICD). ICDs can have dramatic cancer end‐of‐life care implications including painful and distressing shocks. ICD prevalence and association with aggressive end‐of‐life care among individuals with breast, colorectal, and pancreatic cancer was evaluated using the Surveillance, Epidemiology, and End Results‐Medicare dataset.A total of 37,306 Medicare beneficiaries aged ≥66 years with stage 3 or 4 cancer who died between 2005 and 2016 were identified. ICD prevalence, ICD‐related care utilization that might present opportunities to discuss end‐of‐life implications and association with aggressive end‐of‐life care (>1 emergency department visit, intensive care unit admission, >1 hospitalization, terminal hospitalization, chemotherapy, and invasive or life‐extending procedures) in the last month of life was assessed using multivariable logistic regression.Among cancer decedents, 6% had an ICD. More individuals with an ICD (31%) died in the hospital than individuals without an ICD (25%; p < .001). Half (46%) of individuals with an ICD had device programming or interrogation visits that could be an opportunity for device discussion. In adjusted models, ICD presence was associated with higher odds of every indicator of aggressive end‐of‐life care other than chemotherapy.Many older cancer decedents in the United States had an ICD, and those with ICDs received more aggressive care at the end of life. Results suggest there are opportunities to discuss ICD and goals of care, raise awareness and encourage shared decision‐making for this population to ensure goal‐concordant care, and improve end‐of‐life care quality. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)‐targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2‐positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR‐T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer‐related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2‐targeted CAR‐T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs. Experimental Approach: In this study, we generated 10 FAP/CLDN 18.2 dual‐targeted CAR‐T cells and evaluated their anti‐tumour ability in vitro and in vivo. Key Results: Compared with conventional CAR‐T cells, some dual‐targeted CAR‐T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual‐targeted CAR‐T cells with better anti‐tumour effect could suppress the recruitment of myeloid‐derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual‐targeted CAR‐T cells reduced the exhaustion of T cells in transforming TGF‐β dependent manner. Conclusion and Implications: The dual‐targeted CAR‐T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual‐targeted FAP/CLDN 18.2 CAR‐T cells therapy in PDAC. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Endoscopic ultrasound (EUS) is the most sensitive method for evaluation of pancreatic lesions but is limited by significant operator dependency. Artificial intelligence (AI), in the form of computer‐aided detection (CADe) systems, has shown potential in increasing accuracy and bridging operator dependency in several endoscopic domains. However, the complexity of integrating AI into EUS is far more challenging. This aims to develop and test the basis for a CADe system for real‐time detection and segmentation of all pancreatic lesions.In this single‐center study EUS studies of pancreatic findings were included. Lesions were outlined by two expert (>5 years performing EUS) endoscopists, and the two leading types of models were benchmarked. The models' performance was evaluated through per‐pixel intersection over union (IoU).A total of 1497 EUS images from 165 patients were evaluated. The dataset included malignancies, neuroendocrine tumors, benign cysts, chronic and acute pancreatitis, normal fatty pancreas, and benign lesions. The best model demonstrated detection and segmentation on the test set with a mean IoU of 0.73, achieving a PPV, NPV, total accuracy, and ROC of 0.82, 0.96, 0.95, and 0.95, respectively. The algorithm is adaptable for real‐time processing.We developed and tested deep learning models for real‐time detection and segmentation of pancreatic lesions during EUS with promising results. This constitutes the basis for a CADe system for EUS, which could be valuable in future detection and evaluation of pancreatic lesions. Further studies for validation and generalization are underway. [ABSTRACT FROM AUTHOR]

This study aims to analyze the differential expression of METTL14 in pancreatic cancer (PC) tissues and adjacent normal tissues, and its correlation with clinical outcomes. According to the inclusion and exclusion criteria, a total of 80 patients diagnosed in our hospital from January 2021 to January 2023 were chosen as research subjects. RTQ-PCR has detected the mRNA level expression of METTL14 in cancer and para-cancerous tissues. Immunohistochemistry was used to detect the protein expression of METTL14 in cancer and para-cancerous tissues. To compare the relationship between METTL14 expression and clinicopathological parameters in different PC patients. Kaplan–Meier survival analysis of the relationship between METTL14 expression in PC tissues and patient survival prognosis. The Multifactor COX model evaluates factors affecting the prognosis of PC. The expression level of METTL14 mRNA in PC tissues was 5.51 ± 0.35 (kDa), and the positive rate of METTL14 protein expression in PC tissues of all patients was 73.75 (59/80). Tumor location (P = 0.012), tumor differentiation degree (P = 0.028), tumor AJCC stage (P = 0.000), and lymph node metastasis (P = 0.000) were significantly related to the positive rate of METTL14 protein expression in PC tissue. Follow-up results showed that among 80 patients, 63 died. The three-year survival rate of the METTL14 positive group was 13.56% (8/59), and the three-year survival rate of the negative group was 42.86% (9/21). The difference in the three-year survival rate between METTL14 positive and negative expression groups was statistically significant (P = 0.031). Multivariate COX regression analysis results showed that METTL14 was positive (OR 2.797, 95% CI 1.233–5.877), tumor AJCC stage II–III (OR 1.628, 95% CI 1.435–3.859) and lymph node metastasis (OR 1.733, 95% CI 1.122–2.372) were substantive risk factors for poor prognosis in patients with PC. METTL14 expression increases in PC tissue, which is related to tumor AJCC stage, tumor differentiation, and lymph node metastasis, and can be evaluated in the survival prognosis of patients with PC. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients. [ABSTRACT FROM AUTHOR]

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Background: Postoperative shivering is mainly associated with low body temperature. However, postoperative shivering can develop even at normal or high core temperatures. This study aimed to investigate the factors associated with postoperative shivering in patients with maintained core temperature after surgery. Methods: This retrospective study involved 537 patients who had undergone radical surgery for pancreatic cancer under general anesthesia from January 2013 to December 2023. The final analysis included 441 patients whose core temperatures after surgery were ≥ 36.5℃. Logistic regression analysis was performed to estimate the odds ratio (OR) of the incidence of postoperative shivering. Results: Postoperative shivering occurred in 119 patients. After multivariable-adjusted logistic regression, postoperative shivering was significantly associated with patient age (per 1 year increase; OR = 0.98; 95% confidence interval [CI]: 0.96–0.996; p = 0.02), operation time (per 30 min increase; OR = 1.10; 95% CI: 1.01–1.19; p = 0.03), postoperative core temperature (restricted cubic spline, p = 0.001), postoperative peripheral temperature (restricted cubic spline, p = 0.001), effect site fentanyl concentration at extubation (OR = 0.66; 95% CI: 0.24–0.99; p = 0.049), and acetaminophen use (OR = 0.32; 95% CI: 0.18–0.58; p < 0.001). Conclusions: Low peripheral temperature was a risk factor for the occurrence of shivering, even if the core temperature was maintained postoperatively. Peripheral temperature monitoring could be utilized to prevent postoperative shivering. In addition, fentanyl and acetaminophen reduced the occurrence of shivering in patients with maintained core temperature after surgery. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains one of the most lethal malignancies, with conventional treatment options providing limited efficacy. Recent advancements in immunotherapy have offered new hope, yet the unique tumor microenvironment (TME) of pancreatic cancer poses significant challenges to its successful application. This review explores the transformative impact of single-cell technology on the understanding and treatment of pancreatic cancer. By enabling high-resolution analysis of cellular heterogeneity within the TME, single-cell approaches have elucidated the complex interplay between various immune and tumor cell populations. These insights have led to the identification of predictive biomarkers and the development of innovative, personalized immunotherapeutic strategies. The review discusses the role of single-cell technology in dissecting the intricate immune landscape of pancreatic cancer, highlighting the discovery of T cell exhaustion profiles and macrophage polarization states that influence treatment response. Moreover, it outlines the potential of single-cell data in guiding the selection of immunotherapy drugs and optimizing treatment plans. The review also addresses the challenges and prospects of translating these single-cell-based innovations into clinical practice, emphasizing the need for interdisciplinary research and the integration of artificial intelligence to overcome current limitations. Ultimately, the review underscores the promise of single-cell technology in driving therapeutic strategy innovation and improving patient outcomes in the battle against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is one of the deadliest malignant tumors worldwide, known as the 'king of cancers due to its insidious onset, high malignancy, and high mortality rate. PC is highly malignant and progresses rapidly, but its onset is insidious with atypical early symptoms, making it difficult to detect early lesions through conventional imaging studies. It is usually only discovered when symptoms like jaundice, abdominal and back pain occur. Surgical resection is currently the only curative option for PC. However, due to the difficulty in early diagnosis, the majority of patients are already in the middle to late stages at the time of diagnosis, missing the opportunity for surgery. Studies have confirmed that the progression of pancreatic cancer is relatively slow, with the initial tumor cells requiring at least 15 years to gain metastatic ability. Therefore, timely detection of pancreatic cancer through tumor markers could significantly improve the survival rate of patients. The most widely used and diagnostically valuable tumor marker in clinical practice is Carbohydrate antigen 199 (CA199). However, due to about 3% ~ 7% of pancreatic cancer patients being Lewis antigen-negative blood types and not expressing CA19-9, its sensitivity is only 79% ~ 81%, which does not provide good efficacy for the diagnosis of pancreatic cancer. Pancreatic juice, as a fluid near the tumor, has attracted much attention as a good source of tumor-related biomarkers. Many studies have confirmed the accuracy of using proteins, DNA, and exosomes in pancreatic juice for the diagnosis of pancreatic cancer, showing great prospects for pancreatic juice as a source of tumor markers for the diagnosis of pancreatic cancer. Therefore, this thesis reviews the efficacy of pancreatic juice as a specimen for the diagnosis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the impact of renal function impairment on long-term survival outcomes and adjuvant therapy in patients with pancreatic cancer undergoing pancreaticoduodenectomy (PD). Methods: In this study, 264 patients who underwent PD for pancreatic head cancer between 2011 and 2021 were retrospectively analyzed. The patients were subsequently categorized into three groups according to the estimated glomerular filtration rate: normal group (> 90 mL/min/1.73 m2, n = 73), moderate group (45–90 mL/min/1.73 m2, n = 176), and severe group (< 45 mL/min/1.73 m2, n = 15). The primary outcomes evaluated were postoperative complications, overall survival (OS), and relapse-free survival (RFS). Additionally, the completion of adjuvant therapy and risk factors for adjuvant therapy discontinuation were analyzed. Results: The total proportion of patients with complications was significantly higher in the severe group (p = 0.008). The proportion of patients with severe complications (Clavien–Dindo classification ≥ IIIa) did not significantly differ between the chronic kidney disease (CKD) groups (p = 0.730). The proportion of patients in whom adjuvant therapy was completed was notably lower in the severe group (p = 0.011). Multiple logistic regression analysis revealed that CKD groups and hemoglobin levels ≤ 11.5 g/dL were independent predictors of adjuvant therapy completion failure (p = 0.016 and p = 0.016). There was no significant difference in the OS and RFS rates between the CKD groups (p = 0.499, p = 0.688). Conclusions: In patients with pancreatic cancer and CKD, performing PD safely may be feasible; however, adjuvant therapy completion is challenging. [ABSTRACT FROM AUTHOR]

Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies. [ABSTRACT FROM AUTHOR]

With a 5-year survival of ˂ 10%, pancreatic cancer is one of the leading causes of cancer-related deaths. Given the role of the distribution of tumor-infiltrating lymphocyte (TILs) subtypes in the tumor and its microenvironment in predicting prognosis, the development of new targeted therapies based on T-cell adaptive response has gained considerable attention. This study aimed to examine the peritumoral spread of TILs and its relationship with other prognostic parameters and survival. This study included 60 patients with pancreatic cancer who had undergone surgery with follow-up between 2011 and 2021. Demographic characteristics, tumor histopathological features, peritumoral TILs counts, and intratumoral programmed cell death protein-1 (PD-1) and programmed death ligand − 1 (PD-L1) positivity were evaluated. Furthermore, overall survival and their efficacy in predicting survival according to TNM stage were analyzed. The number of cluster differentiation-3 positive (CD3 P) TILs increased with advancing pathological T stage. CD3 P and CD8 P TIL counts were higher in patients with peripancreatic fatty tissue invasion. Patients with PD-L1 positivity and higher TIL counts had better survival rates. PD-L1-negative patients with a low CD8 positive/total lymph node count (P/T) ratio had a longer survival. Moreover, patients with poorly differentiated tumors with low CD3 P/T and CD8 P/T ratios had a longer survival. The CD3 P/T and CD8 P/T ratios were compatible with the automatic and manual measurements. Age, tumor differentiation, N stage, and peritumoral TIL count and subtype, when evaluated together with the presence of PD-L1 in the tumor tissue, may have prognostic significance for survival in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRASG12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRASG12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions. Methods: Two KRASG12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRASG12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry. Results: The bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRASG12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRASG12D inhibitor-resistant PDAC cells. Knockdown or overexpression of MGST1 conferred sensitivity or resistance to KRASG12D inhibitor MRTX1133, respectively. Mechanismly, increased nuclear localization and higher levels of active β-catenin were observed in MRTX1133-resistant PDAC cells, which contributed to higher MGST1 expression. Knockdown of CTNNB1 or TCF4 can decreased MGST1 expression. Additionally, we found that PKF-118-310, an antagonist of β-catenin/Tcf4 complex, repressed MGST1 expression. In both in vitro and in vivo models, a synergistic effect was observed when combining MRTX1133 and PKF-118-310 in KRASG12D inhibitor MRTX1133-resistant PDAC cells and tumors. Conclusion: Our data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions M2‐polarized tumor‐associated macrophages (M2 TAMs) are known to promote cancer progression, and exosomes are crucial mediators of communication within the tumor microenvironment (TME). However, the specific role of exosomes derived from M2 TAMs in pancreatic cancer (PC) progression remains poorly understood. Tyrosine kinase binding protein (TYROBP, also known as DAP12 for DNAX activating protein‐12) is a transmembrane signal transduction polypeptide that interacts with immune cell receptors, influencing cellular functions via signal transduction pathways. TYROBP is prominently found in M2 TAMs exosomes, facilitating its transfer to PC cells and suggesting a potential role in PC pathogenesis.This study initially confirmed the presence of TYROBP in M2 TAMs exosomes and its transfer to PC cells via exosomes. The impact of TYROBP on PC proliferation, apoptosis, migration, and invasion was investigated. Special attention was given to TYROBP's influence on PC metastasis and its underlying mechanisms, focusing particularly on the CD44/AKT/ERK signaling pathway.TYROBP expression in PC cells did not significantly affect tumor cell proliferation or apoptosis but demonstrated a notable inhibitory effect on migration and invasion, which was mediated through the CD44/AKT/ERK pathway. Both in vivo and in vitro experiments consistently showed that TYROBP enhanced PC metastasis.This study elucidates that TYROBP plays a direct role in promoting PC metastasis through its association with M2 TAMs polarization. Therefore, TYROBP represents a potential novel therapeutic target for interventions aimed at combatting PC progression. [ABSTRACT FROM AUTHOR]

Purpose: The overall survival of patients with pancreatic cancer is extremely low. We aimed to establish machine learning (ML) based model to accurately predict three-year survival and prognosis of pancreatic cancer patients. Methods: We analyzed pancreatic cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2021. Univariate and multivariate logistic analysis were employed to select variables. Recursive Feature Elimination (RFE) method based on 6 ML algorithms was utilized in feature selection. To construct predictive model, 13 ML algorithms were evaluated by area under the curve (AUC), area under precision-recall curve (PRAUC), accuracy, sensitivity, specificity, precision, cross-entropy, Brier scores and Balanced Accuracy (bacc) and F Beta Score (fbeta). An optimal ML model was constructed to predict three-year survival, and the predictive results were explained by SHapley Additive exPlanations (SHAP) framework. Meanwhile, 101 ML algorithm combinations were developed to select the best model with highest C-index to predict prognosis of pancreatic cancer patients. Results: A total of 20,064 pancreatic cancer patients from SEER database was consecutively enrolled. We utilized eight clinical variables to establish prediction model for three-year survival. CatBoost model was selected as the best prediction model, and AUC was 0.932 [0.924, 0.939], 0.899 [0.873, 0.934] and 0.826 [0.735, 0.919] in training, internal test and external test sets, with 0.839 [0.831, 0.847] accuracy, 0.872 [0.858, 0.887] sensitivity, 0.803 [0.784, 0.825] specificity and 0.832 [0.821, 0.853] precision. Surgery type had the greatest effects on three-year survival according to SHAP results. For prognosis prediction, "RSF+GBM" algorithm was the best prognostic model with C-index of 0.774, 0.722 and 0.674 in training, internal test and external test sets. Conclusions: Our ML models demonstrate excellent accuracy and reliability, offering more precise personalized prognostic prediction to pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Pancreatic diseases such as pancreatitis and pancreatic cancer represent significant health challenges characterized by high mortality rates and limited survival durations. Autophagy, a crucial cellular catabolic process, has emerged as a focal point in understanding various pathological conditions, spanning inflammation-related disorders to malignant neoplasms. This comprehensive review aims to elucidate the biological intricacies of autophagy and its pivotal roles within two extensively researched pancreatic diseases, namely pancreatitis and pancreatic cancer, drawing upon recent scholarly contributions. The discussion will delve into the nuanced mechanisms underlying autophagy's involvement in these diseases, shedding light on its potential as a therapeutic target. Furthermore, the review will explore cutting-edge therapeutic interventions leveraging autophagy regulation for managing pancreatitis and pancreatic cancer. Through this analysis, we endeavor to offer novel insights into the pathophysiology of pancreatic disorders and contribute to the development of innovative therapeutic modalities in this challenging clinical domain. [ABSTRACT FROM AUTHOR]

Background: Characterized by an immune-suppressive tumor microenvironment (TME), pancreatic ductal adenocarcinoma (PDAC) is well-known for its poor prognosis. Tumor associated macrophages (TAMs) play a critical role in PDAC TME. An in-depth understanding of TAMs is helpful to develop new strategies for immunotherapy. Methods: A large number of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC were collected for systematic bioinformatics analysis. Characterize subtypes of TAMs at single-cell resolution and its effect on prognosis. Differential gene analysis and cell-cell communication were used to describe the effect on prognosis and validated by the TCGA dataset. Results: We used two prognosis-favorable genes, SLC12A5 and ENPP2, to identify a benign M2-like TAMs (bM2-like TAMs), which shared similarities with C1QC + TAMs, CXCL9+ TAMs and CD169+ TAMs, by analyzing scRNA-seq data and bulk RNA data of PDAC. The bM2-like TAMs were revealed to promote T cell activation and proliferation through ALCAM/CD6 interaction. Meanwhile, the bM2-like TAMs were responsible for stroma modeling by altering αSMA+/αSMA-cell ratio. On the contrast, the rest of the M2-like TAMs were defined as malignant M2-like TAMs (mM2-like TAMs), partly overlapping with SPP1+ TAMs. mM2-like TAMs were revealed to promote tumor progression by secretion of MIF and SPP1. Conclusion: Our study used two prognosis-favorable genes to divide M2-like TAMs of PDAC into anti-tumor bM2-like TAMs and pro-tumor mM2-like TAMs. The bM2-like TAMs activate T cells through ALCAM/CD6 and generate prognosis-favorable αSMA+ myofibroblasts through secreting TGFβ, which brings insight into heterogeneity of TAMs, prognosis prediction and immunotherapy of PDAC. [ABSTRACT FROM AUTHOR]

Background: Evidence with regards to the distinction between primary and metastatic tumors in pancreatic cancer and driving factors for metastases remains limited. Methods: Single-cell RNA sequencing (scRNA-seq) was conducted on metastatic pancreatic cancer. Bioinformatics analysis on relevant sequencing data was used to construct a risk model to predict patient prognosis. Furthermore, immune infiltration and metabolic differences were assessed. The biological function of key differential genes was evaluated. Results: Paired primary and metastatic tumor tissues from 3 pancreatic cancer patients were collected and conducted scRNA-seq. Subsequently, the T/NK cell subgroup was the most different cell type between primary tumors and liver metastases and was selected for further analysis. Eventually, 6 specifically expressed genes of T/NK cells (B2M, ZFP36L2, ANXA1, ARL4C, TSPYL2, FYN) were used constructing the prognostic model. The stability of this model was validated by an external cohort. Meanwhile, different immune infiltration abundances occurred between high and low risk groups stratified by the model. The high-risk group had a stronger metabolic capability. Conclusions: A novel prognostic T/NK-cell signature for pancreatic cancer was constructed based on scRNA-seq data and externally validated. The involved key genes may play a role in multiple metabolic pathways of metastasis and affect the tumor immune microenvironment. [ABSTRACT FROM AUTHOR]

Introduction: Endosonography-guided biliary drainage (EUS-BD) serves as a rescue treatment modality for patients with malignant biliary obstruction when endoscopic retrograde cholangiopancreatography (ERCP) fails. Objectives: This study explores the effects of EUS-BD on liver function and quality of life (QoL). Patients and Methods: Patients with malignant biliary obstruction and failed ERCP were enrolled to undergo EUS-BD. QoL, including pruritus severity, was evaluated using EQ-5D-5L and PSS-10 questionnaires before and after EUS-BD. Serum bilirubin and liver function tests were measured on the procedure day, two days, and at least 14 days post-procedure. Results: During a 20-month study period, 1755 ERCPs were performed, with 595 for malignant cases. Of these, 49 underwent EUS-BD following failed ERCP, and 37 (54% women, age range 34–87 years) completed the 14-day follow-up. Pancreatic cancer was the most common (49%) condition, and the median hospital stay was 4 days. Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased 2 and 14 days after EUS-BD (all p < 0.001). Pruritus significantly improved, with an average reduction of 5.19 points on the PSS-10 scale two weeks post-procedure (p < 0.001). EUS-BD led to improvements in anxiety and depression according to the EQ-5D-5L (p = 0.013). Conversely, deteriorations were observed in the Mobility, Self-Care, and Usual Activities domains over time (all p < 0.05). Successful EUS-BD enabled the resumption of chemotherapy in 11 (30%) patients. The median post-procedure survival was 112 (range 27–1030) days. Conclusions: EUS-BD improves liver parameters and some aspects of life quality in patients with malignant biliary obstruction, thereby increasing their eligibility for optimal palliative care. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PC) is one of the most aggressive types of cancer. Despite advances in molecular diagnostics, PC diagnosis relies on imaging technologies and morphological assessment of fine needle aspirates (FNAs). MicroRNA (miRNA) involvement in PC pathogenesis and potential diagnostics application have been suggested, albeit current supporting evidence is lacking. Here, we investigated the association of selected miRNAs with PC incidence and clinical characteristics. Methods: Fold expression of miR‐216a‐3p, ‐217‐5p, ‐221‐3p, ‐222‐3p, and miR‐196a‐5p was assessed in 73 PC FNA cell‐block sections and 6 healthy pancreas tissues using Taqman advanced miRNA assays. Potential miRNA targets were ascertained using immunocytochemistry. Results: miR‐196a‐5p was upregulated in PC compared to healthy pancreatic tissue (β = −0.05, 95% CI: −0.065 – (−0.035); p < 0.001). miR‐221‐3p and miR‐222‐3p fold expression were strongly correlated (r = 0.897, p < 0.001), whereas miR‐196a‐5p fold expression correlated with that of miR‐221‐3p (r = 0.688, p < 0.001) and miR‐222‐3p (r = 0.489, p < 0.001). Moreover, miR‐196a‐5p fold expression positively correlated with tumor stage (r = 0.32, p = 0.034). miR‐217‐5p fold expression inversely correlated with KRAS expression (r = ‐0.69, p = 0.0027). Conclusion: Our study shows miR‐196a‐5p has reasonable specificity to PC and thus may have diagnostic and prognostic potential in PC as proposed in the literature. Moreover, KRAS and NFKBIA may be potential targets for miR‐217‐5p and miR‐196a‐5p, respectively. Thus, these miRNAs may be involved in tumor progression and may have valuable applications in novel therapeutics or treatment monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Individuals who develop new‐onset diabetes have been identified as a high‐risk cohort for pancreatic cancer (PC), exhibiting an incidence rate nearly 8 times higher than the general population. Hence, the targeted screening of this specific cohort presents a promising opportunity for early pancreatic cancer detection. We aimed to develop and validate a novel model capable of identifying high‐risk individuals among those with new‐onset diabetes. Methods: Employing the UK Biobank cohort, we focused on those developing new‐onset diabetes during follow‐up. Genetic and clinical characteristics available at registration were considered as candidate predictors. We conducted univariate regression analysis to identify potential indicators and used a 5‐fold cross‐validation method to select optimal predictors for model development. Five machine learning algorithms were used for model development. Results: Among 12,735 patients with new‐onset diabetes, 100 (0.8%) were diagnosed with PC within 2 years. The final model (area under the curve, 0.897; 95% confidence interval, 0.865–0.929) included 5 clinical predictors and 24 single nucleotide polymorphisms. Two threshold cut‐offs were established: 1.28% and 5.26%. The recommended 1.28% cut‐off, based on model performance, reduces definitive testing to 13% of the total population while capturing 76% of PC cases. The high‐risk threshold is 5.26%. Utilizing this threshold, only 2% of the population needs definitive testing, capturing nearly half of PC cases. Conclusions: We, for the first time, combined clinical and genetic data to develop and validate a model to determine the risk of pancreatic cancer in patients with new‐onset diabetes using machine learning algorithms. By reducing the number of unnecessary tests while ensuring that a substantial proportion of high‐risk patients are identified, this tool has the potential to improve patient outcomes and optimize healthcare sources. [ABSTRACT FROM AUTHOR]

While surgical resection is a mainstay of cancer treatment, many tumors are unresectable due to stage, location, or comorbidities. Ablative therapies, which cause local destruction of tumors, are effective alternatives to surgical excision in several settings. Ethanol ablation is one such ablative treatment modality in which ethanol is directly injected into tumor nodules. Ethanol, however, tends to leak out of the tumor and into adjacent tissue structures, and its biodistribution is difficult to monitor in vivo. To address these challenges, this study presents a cutting‐edge technology known as Light‐Activatable Sustained‐Exposure Ethanol Injection Technology (LASEIT). LASEIT comprises a three‐part formulation: (1) ethanol, (2) benzoporphyrin derivative, which enables fluorescence‐based tracking of drug distribution and the potential application of photodynamic therapy, and (3) ethyl cellulose, which forms a gel upon injection into tissue to facilitate drug retention. In vitro drug release studies showed that ethyl cellulose slowed the rate of release in LASEIT by 7×. Injections in liver tissues demonstrated a 6× improvement in volume distribution when using LASEIT compared to controls. In vivo experiments in a mouse pancreatic cancer xenograft model showed LASEIT exhibited significantly stronger average radiant efficiency than controls and persisted in tumors for up to 7 days compared to controls, which only persisted for less than 24 h. In summary, this study introduced LASEIT as a novel technology that enabled real‐time fluorescence monitoring of drug distribution both ex vivo and in vivo. Further research exploring the efficacy of LASEIT is strongly warranted. [ABSTRACT FROM AUTHOR]

Background Intraductal papillary mucinous neoplasm (IPMN)–derived pancreatic ductal adenocarcinoma (PDAC) is resected at smaller sizes compared with its biologically distinct counterpart, pancreatic intraepithelial neoplasia (PanIN)–derived PDAC. Thus, experts proposed T1 sub-staging for IPMN-derived PDAC. However, this has never been validated. Methods Consecutive upfront surgery patients with IPMN-derived PDAC from 5 international high-volume centers were classified by the proposed T1 sub-staging classification (T1a ≤0.5, T1b >0.5 and ≤1.0, and T1c >1.0 and ≤2.0 cm) using the invasive component size. Kaplan-Meier and log-rank tests were used to compare overall survival (OS). A multivariable Cox regression was used to determine hazard ratios (HRs) with confidence intervals (95% CIs). Results Among 747 patients, 69 (9.2%), 50 (6.7%), 99 (13.0%), and 531 patients (71.1%), comprised the T1a, T1b, T1c, and T2-4 subgroups, respectively. Increasing T-stage was associated with elevated CA19-9, poorer grade, nodal positivity, R1 margin, and tubular subtype. Median OS for T1a, T1b, T1c, and T2-4 were 159.0 (95% CI = 126.0 to NR), 128.8 (98.3 to NR), 77.6 (48.3 to 108.2), and 31.4 (27.5 to 37.7) months, respectively (P  < .001). OS decreased with increasing T-stage for all pairwise comparisons (all P  < .05). After risk adjustment, older than age 65, elevated CA19-9, T1b [HR = 2.55 (1.22 to 5.32)], T1c [HR = 3.04 (1.60 to 5.76)], and T2-4 [HR = 3.41 (1.89 to 6.17)] compared with T1a, nodal positivity, R1 margin, and no adjuvant chemotherapy were associated with worse OS. Disease recurrence was more common in T2-4 tumors (56.4%) compared with T1a (18.2%), T1b (23.9%), and T1c (36.1%, P  < .001). Conclusion T1 sub-staging of IPMN-derived PDAC is valid and has significant prognostic value. Advancing T1 sub-stage is associated with worse histopathology, survival, and recurrence. T1 sub-staging is recommended for future guidelines. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options. Due to a variety of cancer cell-intrinsic factors, including KRAS mutations, chemokine production, and other mechanisms that elicit a dysregulated host immune response, PDAC is often characterized by poor immune infiltration and an immune-privileged fibrotic stroma. As understanding of the tumor microenvironment (TME) evolves, novel therapies are being developed to target immunosuppressive mechanisms. Immune checkpoint inhibitors have limited efficacy when used alone or with radiation. Combinations of immune therapies, along with chemotherapy or chemoradiation, have demonstrated promise in preclinical and early clinical trials. Despite dismal response rates for immunotherapy for metastatic PDAC, response rates with neoadjuvant immunotherapy are somewhat encouraging, suggesting that incorporation of immunotherapy in the treatment of PDAC should be earlier in the disease course. Precision therapy for PDAC may be informed by advances in transcriptomic sequencing that can identify immunophenotypes, allowing for more appropriate treatment selection for each individual patient. Personalized and antigen-specific therapies are an increasing topic of interest, including adjuvant immunotherapy using personalized mRNA vaccines to prevent recurrence. Further development of personalized immune therapies will need to balance precision with generalizability and cost. [ABSTRACT FROM AUTHOR]

Dicer, a cytoplasmic type III RNase, is essential for the maturation of microRNAs (miRNAs) and is implicated in cancer progression and chemoresistance. Our previous research demonstrated that phosphorylation of Dicer at S1016 alters miRNA maturation and glutamine metabolism, contributing to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on the role of Dicer phosphorylation at S1728/S1852 in GEM-resistant PDAC cells. Using shRNA to knock down Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells, we examined cell viability through MTT and clonogenic assays. We also expressed phosphomimetic Dicer 2E (S1728E/S1852E) and phosphomutant Dicer 2A (S1728A/S1852A) to evaluate their effects on GEM resistance and metabolism. Our results show that phosphorylation at S1728/S1852 promotes GEM resistance by reprogramming glutamine metabolism. Specifically, phosphomimetic Dicer 2E increased intracellular glutamine, driving pyrimidine synthesis and raising dCTP levels, which compete with gemcitabine's metabolites. This metabolic shift enhanced drug resistance. In contrast, phosphomutant Dicer 2A reduced GEM resistance. These findings highlight the importance of Dicer phosphorylation in regulating metabolism and drug sensitivity, offering insights into potential therapeutic strategies for overcoming GEM resistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains one of the deadliest malignancies, with a consistently low five-year survival rate for the past several decades. This is in stark contrast to other cancers, which have seen significant improvement in survival and prognosis due to recent developments in therapeutic modalities. These modest improvements in pancreatic cancer outcomes have primarily resulted from minor advances in cytotoxic chemotherapeutics, with limited progress in other treatment approaches. A major focus of current therapeutic research is the further development of immunomodulatory therapies characterized by antibody-based approaches, cellular therapies, and vaccines. Although initial results utilizing immunotherapy in pancreatic cancer have been mixed, recent clinical trials have demonstrated significant improvements in patient outcomes. In this review, we detail these three approaches to immunomodulation, highlighting their common targets and distinct shortcomings, and we provide a narrative summary of completed and ongoing clinical trials that utilize these approaches to immunomodulation. Within this context, we aim to inform future research efforts by identifying promising areas that warrant further exploration. [ABSTRACT FROM AUTHOR]