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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]

Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete. Methods: Herein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells. Results: We focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP+ and podoplanin+/cadherin-11+ CAFs enriched in patients with negative prognosis. Discussion: The present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment. [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]

Background: Telomere shortening and RNA pseudo-uridylation are common features of tumors. NOP10 is a member of the H/ACA snoRNP family, essential for maintaining telomerase activity and RNA pseudouridylation. NOP10 has been indicated to be substantially expressed in tumors such as breast and lung cancers and is associated with poor prognosis. Currently, no investigation exists on NOP10 in pancreatic cancer (PC). This is the first investigation to elucidate the impact on tumorigenesis and prognostic value of NOP10 in pancreatic adenocarcinoma (PAAD). Method: NOP10 expression and its survival prognostic significance were analyzed via clinical PAAD data from the TCGA database and NOP10 expression in other tumors from the GEPIA database. Furthermore, the NOP10 expression and survival prognosis in clinical samples were validated by qRT-PCR. In-vitro experiments were carried out to elucidate the impact of NOP10 on the biological function of PC cells. Results: It was revealed that NOP10 expression was increased in PC tissues than in the normal pancreatic tissues. High NOP10 expression was markedly linked with poorer prognosis. NOP10 may be involved in focal adhesion, channel activity, cAMP signaling pathway, the interaction of neuroactive ligand-receptor, and cell adhesion molecules cams. NOP10 was associated with the tumour immune microenvironment and drug sensitivity. Down-regulation of NOP10 expression suppressed PC cells' ability to proliferate, migrate, and invade. Conclusions: This investigation elucidated the prognostic and predictive importance of NOP10 in PAAD and revealed that NOP10 is associated with poor prognostic features, survival prognosis and TIME. Knockdown of NOP10 inhibits the progression of PAAD. [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]

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]

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]

Objective To assess the association between mood swings and pancreatic cancer using two-sample Mendelian randomization (TSMR) and to identify potential mediators between mood swings and pancreatic cancer through multivariable Mendelian randomization (MVMR). Methods Summary statistics for mood swings were obtained from genome-wide association studies (GWAS). Summary data for pancreatic cancer were derived from a cross-population atlas of 220 human phenotypic genetic associations. Single nucleotide polymorphism (SNP) associated with body mass index (BMI) and several common risk factors for pancreatic cancer, including smoking, alcohol consumption, triglycerides, and total cholesterol, were sourced from the UK Biobank and the IEU database. Causal relationships between mood swings and pancreatic cancer were explored using inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. A series of sensitivity analyses were conducted to evaluate the stability of the results. Results Genetically predicted mood swings were positively associated with pancreatic cancer risk, with the IVW method indicating that individuals with genetically determined mood swings had an increased risk of developing pancreatic cancer (OR =2.05, 95%CI: 1.21-3.48). After adjusting for BMI using MVMR, the association between mood swings and pancreatic cancer was attenuated (OR =1.45, 95%CZ: 0.94-2.23). Mediation analysis estimated that BMI partially mediated the causal relationship between mood swings and pancreatic cancer risk, with a mediation proportion of 48.2%. Conclusion The findings of this study indicate a positive correlation between mood swings and the risk of pancreatic cancer, potentially mediated by effects on BMI. [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]

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]

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth in vitro and to promote the inhibitory effects of gemcitabine (Gem) on PC in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested in vitro and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth in vitro more potently, with IC50 values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: A CRISPR knockout screen was performed targeting all genes of the human genome with about 12 knockout sgRNAs each. By comparing pancreatic cancer cells with high or low metastatic capacity, genes were identified that affect the viability of metastatic cells while not affecting cell viability of non-metastatic cells. Further functional studies looked at some of the identified candidate genes. For one of the metastasis-related genes—MYBL2—a change in its interaction with another regulator gene was found to be implicated in metastasis. Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is challenging to diagnose and treat. Current methods to measure disease burden, monitor treatment response, and predict disease progression have significant limitations. This study explores the utility of circulating neoplastic-immune hybrid cells (CHCs) as a novel blood-based biomarker. We find that pre-operative CHC levels can predict the presence of metastatic disease that may only be detected during surgical exploration, as well as identify patients who are likely to experience rapid metastatic progression after surgery. Further, CHC levels and protein expression patterns are reflective of disease response to chemotherapy. Collectively, these results suggest that CHCs could serve as crucial indicators of disease status and treatment efficacy, offering great potential to enhance survival outcomes for patients with PDAC. Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. Methods: Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. Results: Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. Conclusions: CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: The Yes-associated protein (YAP) is part of a system that regulates cell proliferation in response to changes in cell–cell and cell–matrix interactions. In malignant tumors, that system is almost always disrupted in ways that promote the stability of YAP. Mutations in genes encoding Ras proteins are found in 30% of all human cancers, but the mechanisms by which these mutated proteins promote cancer are still incompletely understood. Here, we investigated the regulation of YAP stability by the Ras oncogenes and found that while Ras does not directly regulate YAP, the stability of YAP is directly controlled by one of Ras's own effectors, the Rac1 GTPase, a small regulatory protein involved in controlling cell shape and migration. This regulation of YAP by Rac1 could potentially play an important role in the development of therapeutic resistance to Ras inhibitors, which we know can be promoted by the overexpression of YAP. Background: Oncogenic mutations in the KRAS gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1T17N mutant. Several E3 ubiquitin ligases, including SCFβTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383–388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a particularly aggressive form of cancer characterized by poor patient survival, highlighting the need for preventive strategies and interventions to improve long-term survival. While physical activity is known to lower the risk of many different forms of cancer and reduce cancer-specific mortality, its effect on pancreatic cancer is less clear. Therefore, this systematic review and meta-analysis aimed to summarize epidemiological evidence on the relationship between physical activity and pancreatic cancer risk and mortality. A meta-analysis of seven case–control and eighteen prospective cohort studies demonstrated that higher levels of physical activity were associated with a lower risk of developing pancreatic cancer. No significant association was found between pre-diagnosis physical activity and pancreatic cancer mortality, based on data from only six prospective cohort studies. These results could help guide further research and contribute to public health recommendations on physical activity for cancer prevention. Background: Physical activity has been associated with a lower risk of various types of cancer and reduced cancer-specific mortality. Less is known about its impact on pancreatic cancer. The aim of this systematic review and meta-analysis was to summarize evidence on the association between physical activity and pancreatic cancer risk and mortality. Methods: PubMed and Embase were searched until May 2024 for studies examining physical activity in relation to pancreatic cancer incidence and mortality. Summary risk estimates for highest vs. lowest physical activity levels were calculated using a random-effects model. The risk of publication bias was assessed with a funnel plot and Egger's regression test. Results: A total of seven case–control and eighteen prospective cohort studies were included that investigated the association between physical activity and pancreatic cancer incidence. Our meta-analysis showed a summary estimate of 0.75 (95% CI 0.64–0.88) for case–control studies (I2 = 23%, n = 7) and a summary estimate of 0.91 (95% CI 0.86–0.97) for prospective cohort studies (I2 = 5%, n = 18). Among the six prospective cohort studies that assessed pancreatic cancer mortality, the summary estimate was 1.03 (95% CI 0.83–1.27), I2 = 50%. Conclusions: Higher levels of physical activity were associated with reduced pancreatic cancer risk. Evidence from a limited number of studies suggests that pre-diagnosis physical activity does not affect pancreatic cancer mortality. [ABSTRACT FROM AUTHOR]

Pancreatic cancer cells have a much higher metabolic demand than that of normal cells. However, the abundant interstitium and lack of blood supply determine the lack of nutrients in the tumour microenvironment. Although pancreatic cancer has been reported to supply extra metabolic demand for proliferation through autophagy and other means, the specific regulatory mechanisms have not yet been elucidated. In this study, we focused on transcription factor EB (TFEB), a key factor in the regulation of autophagy, to explore its effect on the phenotype and role in the unique amino acid utilisation pattern of pancreatic cancer cells (PCCs). The results showed that TFEB, which is generally highly expressed in pancreatic cancer, promoted the proliferation and metastasis of PCCs. TFEB knockdown inhibited the proliferation and metastasis of PCCs by blocking the catabolism of branched‐chain amino acids (BCAAs). Concerning the mechanism, we found that TFEB regulates the catabolism of BCAAs by regulating BCAT1, a key enzyme in BCAA metabolism. BCAA deprivation alone did not effectively inhibit PCC proliferation. However, BCAA deprivation combined with eltrombopag, a drug targeting TFEB, can play a two‐pronged role in exogenous supply deprivation and endogenous utilisation blockade to inhibit the proliferation of pancreatic cancer to the greatest extent, providing a new therapeutic direction, such as targeted metabolic reprogramming of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Abnormal sphingolipid metabolism (SM) is closely linked to the incidence of cancers. However, the role of SM in pancreatic cancer (PC) remains unclear. This study aims to explore the significance of SM in the prognosis, immune microenvironment, and treatment of PC. Methods: Single-cell and bulk transcriptome data of PC were acquired via TCGA and GEO databases. SM-related genes (SMRGs) were obtained via MSigDB database. Consensus clustering was utilized to construct SM-related molecular subtypes. LASSO and Cox regression were utilized to build SM-related prognostic signature. ESTIMATE and CIBERSORT algorithms were employed to assess the tumour immune microenvironment. OncoPredict package was used to predict drug sensitivity. CCK-8, scratch, and transwell experiments were performed to analyze the function of ANKRD22 in PC cell line PANC-1 and BxPC-3. Results: A total of 153 SMRGs were acquired, of which 48 were linked to PC patients' prognosis. Two SM-related subtypes (SMRGcluster A and B) were identified in PC. SMRGcluster A had a poorer outcome and more active SM process compared to SMRGcluster B. Immune analysis revealed that SMRGcluster B had higher immune and stromal scores and CD8 + T cell abundance, while SMRGcluster A had a higher tumour purity score and M0 macrophages and activated dendritic cell abundance. PC with SMRGcluster B was more susceptible to gemcitabine, paclitaxel, and oxaliplatin. Then SM-related prognostic model (including ANLN, ANKRD22, and DKK1) was built, which had a very good predictive performance. Single-cell analysis revealed that in PC microenvironment, macrophages, epithelial cells, and endothelial cells had relatively higher SM activity. ANKRD22, DKK1, and ANLN have relatively higher expression levels in epithelial cells. Cell subpopulations with high expression of ANKRD22, DKK1, and ANLN had more active SM activity. In vitro experiments showed that ANKRD22 knockdown can inhibit the proliferation, migration, and invasion of PC cells. Conclusion: This study revealed the important significance of SM in PC and identified SM-associated molecular subtypes and prognostic model, which provided novel perspectives on the stratification, prognostic prediction, and precision treatment of PC patients. [ABSTRACT FROM AUTHOR]

Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety. [ABSTRACT FROM AUTHOR]