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Key points Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol‐induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol‐induced AP. Intact guinea‐pig pancreatic ducts were pre‐treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX‐809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi‐treated guinea‐pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose‐dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol‐induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol‐induced pancreatitis. This is the first in vivo pre‐clinical evidence of Orkambi efficacy in the treatment of alcohol‐induced AP. Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3– secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol‐induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol‐induced pancreatitis by enhancing pancreatic functions or preventing recurrence. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors that lacks effective treatment options. Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment, associated with tumor progression, prognosis, and treatment response. This work aimed to explore the novel CAFs-associated target to improve treatment strategies in PDAC. Methods: The PDAC single-cell sequencing data (CRA001160, n = 35) were downloaded and integrated based on GSA databases to classify fibroblasts into fine subtypes. Functional enrichment analysis and coexpression regulatory network analysis were used to identify the functional phenotypes and biological properties of the different fibroblast subtypes. Fibroblast differentiation trajectories were constructed using pseudochronological analysis to identify initial and terminally differentiated subtypes of fibroblasts. The changes in the proportions of different fibroblast subtypes before and after PDAC immunotherapy were compared in responsive and nonresponding patients, and the relationships between fibroblast subtypes and PDAC immunotherapy responsiveness were determined based on GSA and GEO database. Using molecular biology methods to confirm the effects of BNIP3 on hypoxia and inflammation in CAFs. CAFs were co cultured with pancreatic cancer cells to detect their effects on migration and invasion of pancreatic cancer. Results: Single-cell data analysis divided fibroblasts into six subtypes. The differentiation trajectory suggested that BNIP3+ Fibro subtype exhibited terminal differentiation, and the expression of genes related to hypoxia and the inflammatory response increased gradually with differentiation time. The specific overexpressed genes in the BNIP3+ Fibro subtype were significantly associated with overall and disease progression-free survival in the patients with PDAC. Interestingly, the greater the proportion of the BNIP3+ Fibro subtype was, the worse the response of PDAC patients to immunotherapy, and the CRTL treatment regimen effectively reduced the proportion of the BNIP3+ Fibro subtype. After knocking out BNIP3, the hypoxia markers and inflammatory factors of CAFs were inhibited. Co-culture of CAFs with pancreatic cancer cells can increase the migration and invasion of pancreatic cancer, but this could be reversed by knocking out BNIP3. Conclusions: This study revealed the BNIP3+ Fibro subtype associated with hypoxia and inflammatory responses, which was closely related to the poor prognosis of patients with PDAC, and identified signature genes that predict the immunotherapy response in PDAC. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Extracorporeal shock wave lithotripsy for pancreatic stones (P‐ESWL) and endoscopic retrograde cholangiopancreatography (ERCP) are the preferred therapeutic approaches for painful chronic pancreatitis (CP) with pancreatic stones. This study aimed to report the short‐ and long‐term outcomes following P‐ESWL and ERCP in a large cohort with CP. Methods: Patients with painful CP and pancreatic stones >5 mm in size, who underwent P‐ESWL and subsequent ERCP between March 2011 and June 2018, were included in this retrospective‐prospective mixed observational study. The total stone clearance rates were recorded. All patients were followed up until the end of March 2024, with the visual analogue scale (VAS) for pain, pain type, quality‐of‐life scores and other relevant information recorded. Results: A total of 2071 patients underwent P‐ESWL, and 93.1% of them subsequently underwent ERCP during the study period. Patients were followed up for an average of 11.8 years from the onset of CP and 6.7 years from the first P‐ESWL procedure. Complete stone clearance was achieved in 73.7% of the patients. At the end of the follow‐up period, 70.1% of the patients achieved complete pain remission. Significant pain type conversion and lower VAS scores were observed in the patients after treatment. Quality‐of‐life scores and body mass indices increased after P‐ESWL and ERCP. Conclusions: P‐ESWL and ERCP are effective and minimally invasive treatments for pancreatic stones in patients with painful CP. Most patients achieved complete pain relief, and pain‐type conversion was common after treatment. (ClinicalTrials.gov: NCT05916547). [ABSTRACT FROM AUTHOR]

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis is a progressive disease characterized by irregular fibrosis, cellular infiltration, and parenchymal loss within the pancreas. Chronic pancreatitis treatment includes lifestyle modifications based on disease etiology, dietary adjustments appropriate for each stage and condition, drug therapy, endoscopic treatments, and surgical treatments. Although surgical treatments of symptomatic chronic pancreatitis provide good pain relief, endoscopic therapies are recommended as the first‐line treatment because they are minimally invasive. In recent years, endoscopic therapy has emerged as an alternative treatment method to surgery for managing local complications in patients with chronic pancreatitis. For pancreatic stone removal, a combination of extracorporeal shock wave lithotripsy and endoscopic extraction is used. For refractory pancreatic duct stones, intracorporeal fragmentation techniques, such as pancreatoscopy‐guided electrohydraulic lithotripsy and laser lithotripsy, offer additional options. Interventional endoscopic ultrasound has become the primary treatment modality for pancreatic pseudocysts, except in the absence of disconnected pancreatic duct syndrome. This review focuses on the current status of endoscopic therapies for common local complications of chronic pancreatitis, including updated information in the past few years. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a highly aggressive cancer with unfavorable prognosis despite the therapeutic interventions. Intraperitoneal chemotherapy has recently shown potential outcomes in the presence of peritoneal metastases. However, a consensus is still lacking on different methods for intraperitoneal chemotherapy in pancreatic cancer. A variety of drugs and doses via three types of intraperitoneal chemotherapy have been studied. The prognosis and treatment strategies for pancreatic ductal adenocarcinoma (PDAC) will be significantly influenced by peritoneal dissemination and resectability of the macroscopic disease. Normothermic intraperitoneal chemotherapy (NIPEC) has been used for the treatment of peritoneal metastases of pancreatic carcinomas. Intraperitoneal chemotherapy is often combined with systemic therapies or surgical procedures which may lead to favorable combination therapies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a relatively new approach that provides a homogenous and deep penetration of the chemotherapy into the peritoneum by producing aerosols. The present study aims to review the literature for recent evidence on intraperitoneal chemotherapy in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background/Objectives: Covered self-expandable metallic stents (CSEMS) are commonly used to treat malignant distal biliary obstructions. A 10-mm CSEMS carries the risk of obstructing the pancreatic and cystic duct orifices by adhering to the bile duct; therefore, postoperative pancreatitis and cholecystitis are reported to occur at a certain frequency. We have adopted a new drainage technique for malignant distal biliary obstruction called "double-slim SEMS stenting" (DSS), where two small-diameter CSEMS are placed side-by-side. We aimed to compare the efficacy and safety of biliary drainage using DSS with those of conventional CSEMS. Methods: In total, 50 patients who underwent endoscopic biliary drainage for malignant distal biliary obstructions between April 2019 and March 2022 at Hyogo Medical University Hospital were enrolled. Patients were divided into DSS and Conventional groups, and the technical success rate, clinical success rate, adverse events, success rate for reintervention, recurrent biliary obstruction (RBO) rate, and time to RBO (TRBO) were evaluated. Results: There were no significant differences in patient characteristics between the DSS (n = 20) and Conventional groups (n = 30). The technical and clinical success rates were 100% in the DSS group. The incidence of adverse events was not significantly different between the two groups (DSS/Conventional: 10.0% [2/20]/20.0% [6/30]) (p = 0.34). No acute cholecystitis was observed in the DSS group. The incidence rates of RBO were 30% (6/20) and 43% (13/30) in the DSS and Conventional groups, respectively (p = 0.92). The median TRBO in the DSS group was 378 days, while the TRBO in the Conventional group was 195 days (p = 0.03), resulting in significantly longer TRBO in the DSS group. Conclusions: DSS emerges as a viable and safe approach for biliary drainage in malignant distal biliary obstruction, demonstrating a lower incidence of adverse events and longer TRBO compared to conventional CSEMS. [ABSTRACT FROM AUTHOR]

Simple Summary: We examined the association of the entire submission of the tumor (ESOT) and the entire submission of the pancreas (ESOP) with clinicopathologic features and survival in 627 pancreatic cancer patients who received neoadjuvant therapy (NAT). We demonstrated that both ESOT and ESOP were associated with lower ypT, less frequent perineural invasion, and better tumor response. Both ESOT and ESOP were associated with less frequent recurrence/metastasis, better disease-free survival (DFS), and overall survival (OS) in the overall study population. ESOP was associated with better DFS and OS in patients with ypT0/ypT1 or ypN0 tumors and better OS in patients with complete or near-complete response. ESOT was associated with better OS in patients with ypT0/ypT1 or ypN0 tumors. Both ESOT and ESOP were independent prognostic factors for OS in multivariate survival analyses. Therefore, ESOP and ESOT are associated with the prognosis of PDAC patients with complete or near-complete response and a ypT0/ypT1 tumor after NAT. 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. [ABSTRACT FROM AUTHOR]

Pancreatic Ductal AdenoCarcinoma (PDAC) is characterized by a poor prognosis and is poorly amenable to modern therapies. A range of cell cultures reflecting different degrees of tumor differentiation and malignancy can serve as a model of PDAC development. Highly differentiated cells with low malignancy are characterized by increased expression of the KLF5 gene. The KLF5 protein is a vivid representative of multifunctional transcription factors, and its involvement in a variety of cellular processes, particularly in the pathology of various cancers, has been demonstrated. We investigated the spatial organization of chromatin of the regulatory regions of the KLF5 gene using highly differentiated Capan2 PDAC cells with a high level of KLF5 expression and poorly differentiated MIA PaCa2 PDAC cells with a low level of expression of this gene by circular chromosome conformation capture (4C-seq). It was shown that the number and distribution of contacts of the KLF5 regulatory region with other chromatin regions are significantly different for these types of cells; the number of contacts is significantly higher for Capan2 cells. There is a correlation between the expression level of genes close to KLF5 and the intensity of their sequence contacts with the KLF5 regulatory region, indicating that their expression is coordinated, possibly within the transcriptional factory. Capan2 is characterized by a high level of contacts of the KLF5 regulatory region with the gene-free region containing a cluster of PDAC-associated single nucleotide polymorphisms (SNP/InDel). Thus, the total number of contacts of the promoter region of the KLF5 gene and the expression level of most of the surrounding KLF5 genes decrease as the grade of cell malignancy increases. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance to various treatment modalities. The genetic heterogeneity of PDAC, coupled with the presence of a desmoplastic stroma within the tumor microenvironment (TME), contributes to an unfavorable prognosis. The mechanisms and consequences of interactions among different cell types, along with spatial variations influencing cellular function, potentially play a role in the pathogenesis of PDAC. Understanding the diverse compositions of the TME and elucidating the functions of microscopic neighborhoods may contribute to understanding the immune microenvironment status in pancreatic cancer. As we delve into the spatial biology of the microscopic neighborhoods within the TME, aiding in deciphering the factors that orchestrate this intricate ecosystem. This overview delineates the fundamental constituents and the structural arrangement of the PDAC microenvironment, highlighting their impact on cancer cell biology. Highlights: • Cancer cells' intrinsic traits shape the microenvironment, causing dynamic changes in genetic and phenotypic features as the tumor grows and spreads. • Exploring how cellular components and molecular features impact cancer biology warrants further investigation into the intricate interactions within the TME • The spatial relationships between individual cellular and acellular components in PDAC hold the potential to provide novel insights into the dynamic and complex functions of PDAC desmoplasia, • Intratumoral sub-TMEs exhibit distinct regional immune compositions, and typical spatial subregion-TLS highlight the spatial heterogeneity of the TME [ABSTRACT FROM AUTHOR]

Purpose: Early dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC. Methods: Here, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented. Whole-exome sequencing and RNA sequencing were performed and drug responses to clinically relevant 18 compounds were assessed. Results: Our results revealed that borderline resectable PDAC organoids exhibited distinct patterns according to their metastatic potency highlighted by multiple genetic and transcriptional factors and strong variances in drug responses. Conclusions: These data suggest that the presence of metastatic PDAC can be identified by integrating molecular compositions and drug responses of borderline resectable PDAC. [ABSTRACT FROM AUTHOR]

This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses. [ABSTRACT FROM AUTHOR]

Background: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. Methods: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. Results: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. Conclusions: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression. [ABSTRACT FROM AUTHOR]

Background: The clustered regulatory interspaced short palindromic repeats (CRISPR)-Cas13a system has strong potential for highly sensitive detection of exogenous sequences. The detection of KRASG12 point mutations with low allele frequencies may prove powerful for the formal diagnosis of pancreatic ductal adenocarcinoma (PDAC). Results: We implemented preamplification of KRAS alleles (wild-type and mutant) to reveal the presence of mutant KRAS with CRISPR-Cas13a. The discrimination of KRASG12D from KRASWT was poor for the generic KRAS preamplification templates and depended on the crRNA design, the secondary structure of the target templates, and the nature of the mismatches between the guide and the templates. To improve the specificity, we used an allele-specific PCR preamplification method called CASPER (Cas13a Allele-Specific PCR Enzyme Recognition). CASPER enabled specific and sensitive detection of KRASG12D with low DNA input. CASPER detected KRAS mutations in DNA extracted from patients' pancreatic ultrasound-guided fine-needle aspiration fluid. Conclusion: CASPER is easy to implement and is a versatile and reliable method that is virtually adaptable to any point mutation. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. Methods: Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort. Results: In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine. Conclusion: This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment. [ABSTRACT FROM AUTHOR]

Purpose: The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery. Methods: The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil. Results: The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells. Conclusions: TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics. [Display omitted] • Lipiodol emulsion (IOE) functions as a simultaneous radiochemosensitizer for PDAC. • IOE increases drug bioavailability, retentivity and diffusion in solid tumor. • Oxidative stress and DNA damage-based therapeutic mechanism is verified. • IOE possesses good biosafety. [ABSTRACT FROM AUTHOR]

To evaluate long-term quality of life and survival in pancreatic ductal adenocarcinoma (PDAC) patients after pancreatoduodenectomy with extended lymphadenectomy (PDEL) and identify candidates. Patients with resectable PDAC with ≥1 examined lymph node (LN) during pancreatoduodenectomy (PD), and were divided into the PD with standard lymphadenectomy (PDSL) and PDEL groups. Perioperative data, long-term quality of life and survival were compared, and the prognostic effect of LNs ± in every peripancreatic station were analysed. Screening 446 PDAC patients, 237 and 126 were included in the PDSL and PDEL groups, respectively. The PDEL group showed a longer operation time, greater intraoperative blood loss, severe diarrhoea, a higher incidence of grade III complications. Notably, the PDEL patients experienced significant relief from low back pain and diarrhoea, with an obvious survival advantage (p = 0.037), especially in patients with preoperative tumor contact with vascular and pathological N0; however, LNs+ in any station (No. 8p, 12, 14, or 16) were associated with a poorer prognosis. The vascular reconstruction, T and N stage were independent risk factors for survival. PDEL can relieve symptoms and prolong the survival of PDAC patients with acceptable complications, and EL should be performed regardless of preoperative LN enlargement. [ABSTRACT FROM AUTHOR]

CA 19–9 is an extremely useful biomarker for pancreatic ductal adenocarcinomas (PDACs). However, the optimal cut-off and prognostic significance at higher cut-offs are yet to be determined. Retrospective analysis included patients with PDAC who underwent curative resection from January 2010 to May 2020 at Tata Memorial Centre, Mumbai. The pretherapy CA 19–9 was dichotomized using various cut-off levels and analysed. In 244 included patients, the median overall survival (OS) for those with CA19-9 level (IU/ml) < or >78, 200, 500, 1000, and 2000 was 27, 24, 23, 22, 21 months versus 18, 16, 15, 14, 13 months; respectively, and was statistically significant (p-value- 0.002, 0.001, 0.002, 0.002 and 0.004, respectively). The number of recurrences and mortality had significant correlation with CA 19–9 cut-offs. On multivariate analysis, adjuvant treatment completion (p-0.004) and decreasing or stable CA19-9 after Neoadjuvant therapy (NAT) (p- 0.031) were associated with improved OS. The prognostic significance of CA 19–9 was observed at all the cut-off levels examined, beyond mere elevated value as per the standard cut-off level. In patients with high CA19-9 level, surgery should be offered if technically and conditionally feasible, only when a response in CA19-9 level to NAT is achieved. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the diagnostic performance of quantitative magnetic resonance (MR) imaging biomarkers in distinguishing between inflammatory pancreatic masses (IPM) and pancreatic cancer (PC). Methods: A literature search was conducted using PubMed, Embase, the Cochrane Library, and Web of Science through August 2023. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to evaluate the risk of bias and applicability of the studies. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were calculated using the DerSimonian-Laird method. Univariate meta-regression analysis was used to identify the potential factors of heterogeneity. Results: Twenty-four studies were included in this meta-analysis. The two main types of IPM, mass-forming pancreatitis (MFP) and autoimmune pancreatitis (AIP), differ in their apparent diffusion coefficient (ADC) values. Compared with PC, the ADC value was higher in MFP but lower in AIP. The pooled sensitivity/specificity of ADC were 0.80/0.85 for distinguishing MFP from PC and 0.82/0.84 for distinguishing AIP from PC. The pooled sensitivity/specificity for the maximal diameter of the upstream main pancreatic duct (dMPD) was 0.86/0.74, with a cutoff of dMPD ≤ 4 mm, and 0.97/0.52, with a cutoff of dMPD ≤ 5 mm. The pooled sensitivity/specificity for perfusion fraction (f) was 0.82/0.68, and 0.82/0.77 for mass stiffness values. Conclusions: Quantitative MR imaging biomarkers are useful in distinguishing between IPM and PC. ADC values differ between MFP and AIP, and they should be separated for consideration in future studies. Clinical relevance statement: Quantitative MR parameters could serve as non-invasive imaging biomarkers for differentiating malignant pancreatic neoplasms from inflammatory masses of the pancreas, and hence help to avoid unnecessary surgery. Key Points: • Several quantitative MR imaging biomarkers performed well in differential diagnosis between inflammatory pancreatic mass and pancreatic cancer. • The ADC value could discern pancreatic cancer from mass-forming pancreatitis or autoimmune pancreatitis, if the two inflammatory mass types are not combined. • The diameter of main pancreatic duct had the highest specificity for differentiating autoimmune pancreatitis from pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively compare inter- and intra-reader agreement of abbreviated MRCP (aMRCP) with comprehensive MRI (cMRCP) protocol for detection of worrisome features, high-risk stigmata, and concomitant pancreatic cancer in pancreatic cyst surveillance. Methods: 151 patients (104 women, mean age: 69[10] years) with baseline and follow-up contrast-enhanced MRIs were included. This comprised 138 patients under cyst surveillance with 5-year follow-up showing no pancreatic ductal adenocarcinoma (PDAC), 6 with pancreatic cystic lesion-derived malignancy, and 7 with concomitant PDAC. The aMRCP protocol used four sequences (axial and coronal Half-Fourier Single-shot Turbo-spin-Echo, axial T1 fat-saturated pre-contrast, and 3D-MRCP), while cMRCP included all standard sequences, including post-contrast. Three blinded abdominal radiologists assessed baseline cyst characteristics, worrisome features, high-risk stigmata, and PDAC signs using both aMRCP and cMRCP, with a 2-week washout period. Intra- and inter-reader agreement were calculated using Fleiss' multi-rater kappa and Intra-class Correlation Coefficient (ICC). 95% confidence intervals (CI) were calculated. Results: Cyst size, growth, and abrupt main pancreatic duct transition had strong intra- and inter-reader agreement. Intra-reader agreement was ICC = 0.93–0.99 for cyst size, ICC = 0.71–1.00 for cyst growth, and kappa = 0.83–1.00 for abrupt duct transition. Inter-reader agreement for cyst size was ICC = 0.86 (aMRCP) and ICC = 0.83 (cMRCP), and for abrupt duct transition was kappa = 0.84 (aMRCP) and kappa = 0.69 (cMRCP). Thickened cyst wall, mural nodule and cyst-duct communication demonstrated varying intra-reader agreements and poor inter-reader agreements. Conclusion: aMRCP showed high intra- and inter-reader agreement for most pancreatic cyst parameters that highly rely on T2-weighted sequences. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality and it is often diagnosed at advanced stages due to non-specific clinical presentation. Disease detection at localized disease stage followed by surgical resection remains the only potentially curative treatment. In this era of precision medicine, a multifaceted approach to early detection of PDAC includes targeted screening in high-risk populations, serum biomarkers and "liquid biopsies", and artificial intelligence augmented tumor detection from radiologic examinations. In this review, we will review these emerging techniques in the early detection of PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis mostly due to the advanced stage at which disease is diagnosed. Early detection of disease at a resectable stage is, therefore, critical for improving outcomes of patients. Prior studies have demonstrated that pancreatic abnormalities may be detected on CT in up to 38% of CT studies 5 years before clinical diagnosis of PDAC. In this review, we highlight commonly missed signs of early PDAC on CT. Broadly, these commonly missed signs consist of small isoattenuating PDAC without contour deformity, isolated pancreatic duct dilatation and cutoff, focal pancreatic enhancement and focal parenchymal atrophy, pancreatitis with underlying PDAC, and vascular encasement. Through providing commentary on demonstrative examples of these signs, we demonstrate how to reduce the risk of missing or misinterpreting radiological features of early PDAC. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. Methods: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first‐degree relatives (FDRs) or second‐degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. Results: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p =.004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p =.003) but there was no statistical difference when assessing only affected SDRs (p =.344). Conclusions: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors. Results from this multicenter study show that individuals with pancreatic cancer and a germline pathogenic variant in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 are more likely to have a family history of pancreatic cancer, especially a first‐degree relative, compared to individuals with pancreatic cancer and no germline pathogenic variant. However, most individuals diagnosed with pancreatic cancer who have a germline pathogenic variant in one of these genes would not have met current guidelines for pancreatic surveillance because of a lack of family history. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors. Methods: Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs. Results: Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers. Conclusions: Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting. [ABSTRACT FROM AUTHOR]

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology. The development of cancer is typically accompanied by changes in the tumor microenvironment that support tumor growth and affect therapy response. Here, the authors show that increased intratumoral temperature is an inherent feature of human pancreatic cancer and contributes to therapy resistance by altering the lipid content of the tumor. [ABSTRACT FROM AUTHOR]

Acinar cell carcinoma (ACC) and pancreatoblastoma (PBL) are rare pancreatic malignancies with acinar differentiation. Proteogenomic profiling of ACC and PBL revealed distinct protein expression patterns compared to pancreatic ductal adenocarcinoma (PDAC) and benign pancreas. ACC and PBL exhibited similarities, with enrichment in proteins related to RNA processing, chromosome organization, and the mitoribosome, while PDACs overexpressed proteins associated with actin-based processes, extracellular matrix, and immune-active stroma. Pathway activity differences in metabolic adaptation, epithelial-to-mesenchymal transition, and DNA repair were characterized between these diseases. PBL showed upregulation of Wnt-CTNNB1 and IGF2 pathways. Seventeen ACC-specific proteins suggested connections to metabolic diseases with mitochondrial dysfunction, while 34 PBL-specific proteins marked this pediatric cancer with an embryonic stem cell phenotype and alterations in chromosomal proteins and the cell cycle. This study provides novel insights into the proteomic landscapes of ACC and PBL, offering potential targets for diagnostic and therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8+ T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms. Methods: Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry. Results: The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8+ T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells. Conclusions: Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) features KRAS mutations in approximately 90% of human cases and excessive stromal response, termed desmoplastic reaction. Oncogenic KRAS drives pancreatic carcinogenesis by acting on both epithelial cells and tumor microenvironment (TME). We have previously shown that Homeodomain-Interacting Protein Kinase 2 (HIPK2) cooperates with KRAS in sustaining ERK1/2 phosphorylation in human colorectal cancers. Here, we investigated whether HIPK2 contributes to oncogenic KRAS-driven tumorigenesis in vivo, in the onset of pancreatic cancer. Methods: We employed an extensively characterized model of KRASG12D-dependent preinvasive PDAC, the Pdx1-Cre;LSL-KRasG12D/+ (KC) mice. In these mice, HIPK2 was inhibited by genetic knockout in the pancreatic epithelial cells (KCH−/−) or by pharmacologic inactivation with the small molecule 5-IodoTubercidin (5-ITu). The development of preneoplastic acinar-to-ductal metaplasia (ADM), intraepithelial neoplasia (PanIN), and their associated desmoplastic reaction were analyzed. Results: In Hipk2-KO mice (KCH−/−), ERK phosphorylation was lowered, the appearance of ADM was slowed down, and both the number and pathologic grade of PanIN were reduced compared to Hipk2-WT KC mice. The pancreatic lesion phenotype in KCH−/− mice was characterized by abundant collagen fibers and reduced number of αSMA+ and pSTAT3+ desmoplastic cells. These features were reminiscent of the recently described human "deserted" sub-TME, poor in cells, rich in matrix, and associated with tumor differentiation. In contrast, the desmoplastic reaction of KC mice resembled the "reactive" sub-TME, rich in stromal cells and associated with tumor progression. These observations were confirmed by the pharmacologic inhibition of HIPK2 in KC mice. Conclusion: This study demonstrates that HIPK2 inhibition weakens oncogenic KRAS activity and pancreatic tumorigenesis providing a rationale for testing HIPK2 inhibitors to mitigate the incidence of PDAC development in high-risk individuals. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of malignancies with worst outcomes among digestive system tumors. Identification of novel biomarkers is of great significance for treatment researches and prognosis prediction of pancreatic cancer patients. Due to OSBPL10 known involvement in oncogenic activity in other tumors, we elucidated the mechanism underlying its contribution to pancreatic cancer progression. We employed data from the Gene Expression Omnibus database to detect the expression of OSBPL10 in normal and pancreatic cancer tissues. A series of assays were conducted to assess the impact of OSBPL10 on the proliferation and metastatic capacities of pancreatic cancer cells and the influence of OSBPL10 on macrophages were evaluated by Flow cytometry. In addition, Co‐immunoprecipitation, mass spectrometry, and western blot assays were utilized to investigate the potential mechanisms of OSBPL10 activity. From our study, OSBPL10 is revealed to be upregulated in pancreatic cancer, with poor prognosis. The overexpression promotes malignant behaviors of pancreatic cancer cells and has an impact on tumor immune microenvironment by stimulating the transformation M1 macrophages into M2 macrophages. Mechanistically, hypoxia induces the expression of OSBPL10 through interaction between hypoxia‐inducible factor 1‐α and the promoter region of OSBPL10. Additionally, OSBPL10 directly bound to CNBP, mediating CNBP expression and ultimately regulating the proliferation and metastasis capacity of pancreatic cancer cells, as well as influencing macrophage polarization. The research emphasized the oncogenic role of OSBPL10 in pancreatic cancer, uncovering key mechanisms involving hypoxia, HIF‐1α, and CNBP. The finding suggests that OSBPL10 is a novel biomarker in pancreatic cancer, making it a potential therapeutic target for intervention in this malignancy. [ABSTRACT FROM AUTHOR]

Objectives: This research aimed to assess the value of radiomics combined with multiple machine learning algorithms in the diagnosis of pancreatic ductal adenocarcinoma (PDAC) lymph node (LN) metastasis, which is expected to provide clinical treatment strategies. Methods: A total of 128 patients with pathologically confirmed PDAC and who underwent surgical resection were randomized into training (n=93) and validation (n=35) groups. This study incorporated a total of 13 distinct machine learning algorithms and explored 85 unique combinations of these algorithms. The area under the curve (AUC) of each model was computed. The model with the highest mean AUC was selected as the best model which was selected to determine the radiomics score (Radscore). The clinical factors were examined by the univariate and multivariate analysis, which allowed for the identification of factors suitable for clinical modeling. The multivariate logistic regression was used to create a combined model using Radscore and clinical variables. The diagnostic performance was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). Results: Among the 233 models constructed using arterial phase (AP), venous phase (VP), and AP+VP radiomics features, the model built by applying AP+VP radiomics features and a combination of Lasso+Logistic algorithm had the highest mean AUC. A clinical model was eventually constructed using CA199 and tumor size. The combined model consisted of AP+VP-Radscore and two clinical factors that showed the best diagnostic efficiency in the training (AUC = 0.920) and validation (AUC = 0.866) cohorts. Regarding preoperative diagnosis of LN metastasis, the calibration curve and DCA demonstrated that the combined model had a good consistency and greatest net benefit. Conclusions: Combining radiomics and machine learning algorithms demonstrated the potential for identifying the LN metastasis of PDAC. As a non-invasive and efficient preoperative prediction tool, it can be beneficial for decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is the sixth leading cause of cancer-related deaths worldwide, primarily due to late-stage diagnosis and limited treatment options. While novel biomarkers and immunotherapies are promising, further research into specific molecular targets is needed. Glycans, which are carbohydrate structures mainly found on cell surfaces, play crucial roles in health and disease. The Thomsen-Friedenreich-related carbohydrate antigen Sialyl-Tn (STn), a truncated O-glycan structure, is selectively expressed in epithelial tumors, including PC. In this study, we performed a comprehensive analysis of STn expression patterns in normal, premalignant, and malignant pancreatic lesions. Additionally, we analyzed the association between STn expression and various clinicopathological features. STn expression was statistically associated with pathological diagnosis; it was absent in normal pancreatic tissue but prevalent in pancreatic carcinoma lesions, including pancreatic ductal adenocarcinoma (PDAC), pancreatic acinar cell carcinoma, and pancreatic adenosquamous carcinoma. Moreover, we found a significant association between STn expression and tumor stage, with higher STn levels observed in stage II tumors compared to stage I. However, STn expression did not correlate with patient survival or outcomes. Furthermore, STn expression was assessed in PDAC patient-derived xenograft (PDX) models, revealing consistent STn levels throughout engraftment and tumor growth cycles. This finding supports the PDX model as a valuable tool for testing new anti-STn therapeutic strategies for PC in clinical setting. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: A choledochal cyst (CC), or biliary cyst, is a congenital or acquired anomaly of the biliary tree. Pancreas divisum (PD) is a rare congenital anomaly due to incomplete fusion of pancreatic ducts, which can complicate the clinical course of choledochal cysts. This rare combination is a surgical management challenge. This report presents the diagnosis and management of a 23-year-old woman with a combined choledochal cyst and pancreas divisum treated with pancreaticoduodenectomy. Case Report: This article presents the case of a 23-year-old woman who presented with severe, stabbing abdominal pain radiating to the back and epigastric tenderness and was diagnosed with pancreatitis. Initial imaging revealed a choledochal cyst, prompting further investigation with ERCP that showed concomitant PD. She was treated via pancreaticoduodenectomy. During the following 9 years, she was hospitalized over 2 dozen times for recurrent pancreatitis. Conclusions: This report presents a complex case of a combined choledochal cyst and pancreas divisum, which was surgically managed by pancreaticoduodenectomy. The association of CC with PD should be suspected in patients with recurrent acute pancreatitis and/or cholangitis with no identifiable cause. Surgical treatment of CC with PD depends on the classification of the CC, and complications can include recurrent pancreatitis, although the prognosis is often favorable. The purpose of this report is to emphasize that pancreaticoduodenectomy is unlikely to provide favorable outcomes for CC with PD, especially considering there is evidence that less extensive surgical interventions produce better outcomes. [ABSTRACT FROM AUTHOR]

Background: Pancreatic Ductal Adenocarcinoma (PDAC) primarily affects older individuals with diminished physiological reserves. The Modified 5-Item Frailty Index (mFI-5) is a novel risk stratification tool proposed to predict postoperative morbidity and mortality. This study aimed to validate the mFI-5 for predicting surgical outcomes in patients undergoing pancreatoduodenectomy (PD) for PDAC. Methods: Our retrospective PDAC database included patients who underwent PD between 2014 and 2023. Patients were stratified by mFI-5 scores (0 best − 5 worst), which assess preoperative CHF, diabetes mellitus, history of COPD or pneumonia, functional health status, and hypertension requiring medication. Associations between mFI-5 scores and outcomes, including postoperative complications and mortality, were analyzed using logistic regression, Cox proportional hazards models, and Kaplan-Meier survival analysis. Results: Among 250 PDAC patients undergoing PD, 142 (56.8%) had mFI-5 scores ≤ 1, and 25 (10%) had scores ≥ 3. No patients had scores > 4. Higher mFI-5 scores correlated with older age (p < 0.001) and tobacco use (p = 0.036). Multivariate analysis identified age (RR 1.02, p = 0.038), ASA class (ASA III; RR 2.61, p < 0.001; ASA IV; RR 2.63, p = 0.026), and moderate alcohol consumption (RR 0.56, p = 0.038) as frailty predictors. An mFI-5 score > 2 independently associated with higher mortality (HR 2.08, p = 0.026). Median overall survival was significantly lower for patients with mFI-5 scores > 2 than for those with scores ≤ 2 (21.3 vs. 42.1 months, p = 0.022). Conclusions: The mFI-5 is a valuable tool for predicting postoperative morbidity and mortality in PDAC patients undergoing PD. Integrating frailty assessment into preoperative evaluations can enhance patient selection and surgical outcomes. Future research should focus on incorporating frailty assessments into surgical planning and patient management to improve outcomes in this vulnerable population. [ABSTRACT FROM AUTHOR]

Introduction: Focal autoimmune pancreatitis (AIP) without elevated serum IgG4 levels presents a diagnostic challenge compared to pancreatic tumors, often leading to surgical intervention. Case Presentation: We report a case of serum IgG4-negative focal AIP type 1 in a 52-year-old male. Despite repeated endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and fine-needle biopsy (FNB), preoperative diagnosis was elusive. Initially, a 30-mm hypoechoic mass in the pancreatic head was detected by ultrasonography, with dynamic computed tomography revealing well-defined borders and homogeneous delayed enhancement. Serum IgG4 levels were within the normal range (115 mg/dL). Two EUS-FNAs and one EUS-FNB failed to provide a definitive diagnosis, leading to suspicion of a solid pseudopapillary neoplasm and subsequent pancreaticoduodenectomy. Postoperative histopathology confirmed focal AIP type 1 with IgG4-positive plasma cells. After 38 months, there is no recurrence, and serum IgG4 levels remain normal. Conclusion: Diagnosis of focal AIP, particularly when serum IgG4 is negative, warrants consideration despite its difficulty. Imaging findings, such as a well-defined mass with homogeneous delayed enhancement, should prompt evaluation for characteristic features like capsule-like rim, pancreatic duct penetration, and biliary tract wall thickening. [ABSTRACT FROM AUTHOR]

Background: The cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers. Methods: A partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model's robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold. Results: In the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction). Conclusions: NALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. Up to now, no specific screening or diagnostic tests are available for early PDAC detection. As a result, most patients are diagnosed with advanced or metastatic disease, which leads to a poor prognosis. In this study, we aimed to evaluate the diagnostic value of urinary CRP (uCRP) alone and in combination with our previously established urine biomarker panel (REG1B, LYVE1 and TFF1) for early detection of PDAC. A total of 534 urine samples from multiple centres were analysed: 93 from healthy individuals, 265 from patients with benign hepatobiliary diseases and 176 from PDAC patients. The uCRP and the urinary biomarker panel were assessed using commercial ELISA assays, while plasma CA19-9 and blood CRP (bCRP) were measured using Roche Cobas platform. Multiple logistic regression and nonparametric Kruskal-Wallis test were used for statistical analysis. An internal validation approach was applied, and the validated AUC estimators were reported to ensure accuracy. A significant difference was observed in the medians of uCRP between healthy and benign controls and PDAC sample groups (p < 0.001). uCRP levels were not dependent on gender and age, as well as cancer stage. When uCRP was combined with the urinary biomarker panel, it achieved AUCs of 0.878 (95% CI: 0.802-0.931), 0.798 (95% CI: 0.738-0.859) and 0.813 (95% CI: 0.758-0.869) in healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC sample groups, respectively. However, adding plasma CA19-9 to the urinary biomarker panel yielded a better performance, with AUCs of 0.978 (95% CI: 0.959-0.996), 0.911 (95% CI: 0.873-0.949) and 0.919 (95% CI: 0.883-0.955) in the healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC comparisons, respectively. In conclusion, we show that measuring CRP in urine is a feasible analytical method, and that uCRP could potentially be a promising biomarker in various diseases including other cancer types. [ABSTRACT FROM AUTHOR]

Highlights: What are the main findings? CP and ARP are common in paediatric populations with varied aetiologies. ERCP is more commonly used compared to EUS in paediatrics and is limited to specialist centres. What is the implication of the main finding? ERCP and EUS are safe and efficacious, with minimal complications in the management of CP and ARP in a paediatric cohort. Indications for both diagnostic and therapeutic EUS are increasing. ERCP and EUS offer a more 'patient-friendly', minimally invasive approach to CP and ARP. Objectives: To evaluate the role of ERCP (endoscopic retrograde cholangio-pancreatography) and EUS (endoscopic ultrasound) and to describe the efficacy and safety of these procedures in a paediatric cohort with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). Methods: All patients (<18 years) undergoing an ERCP or EUS for ARP and CP between January 2008 and December 2022 were included. Data collection included indications for the procedure, technical success, adverse events and outcome data. Results: A total of 222 ERCPs were performed in 98 patients with CP and ARP (60% female, median age 10 years). The commonest indications were a main pancreatic duct stricture (PD) with or without a stone within the main PD. Successful cannulation was achieved in 98% of cases. Improved stricture resolution was demonstrated in 63% of patients. The overall adverse event rate for ERCP was low (n = 8/222, 3.6%). An improvement in abdominal pain was demonstrated in (75/98) 76% of patients. Their Body Mass Index also significantly improved post ERCP (15.5 ± 1.41 vs. 12.9 ± 1.16 kg/m2, p = 0.001). A total of 54 EUS procedures were undertaken in 48 individuals. Moreover, 35 individuals underwent a therapeutic EUS procedure, for which the commonest indication was the drainage of a pancreatic fluid collection. The overall complication rate was low (n = 2.4%) in all EUS cases. Conclusions: ERCP and EUS can be safely and effectively used in a paediatric population with indications analogous to an adult cohort. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PDA) represents the fourth leading cause of cancer-related mortality in the USA. Only 20% of patients present surgically resectable and potentially curable tumors at diagnosis, while 80% are destined for poor survival and palliative chemotherapy. Accordingly, the advancement of innovative and effective therapeutic strategies represents a pivotal medical imperative. It has been demonstrated that targeting the immune system represents an effective approach against several solid tumors. The immunotherapy approach encompasses a range of strategies, including the administration of antibodies targeting checkpoint molecules (immune checkpoint inhibitors, ICIs) to disrupt tumor suppression mechanisms and active immunization approaches that aim to stimulate the host's immune system. While vaccines have proved effective against infectious agents, vaccines for cancer remain an unfulfilled promise. Vaccine-based therapy targeting tumor antigens has the potential to be a highly effective strategy for initiating and maintaining T cell recognition, enhancing the immune response, and ultimately promoting cancer treatment success. In this review, we examined the most recent clinical trials that employed diverse vaccine types to stimulate PDA patients' immune systems, either independently or in combination with chemotherapy, radiotherapy, ICIs, and monoclonal antibodies with the aim of ameliorating PDA patients' quality of life and extend their survival. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has a high recurrence rate even after radical resection because of subclinical tumors. To manage them, a reliable biomarker that can indicate the presence of subclinical tumors and predict their chemosensitivity is required. This study aimed to identify a miRNA as a biomarker that can be used to individualize postoperative adjuvant chemotherapy using postoperative peripheral blood samples. Integrating miRNA microarray data from the blood of 18 patients with PDAC and the in vitro results regarding the phenotypes of chemoresistant PDAC cells, a candidate miRNA was identified. The relationships between candidate miRNA expression and chemosensitivity were examined in vitro and in clinical samples from other cohorts of 33 patients with recurrence. Comprehensive analyses of blood samples detected 5 candidate miRNAs. Of these, miR-26a-5p was considered a candidate biomarker of chemosensitive phenotypes. In validation experiments, chemosensitivity was inversely correlated with miR-26a-5p expression in vitro. Moreover, the ability of miR-26a-5p to predict chemosensitivity was clinically evaluated using blood samples. Patients with high miR-26a-5p expression in the blood after radical resection exhibited a significantly longer survival time after recurrence. Thus, we concluded that miR-26a-5p is a potentially useful biomarker for managing patients with PDAC, especially those undergoing adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: A pancreatic duct rupture can lead to various complications such as a fistula, pseudocyst, ascites, or walled-off necrosis. Due to pleural effusion, pancreaticopleural fistula typically causes dyspnea and chest pain. Leaks of enzyme-rich pancreatic fluid forming a pleural effusion can be verified in a thoracocentesis following radiological imaging such as computed tomography or magnetic resonance tomography. While management strategies range from a conservative to endoscopic and surgical approach, we report a case with successful minimally invasive treatment of pancreaticopleural fistula and effusion. Case presentation: We present a case of a patient with pancreaticopleural fistula and successful minimally invasive surgical treatment. A 62-year old Caucasian man presented with acute chest pain and dyspnea. A computed tomography scan identified a left-sided cystoid formation, extending from the abdominal cavity into the left hemithorax with concomitant pleural effusion. Pleural effusion analysis indicated significantly elevated pancreatic enzymes. Magnetic resonance cholangiopancreatography revealed a rupture of the pancreatic duct and nearby fluid accumulation. Endosonography later confirmed proximity to the tail of the pancreas, suggesting a pancreatic pseudocyst with visible tract into the pancreas. We assumed a pancreatic duct rupture with a fistula from the tail of the pancreas transdiaphragmatically into the left hemithorax with a commencing pleural empyema. A visceral and parietal decortication on the left hemithorax and a laparoscopic distal pancreatectomy with splenectomy was performed. The suspected diagnosis of a fistula arising from the pancreatic duct was confirmed histologically. Conclusion: Pancreaticopleural fistulas often have a long course and may remain undiagnosed for a long time. At this point diagnostic management and therapy demand a high level of expertise. In instances of unclear symptomatic pleural effusion, considering an abdominal focus is crucial. If endoscopic treatment is not feasible, minimally invasive surgery should strongly be considered, especially when located in the distal pancreas. [ABSTRACT FROM AUTHOR]

Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy. [ABSTRACT FROM AUTHOR]

AbstractPancreatic ductal adenocarcinoma remains a highly aggressive and untreatable cancer. There is a need to develop a new PDAC-associated antigen-targeting drug delivery system to tackle this disease. We validated choosing ZIP4 as a putative target in PDAC theranostics. We developed a nanosystem composed of a fluorescent polystyrene core coated with gold nanoparticles onto which a ZIP4-specific polyclonal antibody is attached. The polystyrene core’s fluorescence properties allow the nanosystem tracking by intravital imaging. We also developed two ZIP4-expressing cell lines by stably transfecting HEK293 and RWP1 cells with a ZIP4-coding plasmid that simultaneously provides cells with puromycin resistance. We studied the cell internalisation of the as-synthesised nanoparticles and demonstrated that ZIP4-expressing HEK293 and ZIP4-expressing RWP1 cells tended to take up more ZIP4-targeting nanoparticles. Moreover, we observed that ZIP4-targeting nanoparticles accumulated more in ZIP4-expressing HEK293 and RWP1 tumours when injected intravenously in a subcutaneous xenograft and an orthotopic in vivo model, respectively. Furthermore, the administration of these nanoparticles did not induce any significant systemic toxicity as determined by histological analysis of all organs. Altogether, these results provide the first evidence of the feasibility of using a ZIP4-targeting nanosystem further to design efficient therapeutic and diagnostic tools for PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly metastatic potential and a heterogeneous tumor microenvironment. It exhibits limited sensitivity to conventional therapies, necessitating a deeper understanding of its pathogenesis. The role of the intratumoral microbiome in regulating cancer development in PDAC has been the subject of debate. Previous investigations into intra-tumor microbiomes have yielded uncertain results due to sample size limitations and insufficient decontamination procedures. Further research is imperative to elucidate the intricate relationship between intra-tumor microbiomes, the immune landscape of PDAC, and overall prognosis. Results: Our findings revealed that the intratumor microbiota in PDAC tissue exhibited lower diversity and distinct communities compared to non-tumor tissues. The top microorganisms distinguishing between patients with long or short survival were used to construct the risk signature. We found that Stenotrophomonas is implicated in short survival of PDAC patients, while Neorickettia and Mediterraneibacter are correlated with long survival. This microbiome-based PDAC subtyping, grounded in prognosis-related signatures, exhibited significant correlations with distinct clinical prognoses and immune microenvironments. Microorganisms associated with negative prognoses were linked to pro-tumor immune activation, while those associated with positive prognoses were linked to anti-tumor immune response activation and a more favorable prognosis. Conclusions: Our PDAC subtyping approach, based on a microbiome-derived prognostic risk signature, unveiled compelling associations between the PDAC microbiota and disparities in both clinical prognosis and the tumor microenvironment. These findings suggest that microbiota may serve as a promising biomarker for predicting the prognosis of PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) presents a fatal clinical challenge characterized by a dismal 5-year overall survival rate, primarily due to the lack of early diagnosis and limited therapeutic efficacy. Immunotherapy, a proven success in multiple cancers, has yet to demonstrate significant benefits in PDAC. Recent studies have revealed the immunosuppressive characteristics of the PDAC tumor microenvironment (TME), including immune cells with suppressive properties, desmoplastic stroma, microbiome influences, and PDAC-specific signaling pathways. In this article, we review recent advances in understanding the immunosuppressive TME of PDAC, TME differences among various mouse models of pancreatic cancer, and the mechanisms underlying resistance to immunotherapeutic interventions. Furthermore, we discuss the potential of targeting cancer cell-intrinsic pathways and TME components to sensitize PDAC to immune therapies, providing insights into strategies and future perspectives to break through the barriers in improving pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: To construct a CT-based diagnostic nomogram for distinguishing grade 3 pancreatic neuroendocrine tumors (G3 PNETs) from pancreatic ductal adenocarcinomas (PDACs) and assess their respective survival outcomes. Methods: Patients diagnosed with G3 PNETs (n = 30) and PDACs (n = 78) through surgery or biopsy from two medical centers were retrospectively identified. Demographic and radiological information, including age, gender, tumor diameter, shape, margin, dilatation of pancreatic duct, and invasive behavior, were carefully collected. A nomogram was established after univariate and multivariate logistic regression analyses. The Kaplan–Meier survival was performed to analyze their survival outcomes. Results: Factors with a p-value <0.05, including age, CA 19-9, pancreatic duct dilatation, irregular shape, ill-defined margin, pancreatic atrophy, combined pancreatitis, arterial/portal enhancement ratio, were included in the multivariate logistic analysis. The independent predictive factors, including age (OR, 0.91; 95% CI, 0.85–0.98), pancreatic duct dilatation (OR, 0.064; 95% CI, 0.01–0.32), and portal enhancement ratio (OR, 1,178.08; 95% CI, 5.96–232,681.2) were determined to develop a nomogram. The internal calibration curve and decision curve analysis demonstrate that the nomogram exhibits good consistency and discriminative capacity in distinguishing G3 PNETs from PDACs. Patients diagnosed with G3 PNETs exhibited considerably better overall survival outcomes compared to those diagnosed with PDACs (median survival months, 42 vs. 9 months, p < 0.001). Conclusions: The nomogram model based on age, pancreatic duct dilatation, and portal enhancement ratio demonstrates good accuracy and discriminative ability effectively predicting the probability of G3 PNETs from PDACs. Furthermore, patients with G3 PNETs exhibit better prognosis than PDACs. [ABSTRACT FROM AUTHOR]

Objective: To delineate the risk factors and causes of unplanned reoperations within 30 days following laparoscopic pancreaticoduodenectomy (LPD). Methods: A retrospective study reviewed 311 LPD patients at Ningbo Medical Center Li Huili Hospital from 2017 to 2024. Demographic and clinical parameters were analyzed using univariate and multivariate analyses, with P < 0.05 indicating statistical significance. Results: Out of 311 patients, 23 (7.4%) required unplanned reoperations within 30 days post-LPD, primarily due to postoperative bleeding (82.6%). Other causes included anastomotic leakage, abdominal infection, and afferent loop obstruction. The reoperation intervals varied, with the majority occurring within 0 to 14 days post-surgery. Univariate analysis identified significant risk factors: diabetes, liver cirrhosis, elevated CRP on POD-3 and POD-7, preoperative serum prealbumin < 0.15 g/L, prolonged operation time, intraoperative bleeding > 120 ml, vascular reconstruction, soft pancreatic texture, and a main pancreatic duct diameter =3 mm (all P < 0.05). Multivariate analysis confirmed independent risk factors: pre-operative serum prealbumin < 0.15 g/L (OR = 3.519, 95% CI 1.167-10.613), CRP on POD-7 (OR = 1.013, 95% CI 1.001-1.026), vascular reconstruction (OR = 9.897, 95% CI 2.405-40.733), soft pancreatic texture (OR = 5.243, 95% CI 1.628-16.885), and a main pancreatic duct diameter =3 mm (OR = 3.462, 95% CI 1.049-11.423), all associated with unplanned reoperation within 30 days post-LPD (all P < 0.05). Conclusion: Postoperative bleeding is the primary cause of unplanned reoperations after LPD. Independent risk factors, confirmed by multivariate analysis, include low pre-operative serum prealbumin, elevated CRP on POD-7, vascular reconstruction, soft pancreatic texture, and a main pancreatic duct diameter of =3 mm. Comprehensive peri-operative management focusing on these risk factors can reduce the likelihood of unplanned reoperations and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1–L8) and Pt(II) complexes (C1–C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1–C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1–C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway. [ABSTRACT FROM AUTHOR]