Pancreatic Cancer (PC) is a highly aggressive tumor that is mainly diagnosed at later stages. Various imaging technologies, such as CT, MRI, and EUS, possess limitations in early PC diagnosis. Therefore, this review article explores the various innovative biomarkers for PC detection, such as DNA methylation, Noncoding RNAs, and proteomic biomarkers, and the role of AI in PC detection at early stages.

Innovative biomarkers, such as DNA methylation genes, show higher specificity and sensitivity in PC diagnosis. Additionally, various non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs, show high diagnostic accuracy and serve as diagnostic and prognostic biomarkers. Additionally, proteomic biomarkers retain higher diagnostic accuracy in different body fluids. Apart from this, the utilization of AI showed that AI surpassed the radiologist's diagnostic performance in PC detection.

The combination of AI and advanced biomarkers can revolutionize early PC detection. However, large-scale, prospective studies are needed to validate its clinical utility. Further. standardization of biomarker panels and AI algorithms is a vital step toward their reliable applications in early PC detection, ultimately improving patient outcomes. [Figure: see text].

Pancreatic cancer (PC) is becoming one of the most serious health problems at present, but its causes and risk factors are still unclear. One of the drivers in pancreatic carcinogenesis is altered genomic (DNA) integrity with subsequent genomic instability in cancer cells. The latter comprises a) DNA damage response and DNA repair mechanisms, b) DNA replication and mitosis, c) epigenetic regulation, and d) telomere maintenance. In our review we addressed the above aspects in relation to the most abundant and severe form of PC, pancreatic ductal adenocarcinoma (PDAC). In summary, the interactions between the DNA damage response, telomere homeostasis and mitotic regulation are not comprehensively understood at present, including the epigenetic factors entering the trait of genomic stability maintenance. In addition, the complexity of telomere homeostasis in relation to PDAC risk, prognosis and prediction also warrants further investigations.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor. Surgical resection is the most promising therapeutic strategy for PDAC, and how to improve the survival rate remains a vital key point. This study aimed to establish and validate a nomogram for predicting the prognosis of resected PDAC.

A total of 174 patients with PDAC who underwent surgical resection at Lanzhou University Second Hospital and the First Affiliated Hospital of Zhengzhou University from January 2012 to July 2022 were enrolled. The clinicopathological characteristics and survival data were analyzed by R software (version 4.1.3). Univariate and multivariate Cox regression analyses were used to analyze the effects of clinicopathological characteristics on overall survival (OS).

Multivariate Cox regression showed that carbohydrate antigen 19-9 (CA19-9) ≥ 476 U/mL, carbohydrate antigen 125 (CA125) ≥ 32 U/mL, fasting blood glucose (FBG) < 6.86 mmol/L, aspartate aminotransferase (AST) ≥ 107 U/L, positive surgical margin, and more than 4 cycles of postoperative chemotherapy were independent prognostic factors for OS. Patients were divided into the high-risk and low-risk groups based on the median risk score calculated by multivariate Cox regression analysis. Kaplan-Meier survival curves revealed that the 5-year survival rates of the high-risk and low-risk groups in the training cohort were 5.79% and 24.3%, respectively, and those in the validation cohort were 0 and 19.0%, respectively (P < 0.05). Receiver operating characteristic (ROC) curve analysis revealed that area under the ROC curve (AUC) of the risk score in the training set and the validation set were 0.855 and 0.838, respectively. The C-indexes of the nomogram in the training set and validation set were 0.788 (95% CI: 0.745-0.831) and 0.773 (95% CI: 0.718-0.828), respectively.

We developed a nomogram that predicts OS in patients with resected PDAC, and the validation results showed that the nomogram model had a strong predictive ability. Particularly, FBG < 6.86 mmol/L and more than 4 cycles of postoperative chemotherapy can predict better OS of PDAC after surgery.

The peripheral nervous system (PNS) orchestrates organ function in health and disease. Most cancers, including pancreatic ductal adenocarcinoma (PDAC), are infiltrated by PNS neurons, and this contributes to the complex tumour microenvironment (TME)1,2. However, neuronal cell bodies reside in various PNS ganglia, far from the tumour mass. Thus, cancer-innervating or healthy-organ-innervating neurons are lacking in current tissue-sequencing datasets. To molecularly characterize pancreas- and PDAC-innervating neurons at single-cell resolution, we developed Trace-n-Seq. This method uses retrograde tracing of axons from tissues to their respective ganglia, followed by single-cell isolation and transcriptomic analysis. By characterizing more than 5,000 individual sympathetic and sensory neurons, with about 4,000 innervating PDAC or healthy pancreas, we reveal novel neuronal cell types and molecular networks that are distinct to the pancreas, pancreatitis, PDAC or melanoma metastasis. We integrate single-cell datasets of innervating neurons and the TME to establish a neuron-cancer-microenvironment interactome, delineate cancer-driven neuronal reprogramming and generate a pancreatic-cancer nerve signature. Pharmacological denervation induces a pro-inflammatory TME and increases the effectiveness of immune-checkpoint inhibitors. The taxane nab-paclitaxel causes intratumoral neuropathy, which attenuates PDAC growth and, in combination with sympathetic denervation, results in synergistic tumour regression. Our multi-dimensional data provide insights into the networks and functions of PDAC-innervating neurons, and support the inclusion of denervation in future therapies.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with increasing incidence and low survival rate, primarily due to the late detection of the disease. Radiomics has demonstrated its utility in recognizing patterns and anomalies not perceptible to the human eye. This systematic literature review aims to assess the application of radiomics in the analysis of pancreatic parenchyma images to identify early indicators predictive of PDAC.

A systematic search of original research papers was performed on three databases: PubMed, Embase, and Scopus. Two reviewers applied the inclusion and exclusion criteria, and one expert solved conflicts for selecting the articles. After extraction and analysis of the data, there was a quality assessment of these articles using the Methodological Radiomics Score (METRICS) tool. The METRICS assessment was carried out by two raters, and conflicts were solved by a third reviewer.

Ten articles for analysis were retrieved. CT scan was the diagnostic imaging used in all the articles. All the studies were retrospective and published between 2019 and 2024. The main objective of the articles was to generate radiomics-based machine learning models able to differentiate pancreatic tumors from healthy tissue. The reported diagnostic performance of the model chosen yielded very high results, with a diagnostic accuracy between 86.5% and 99.2%. Texture and shape features were the most frequently implemented. The METRICS scoring assessment demonstrated that three articles obtained a moderate quality, five a good quality, and, finally, two articles yielded excellent quality. The lack of external validation and available model, code, and data were the major limitations according to the qualitative assessment.

There is high heterogeneity in the research question regarding radiomics and pancreatic cancer. The principal limitations of the studies were mainly due to the nature of the trials and the considerable heterogeneity of the radiomic features reported. Nonetheless, the work in this field is promising, and further studies are still required to adopt radiomics in the early detection of PDAC.

To explore the potential of serum exosomal miRNAs as novel biomarkers for pancreatic ductal adenocarcinoma (PDAC).

Serum exosomal miRNAs were screened and verified by microarray analysis and quantitative real-time PCR (qRT-PCR) in patients with PDAC and healthy controls. The correlation between the clinical characteristics of PDAC and candidate exosomal miRNAs was analyzed, and the diagnostic performance of the candidate biomarkers was evaluated.

Serum exosomal miR-7977 and miR-451a were significantly upregulated in PDAC patients compared with healthy controls, and the levels of miR-7977 and miR-451a in serum exosomes were closely associated with the clinical stage and metastasis of PDAC patients. The area under curve (AUC) values of serum exosomal miR-7977 and miR-451a for PDAC were 0.825 and 0.804 in the training set and 0.796 and 0.830 in the validation set, respectively. A biomarker panel consisting of these two miRNAs resulted in a diagnostic power with an AUC of 0.901 in the training set and 0.918 in the validation set.

Serum exosomal miR-7977 and miR-451a might be diagnostic biomarkers for PDAC. These two miRNAs, when combined, exhibit optimal diagnostic performance.

Cancers are a class of disorders that entail uncontrollably unwanted cell development with dissemination. One in six fatalities globally is attributed to cancer, a global health issue. The analysis of the entire DNA sequence and how it expresses itself in tumor cells is known as cancer genomics. The development of novel cancer treatments has been facilitated because of the genomics method. COL10A1 gene, a short chain collagen, and an interstitial matrix component, acts as a predictive biomarker for cancer prognosis. Recognizing the fundamental consequences of mutations in the COL10A1 gene and its expression in cancer is crucial. Analyzing the COL10A1 gene expression with a data set and gene expression patterns shows the level of display of the tumor. Examining the therapeutic techniques of COL10A1 gene expression leads to early detection, screening, radiation therapy, and advanced developments. This review highlights the value of the COL10A1 gene in breast, gastric, pancreatic, lung, and colorectal cancers, emphasizing its role in gene expression patterns and therapeutic techniques.

Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.

Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.

Pancreatic adenocarcinoma remains a challenging malignancy with a poor prognosis. Radiofrequency ablation (RFA) has emerged as a potential treatment for unresectable pancreatic adenocarcinoma (UPAC) aimed at improving survival and quality of life. This meta-analysis and systematic review evaluates the outcomes of RFA in UPAC.

A comprehensive search was conducted in MEDLINE, Embase, Scopus, and Cochrane Central databases from inception to October 2023. Studies included patients over 18 years with UAPC undergoing RFA. Survival rates and complication rates were assessed as primary outcomes. Data were pooled using random-effects models, and heterogeneity was assessed with I2 statistics. ROBINS-I tool was used for quality assessment.

Nine studies encompassing 265 patients met the inclusion criteria. The mean age was 64.5 years, with 42.5% female participants. Survival analysis showed that at 30 days post-RFA, the mortality rate was 3.3%. At 6 months, the mortality rate was 20.9%, increasing to 50.4% at 12 months. At 24 months, the mortality rate was 61.9%. The pooled mean survival period at 12 and 24 months was 9.18 months and 14.26 months, respectively. Overall, 78.4% of patients died during the follow-up period, with an overall mean survival period of 12.27 months. The most common were intra-abdominal (10.1%), pancreatic (9.8%), and hepatobiliary (6.7%) complications.

RFA shows potential in the management of unresectable pancreatic adenocarcinoma, with a manageable safety profile. However, the high heterogeneity and risk of bias in available studies highlight the need for well-designed randomized controlled trials to confirm these findings and establish standardized protocols.

Background: Pancreatic cancer is among the malignancies with the poorest prognosis, largely due to its aggressive nature and resistance to conventional therapies. Case Summary: This report describes the case of a 69-year-old male patient with stage IV primary lung adenocarcinoma presenting with high levels of programmed death-ligand 1 (PD-L1). Simultaneously, abdominal computed tomography (CT) showed a dilated pancreatic duct at the level of the pancreatic head and a hypodense lesion in the uncinate process involving the superior mesenteric artery. Fine-needle aspiration (FNA) of the pancreatic lesions was negative. After three cycles of chemoimmunotherapy, positron emission tomography-computed tomography (PET-CT) showed complete remission of the lung nodules, lymphadenopathy, and pleural thickening, as well as a decrease in the size of the pancreatic lesion. After another six months, a PET-CT scan showed a focal increased uptake in the pancreatic mass in the same location, indicating disease progression. A core biopsy of the pancreatic tumor showed atypical spindle cell morphology with positive staining for vimentin, characteristic of mesenchymal differentiation with no apparent epithelial features. Comprehensive molecular profiling through Caris Molecular Intelligence® revealed four genes with actionable mutations in the pancreatic tissue, including KRAS (p.G12D) and TP53 (p.R175H). These molecular findings suggested the diagnoses of sarcomatoid carcinoma and conventional pancreatic ductal adenocarcinoma with epithelial-mesenchymal transition. Primary mesenchymal tumors and neuroendocrine neoplasms were excluded because immunohistochemistry was negative for anaplastic lymphoma kinase (ALK), smooth muscle actin (SMA), desmin, CD34, signal transducer and activator of transcription 6 (STAT6), S100, HMB45, CD117, discovered on GIST-1 (DOG1), CD56, progesterone, and synaptophysin. However, despite multiple rounds of systemic chemotherapy, immunotherapy, and radiation, his pancreatic disease rapidly deteriorated and metastasized to the liver and bone. Conclusions: Despite multiple lines of treatment, the patient's condition worsened and he succumbed to his pancreatic malignancy. This study highlights the clinical characteristics, diagnosis, and treatment of rare pancreatic cancer, emphasizing the importance of molecular testing and histopathological biomarkers in personalizing treatment. It also provides insights into promising therapeutic approaches for similar cases with an unusual presentation.

The most frequently invaded margins on pancreatoduodenectomy specimens for pancreatic ductal adenocarcinoma are vascular margins, particularly the superior mesenteric artery (or mesopancreatic) margin. Due to limited exploration of the radiological aspect of the mesopancreas, the aim of this study was to evaluate mesopancreatic infiltration through imaging of patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy, to correlate these findings with histopathology and evaluate their impact on survival.

Data for all patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma from 2015 to 2021 were reviewed, including review of surgical margin histopathology and blinded review of preoperative diagnostic imaging. According to qualitative radiological assessment, the mesopancreas was characterized as having normal fat, fat stranding, or solid infiltration. Survival data were analysed using Cox regression.

A total of 149 patients were included. At baseline imaging, mesopancreatic fat stranding or solid infiltration was present in 47 patients (31.5%) and 20 patients (13.4%) respectively. Median overall survival and disease-free survival were significantly lower with mesopancreatic solid infiltration (17 and 8 months) compared with normal fat (30 and 14 months) and fat stranding (29 and 16 months) (P = 0.017 and 0.028 respectively). In multivariable analysis, pathological tumour size was an independent prognostic factor for overall survival, and tumour location in the uncinate process and pathological tumour size were independent prognostic factors for disease-free survival.

At diagnostic imaging, solid infiltration (but not fat stranding) of the mesopancreas is associated with a poor prognosis for pancreatic ductal adenocarcinoma patients who undergo pancreatoduodenectomy. Pathological tumour size significantly influences the prediction of overall survival, and tumour location in the uncinate process and pathological tumour size significantly influence the prediction of disease-free survival, suggesting further exploration of underlying mechanisms related to retroperitoneal tumoral invasion of vascular margins and the mesopancreas.

Pancreatic ductal adenocarcinoma (PDAC) can be classified into distinct histological subtypes based on the WHO nomenclature. The aim of this study was to compare the prognosis of conventional PDAC (cPDAC) against the other histological variants at the population level.

The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients with microscopically confirmed PDAC. These patients were divided into 9 histological subgroups. Overall survival was assessed using the Kaplan-Meier method and Cox regression models stratified by tumor histology.

A total of 159,548 patients with PDAC were identified, of whom 95.9% had cPDAC, followed by colloid carcinoma (CC) (2.6%), adenosquamous carcinoma (ASqC) (0.8%), signet ring cell carcinoma (SRCC) (0.5%), undifferentiated carcinoma (UC) (0.1%), undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) (0.1%), hepatoid carcinoma (HC) (0.01%), medullary carcinoma of the pancreas (MCP) (0.006%) and pancreatic undifferentiated carcinoma with rhabdoid phenotype (PUCR) (0.003%). Kaplan-Meier curves showed that PUCR had the worst prognosis (median survival: 2 months; 5-year survival: 0%), while MCP had the best prognosis (median survival: 41 months; 5-year survival: 33.3%). In a multivariable Cox model, several histological subtypes (i.e. CC, ASqC, SRCC, UCOGC) were identified as independent predictors of overall survival when compared to cPDAC.

PDAC is a heterogenous disease and accurate identification of variant histology is important for risk stratification, as these variants may have different biological behavior.

Mucinous cystic neoplasm (MCN) is one of the precursor lesions of pancreatic ductal adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to examine the presence of short telomeres in promoting the tumorigenesis of MCN by measuring telomere lengths in distinct components of MCN, including the mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma. A total of 45 patients with MCN (30 pancreatic and 15 hepatic cases) were obtained. Quantitative telomere-specific fluorescent in situ hybridization was performed to measure the telomere length of specific cell types within MCNs, including mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma, as well as normal ductal epithelium and adenocarcinoma. Relative telomere lengths tended to decrease between normal ductal epithelium, ovarian-type stroma, non-mucinous lining epithelium, mucinous lining epithelium, and adenocarcinoma regardless of the involved organs. Among the analyzed cell types, relative telomere lengths were significantly different between normal ductal epithelium (3.31 ± 0.78), ovarian-type stroma (2.90 ± 0.93), non-mucinous lining epithelium (2.84 ± 0.79), mucinous lining epithelium (2.49 ± 0.93), and adenocarcinoma (1.19 ± 0.59), respectively (P < 0.001, mixed-effects model). As expected, no difference in relative telomere lengths was observed between normal ductal epithelium and ovarian-type stroma; however, significant differences were observed in pair-wise comparisons between ovarian-type stroma vs. non-mucinous lining epithelium (P = 0.001), non-mucinous lining epithelium vs. mucinous lining epithelium (P = 0.005), and mucinous lining epithelium vs. adenocarcinoma (P < 0.001). These findings suggest gradual telomere shortening occurs in the tumorigenesis of MCN, which may have important implications for the progression of this disease.

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.

The highly metastatic nature of pancreatic ductal adenocarcinoma (PDAC) and the difficulty to achieve favorable patient outcomes emphasize the need for novel therapeutic solutions. For preclinical evaluations, genetically engineered mouse models are often used to mimic human PDAC but frequently fail to replicate synchronous development and metastatic spread. This study aimed to develop a transplantation model to achieve synchronous and homogenous PDAC growth with controlled metastatic patterns in the liver.

To generate an orthotopic PDAC model, the DT6606 cell line was injected into the pancreas head of C57BL/6 mice, and their survival was monitored over time. To generate a heterotopic transplantation model, growing doses of three PDAC cell lines (DT6606, DT6606lm, and K8484) were injected into the portal vein of mice. Magnetic resonance imaging (MRI) was used to monitor metastatic progression, and histologic analysis was performed.

Orthotopically injected mice succumbed to the tumor within an 11-week period (average survival time, 78.2 ± 4.45 days). Post-mortem examinations failed to identify liver metastasis. In the intraportal model, 2 × 105 DT6606 cells resulted in an absence of liver metastases by day 21, whereas 5 × 104 DT6606lm cells and 7 × 104 K8484 cells resulted in steady metastatic growth. Higher doses caused significant metastatic liver involvement. The use of K8484 cells ensured the growth of tumors closely resembling the histopathologic characteristics of human PDAC.

This report details the authors' efforts to establish an "optimal" murine model for inducing metastatic PDAC, which is critical for advancing our understanding of the disease and developing more effective treatments.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid malignancy with low 5-year survival and limited treatment options. We conducted an unbiased screening using FDA-approved drug and demonstrated that cetylpyridinium chloride (CPC), a component commonly found in mouthwash and known for its robust bactericidal and antifungal attributes, exhibits anticancer activity against human PDAC cells. CPC inhibited PDAC cell growth and proliferation by inducing paraptosis, rather than apoptosis. Mechanistically, CPC induced paraptosis through the initiation of endoplasmic reticulum stress, leading to the accumulation of misfolded proteins. Subsequently, the endoplasmic reticulum stress to nucleus signaling 1 (ERN1)-mitogen-activated protein kinase kinase kinase 5 (MAP3K5)-p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated, ultimately culminating in the induction of paraptosis. In vivo experiments, including those involving patient-derived xenografts, orthotopic models, and genetically engineered mouse models of PDAC, provided further evidence of CPC's effectiveness in suppressing the growth of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death and presents the lowest 5-year survival rate of any form of cancer in the US. Only 20% of PDAC patients are suitable for surgical resection and adjuvant chemotherapy, which remains the only curative treatment. Chemotherapeutic and gene therapy treatments are associated with adverse effects and lack specificity/efficacy. In this study, we assess the oncolytic potential of immuno-oncolytic tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP-1 or mCCL2) and mouse interleukin (mIL)-2 in human pancreatic BxPc-3 cells using immunocompromised and CD-3+ T-cell-reconstituted mice. Intratumoral treatment with TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 resulted in a regression in BxPc-3 xenograft volume compared to control in immunocompromised mice; mCCL-2 expressing TPV OV resulted in a significant difference from control at p < 0.05. Histological analysis of immunocompromised mice treated with TPV/∆66R/mCCL2 or TPV/∆66R/mIL-2 demonstrated multiple biomarkers indicative of increased severity of chronic, active inflammation compared to controls. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 demonstrated a therapeutic effect via regression in BxPc-3 tumor xenografts. Considering the enhanced oncolytic potency of TPV recombinants demonstrated against PDAC in this study, further investigation as an alternative or combination treatment option for human PDAC may be warranted.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult to treat tumors. The Src (sarcoma) inhibitor dasatinib (DASA) has shown promising efficacy in preclinical studies of PDAC. However, clinical confirmation could not be achieved. Overall, our aim was to deliver arguments for the possible reinitiating clinical testing of this compound in a biomarker-stratifying therapy trial for PDAC patients. We tested if the nanofunctionalization of DASA can increase the drug efficacy and whether certain Src members can function as clinical predictive biomarkers.

Methods include manufacturing of poly(vinyl alcohol) stabilized gold nanoparticles and their drug loading, dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, Zeta potential measurement, sterile human cell culture, cell growth quantification, accessing and evaluating transcriptome and clinical data from molecular tumor dataset TCGA, as well as various statistical analyses.

We generated homo-dispersed nanofunctionalized DASA as an AuNP@PVA-DASA conjugate. The composite did not enhance the anti-growth effect of DASA on PDAC cell lines. The cell model with high LYN expression showed the strongest response to the therapy. We confirm deregulated Src kinetome activity as a prevalent feature of PDAC by revealing mRNA levels associated with higher malignancy grade of tumors. BLK (B lymphocyte kinase) expression predicts shorter overall survival of diabetic PDAC patients.

Nanofunctionalization of DASA needs further improvement to overcome the therapy resistance of PDAC. LYN mRNA is augmented in tumors with higher malignancy and can serve as a predictive biomarker for the therapy resistance of PDAC cells against DASA. Studying the biological roles of BLK might help to identify underlying molecular mechanisms associated with PDAC in diabetic patients.

Neoadjuvant therapy is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis, allysine residues are formed on collagen proteins by the action of lysyl oxidases. Here, we report the application of an allysine-targeted molecular MRI probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of neoadjuvant therapy with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, whereas no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes. Significance: Allysine-targeted molecular MRI can quantify fibrogenesis in pancreatic tumors and predict response to chemotherapy, which could guide rapid clinical management decisions by differentiating responders from nonresponders after treatment initiation.

Pancreatic cancer has one of the worst prognoses among all malignancies and few available treatment options. Patient-derived xenografts can be used to develop personalized therapy for pancreatic cancer. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) may provide a powerful alternative to surgery for obtaining sufficient tissue for the establishment of patient-derived xenografts. In this study, EUS-FNA samples were obtained for 30 patients referred to the Ottawa Hospital, Ottawa, Ontario, Canada. These samples were used for xenotransplantation in NOD-SCID mice and for genetic analyses. The gene expression of pancreatic-cancer-relevant genes in xenograft tumors was examined by immunohistochemistry. Targeted sequencing of both the patient-derived tumors and xenograft tumors was performed. The xenografts' susceptibility to oncolytic virus infection was studied by infecting xenograft-derived cells with VSV∆51-GFP. The xenograft take rate was found to be 75.9% for passage 1 and 100% for passage 2. Eighty percent of patient tumor samples were successfully sequenced to a high depth for 42 cancer genes. Xenograft histological characteristics and marker expression were maintained between passages. All tested xenograft samples were susceptible to oncoviral infection. We found that EUS-FNA is an accessible, minimally invasive technique that can be used to acquire adequate pancreatic cancer tissue for the generation of patient-derived xenografts and for genetic sequencing.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment methods. Long non-coding RNAs (lncRNAs) have been found involved in tumorigenic and progression. The present study revealed that LINC01133, a fewly reported lncRNA, was one of 16 hub genes that could predict PDAC patients' prognosis. LINC01133 was over-expressed in PDAC tumors compared to adjacent pancreas and could promote PDAC proliferation and metastasis in vitro and in vivo, as well as inhibit PDAC apoptosis. LINC01133 expression positively correlated to secreted phosphoprotein 1 (SPP1) expression, leading to an enhanced epithelial-mesenchymal transition (EMT) process. LINC01133 bound with actin-related protein 3 (Arp3), the complex reduced SPP1 mRNA degradation which increased SPP1 mRNA level, ultimately leading to PDAC proliferation. This research revealed a novel mechanism of PDAC development and provided a potential prognosis indicator that may benefit PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of death in the United States and is expected to be ranked second in the next 10 years due to poor prognosis and a rising incidence. Distant metastatic PDAC is associated with the worst prognosis among the different phases of PDAC. The diagnostic options for PDAC are convenient and available for staging, tumor response evaluation, and management of resectable or borderline resectable PDAC. However, imaging is crucial in PDAC diagnosis, monitoring, resectability appraisal, and response evaluation. The advancement of medical technologies is evolving, hence the use of imaging in PDAC treatment options has grown as well as the utilization of ctDNA as a tumor marker. Treatment options for metastatic PDAC are minimal with the primary goal of therapy limited to symptom relief or palliation, especially in patients with low functional capacity at the point of diagnosis. Molecular profiling has shown promising potential solutions that would push the treatment boundaries for patients with PDAC. In this review, we will discuss the latest updates from evidence-based guidelines regarding diagnosis, therapy response evaluation, prognosis, and surveillance, as well as illustrating novel therapies that have been recently investigated for PDAC, in addition to discussing the molecular profiling advances in PDAC.

Pancreatic cancer (PC) is a lethal cancer with poor prognoses. Identifying and characterizing pancreatic cystic lesions (PCLs) in the early detection and follow-up plans is thought to help detect pancreatic malignancy. Besides, the molecular features of PCLs are thought to unravel potentials for targeted therapies. We present a narrative review of the existing literature on the role of PCLs in the early detection, risk stratification, and medical management of PC. High-grade intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasia (PanIN) stage III are high-risk lesions for developing PC. These lesions often require thorough histomolecular characterization using endoscopic ultrasound (EUS), before a surgical decision is made. EUS is also useful in the risk assessment of PCLs with tentative plans-for instance, in branch-duct IPMNs (BD-IPMN)- where the final decision might change. Besides the operative decisions, recent improvements in the application of targeted therapies are expected to improve survival measures. Knowledge of molecular features has helped develop targeted therapies. In summary, the histomolecular characterization of PCLs is helpful in optimizing management plans in PC. Further improvements are still needed for the broad application of this knowledge in the clinical setting.

Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.

Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.

Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer.

This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS).

Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms.

Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma, remains a devastating disease with a dismal prognosis and limited survival rates. Despite various drug treatments and regimens showing promise in managing the disease, the clinical outcomes have not significantly improved. Immunotherapy however, has become a forefront area in pancreatic cancer treatment. This approach comprises a range of agents, including small molecule drugs, antibodies, combination therapies, and vaccines. In the last 5-8 years, there has been an upsurge of research into the use of monoclonal antibodies to block receptors on cancer or immune cells, revolutionising cancer treatment and management. Several targets have been identified and studied, with the most encouraging noted in relation to checkpoint markers, namely, antibodies targeting anti-programmed cell death 1 (PD-1) and its receptor PD-L1. Herein, we present the clinical developments in immunotherapy in the last 5 years especially those which have been tested in humans against pancreatic cancer.

Survival in pancreatic ductal adenocarcinoma (PDAC) remains poor due to late diagnosis. Electronic Health Records (EHRs) can be used to study this rare disease, but validated algorithms to identify PDAC in the United States EHRs do not currently exist.

To develop and validate an algorithm using Veterans Health Administration (VHA) EHR data for the identification of patients with PDAC.

We developed two algorithms to identify patients with PDAC in the VHA from 2002 to 2023. The algorithms required diagnosis of exocrine pancreatic cancer in either ≥ 1 or ≥ 2 of the following domains: (i) the VA national cancer registry, (ii) an inpatient encounter, or (iii) an outpatient encounter in an oncology setting. Among individuals identified with ≥ 1 of the above criteria, a random sample of 100 were reviewed by three gastroenterologists to adjudicate PDAC status. We also adjudicated fifty patients not qualifying for either algorithm. These patients died as inpatients and had alkaline phosphatase values within the interquartile range of patients who met ≥ 2 of the above criteria for PDAC. These expert adjudications allowed us to calculate the positive and negative predictive value of the algorithms.

Of 10.8 million individuals, 25,533 met ≥ 1 criteria (PPV 83.0%, kappa statistic 0.93) and 13,693 individuals met ≥ 2 criteria (PPV 95.2%, kappa statistic 1.00). The NPV for PDAC was 100%.

An algorithm incorporating readily available EHR data elements to identify patients with PDAC achieved excellent PPV and NPV. This algorithm is likely to enable future epidemiologic studies of PDAC.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.