Search Results (2,186)

Small molecules either derived from cell metabolic reactions or produced by gut bacterial flora have shown the potential of affecting gene expression, which suggests the possibility of interactions able to modulate cellular functions. In this context, the reported experiments were aimed at verifying a possible interplay between lactate and butyrate in modulating the efficacy of antineoplastic drugs. Butyrate is a product of gut bacterial flora, shown to be endowed with anticancer properties; conversely, increased lactate levels in cancer cells were found to be associated with higher proliferation and drug resistance. For the reported experiments, we adopted two cell lines from clinically relevant, but different cancer forms: pancreatic and triple-negative mammary adenocarcinomas. In spite of their different tissue origin, the two cell lines appeared to similarly respond to the effects of the two metabolites, which were found to modulate in opposite ways the expression of key genes involved in DNA repair by homologous recombination. As a consequence, changed efficacy of this repair pathway and modified response to PARP inhibitors were observed. Notably, our results also suggest that the counteracting effect between these two metabolites may be leveraged to address additional challenges limiting the success of anticancer therapies. Full article

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA. Full article

Background/Objectives: Intraductal papillary mucinous neoplasms (IPMN) are the most common pancreatic cystic lesions and are established precancerous entities. Side-branch IPMN (SB-IPMN) is the most prevalent subtype and generally carries a low risk of malignant transformation. The revised 2024 Kyoto guidelines define management and surveillance strategies based on high-risk stigmata and worrisome features; however, real-life adherence to these recommendations remains variable. To compare real-world management of SB-IPMN at a tertiary medical center with Kyoto guideline-based recommendations using an AIgo-based decision-support tool. Methods: SB-IPMN cases were retrospectively analyzed. An algorithm implementing the Kyoto guidelines was used to generate recommended management strategies based on imaging, clinical, and laboratory data, and these recommendations were compared with actual clinical decisions. Long-term clinical and radiological follow-up data were collected, including development of pancreatic ductal adenocarcinoma (PDAC). Results: A total of 368 patients (69% male; median age 69.5 years) were followed for a median of 48.5 months radiologically and 64 months clinically. Median cyst size at presentation was 10 (6–14) mm. Only 58 patients (15.8%) were managed in accordance with the Kyoto guidelines; most underwent more intensive surveillance (60.3%), while 23.9% received less intensive monitoring (p = 0.04). Larger cyst size (>2 cm) was associated with higher concordance with current guidelines. Younger patients, including all patients under 50 years of age, were more frequently over-surveilled. Over-surveillance resulted in an excess of 0.42 MRI/MRCP examinations per patient-year. Only one PDAC case occurred, arising after more than five years of cyst stability. Conclusions: Fewer than 20% of patients with SB-IPMN were managed according to Kyoto guidelines. Over-surveillance was common, particularly in younger patients, without apparent oncologic benefit. AIgo-based decision-support tools may help standardize care and optimize resource utilization. Full article

Surgical resection combined with chemotherapy offers the best chance of survival in pancreatic ductal adenocarcinoma (PDAC), but many will experience recurrence and early mortality. We examined soluble AXL (sAXL), a blood protein, for its ability to predict 6-month mortality after resection and compared it to CA19-9. Fifty-four patients with PDAC who underwent tumour resection were analyzed to assess biomarker performance and identify optimal cut-off levels. The cut-off for sAXL was 40.26 ng/mL (sensitivity 0.729; specificity 0.643), while it 253.3 U/mL for CA19-9 (sensitivity 0.591; specificity 0.621). Patients with sAXL > 40.26 ng/mL had a non-significant trend toward worse survival (log-rank p = 0.088). Univariate Cox regression revealed that high tumour grade (3 + 4) and positive resection margin significantly predicted early mortality. Multivariate Cox regression showed that sAXL > 40.26 ng/mL remained associated with 6-month mortality (hazard ratio 2.42, bootstrap 95% CI 1.15–5.65, p = 0.020), independent of high tumour grade (hazard ratio 4.02, bootstrap 95% CI 1.68–13.2, p = 0.002). These findings suggest that a preoperative blood test (sAXL) has utility for predicting futile surgery beyond the current standard, CA19-9, and can be incorporated into larger models to assist in risk stratification and follow-up planning. Full article

Background: Pancreatic cancer (PC) is expected to be the second leading cause of cancer-related death by 2030. Surgical resection with R0 margins remains the only available treatment capable of improving the overall survival of the patients; thus, appropriate characterization of pancreatic tumors is mandatory for the correct assessment of PC resectability. Despite advances in pancreatic surgery, POPF remains a frequent and dreaded complication that impacts the morbidity and mortality of PC patients, entailing both clinical and economic consequences. Soft pancreatic texture is known as an independent risk factor for POPF occurrence in pancreatic surgery. Intraoperative exploration of the pancreas is most frequently assessed subjectively, through the surgeon’s palpation. Intraoperative elastography is a modern ultrasound technique suitable to replace the surgeon’s intraoperative palpation to better evaluate pancreatic lesions, pancreatic texture, and improve surgical management. Thus, intraoperative elastography could provide quantifiable and reproducible information in pancreatic parenchyma characterization. Real-time intraoperative assessment of pancreatic texture through an objective method could improve surgical decisions. This systematic review analyzes the role of intraoperative elastography in differentiating benign from malignant pancreatic tumors and the efficacy of this technique in the assessment of pancreatic texture as a predictor of postoperative pancreatic fistula (POPF). Methods: We conducted a comprehensive systematic literature research on PubMed, Google Scholar, Scopus, Web of Science, Embase and Cochrane Library Database using PRISMA framework guided by the words “intraoperative elastography” or “intraoperative elasticity imaging” or “intraoperative shear wave elastography” or “intraoperative strain elastography” and “pancreatic cancer” or “pancreatic neoplasm” or “pancreatic adenocarcinoma” or “pancreatic tumor” or “pancreatic fistula” or “postoperative pancreatic fistula” or “pancreatic leak”. Articles that were listed between 2000 and 2025 and written in the English language were screened for potentially relevant articles. The primary outcome was to evaluate the use of intraoperative elastography in differentiating between benign and malignant lesions of the pancreas. The second outcome was to assess the role of intraoperative elastography in the evaluation of pancreatic texture as a predictive factor for the occurrence of postoperative pancreatic fistula. Results: From a total of 17 publications, 2 scientific articles were considered relevant for the role of intraoperative elastography in differentiating benign from malignant pancreatic lesions, while 4 articles analyzed the role of intraoperative pancreatic elastography as a predictor of postoperative pancreatic fistula (POPF). Based on the results, detection of pancreatic cancer through intraoperative SWE is possible at cut-off values of 3 m/s and 28.7 kPa, and values of 2.2 m/s or less obtained after intraoperative elastography of the pancreas are considered an independent risk factor for POPF in pancreatic surgery. Reported cut-off values should, however, be interpreted as exploratory and should represent a starting point for further studies aimed at validating their clinical implementation. Conclusions: Intraoperative elastography can be a promising tool in pancreatic tumor characterization and could differentiate between benign and malignant pancreatic tumors and predict the risk of POPF, but further prospective studies are required before cut-off values can be routinely applied in clinical practice. Full article

Glycogen synthase kinase-3 beta (GSK-3β) is a multifunctional serine/threonine kinase mediating multiple cellular functions, such as differentiation, apoptosis, and cell proliferation. Because of their ability to alter carcinogenic pathways, GSK-3β inhibitors are being explored for the development of anticancer molecules. In the present study, we synthesized and evaluated the cytotoxic properties of a series of twenty indole–triazole-linked pyrazolone derivatives, 10Aa–Ed. All derivatives were characterized by FTIR, ¹H/¹³C NMR, and high-resolution mass spectrometry (HRMS) methods. All compounds and standards, sunitinib and 5-Fluorouracil (5-FU), were screened against four adherent cell lines, including pancreatic adenocarcinoma (Capan-1), colorectal carcinoma (HCT-116), glioblastoma(LN229), and lung carcinoma (NCI-4460), and four non-adherent cell lines, including acute myeloid leukemia (HL-60), chronic myeloid leukemia (K562), T lymphoblast (MOLT4), and non-Hodgkin lymphoma (Z138). Among the screened derivatives, molecule 10Aa showed cytotoxicity against MOLT 4, Z138, and HL60 with CC₅₀ values of 14.45 μM, 15.34 μM, and 17.56 μM, respectively. GSK-3β kinase inhibition was evaluated with the 10Aa, which is capable of inhibiting GSK-3β in a dose-dependent manner. Additionally, molecular docking was performed to estimate the correlation between invitro data and GSK-3β binding affinity. The outcomes of the invitro experiments demonstrated strong concordance with the insilico data. The discovery yielded compounds 10Aa and 10Cd, which can be modified to create effective anticancer agents that target GSK-3β. Full article

Pancreatic cancer frequently presents with obstructive jaundice resulting from distal malignant biliary obstruction. Neoadjuvant chemotherapy (NAC) is increasingly applied in resectable and borderline resectable disease. In this context, uncontrolled cholestasis or cholangitis may hinder timely chemotherapy initiation and cause unplanned hospitalizations and treatment delays; therefore, preoperative biliary drainage is essential to ensure safe and uninterrupted NAC. This review summarizes current biliary drainage strategies during NAC, focusing on key clinical goals, maintaining durable patency throughout the planned NAC course, minimizing infectious and procedure-related morbidity, reducing the need for reintervention, and avoiding adverse effects on subsequent pancreatoduodenectomy, as well as on practical decision-making in clinical practice. We compare transpapillary drainage via endoscopic retrograde cholangiopancreatography (ERCP) using plastic stents and self-expandable metal stents (SEMSs) and discuss the emerging “slim” fully covered SEMSs designed to reduce the risks of pancreatitis and cholecystitis while maintaining sufficient patency. Endoscopic ultrasound-guided biliary drainage is also reviewed as an important salvage option after failed ERCP and as a potential primary approach in selected patients, and we also discuss conventional percutaneous approaches. Overall, current evidence supports an individualized, algorithm-based strategy that prioritizes durable internal drainage to maintain NAC schedules, reserves percutaneous transhepatic biliary drainage for specific indications, and underscores the need for further prospective studies evaluating long-term surgical and oncologic outcomes in resectable disease. Full article

Background: The tumor microenvironment (TME) plays a central role in pancreatic ductal adenocarcinoma (PDAC) progression, yet how mechanical cues shape stromal cell behavior remains poorly defined. Here, we investigate how dimensional priming of adipose-derived stromal cells (ADSCs) alters their immunomodulatory functions and subsequent impact on PDAC growth. Methods: ADSCs were cultured under two-dimensional (2D) or three-dimensional (3D) conditions and evaluated using in vitro co-culture systems with PDAC organoids and in vivo xenograft models. Stromal phenotype, cytokine secretion, tumor growth, invasion, and immune cell infiltration were assessed. Results: ADSCs cultured in three-dimensional (3D) hydrogels exhibited reduced Caveolin-1 (CAV-1) expression and reprogramming toward a stress-adapted, CAF-like phenotype compared with two-dimensional (2D) cultures. In vitro, 2D-primed ADSCs constrained PDAC organoid growth, increased MMP-2 activity, and required direct cell–cell contact to suppress tumor viability. By contrast, 3D-primed ADSCs preserved organoid structure but markedly enhanced tumor cell migration through soluble factors, accompanied by increased IL-6 and TNF-α and reduced IL-10 secretion during co-culture. In vivo, 3D-primed ADSCs promoted the largest tumors with aggressive invasion and loss of Col-Tgel containment associated with tumor expansion, whereas 2D-primed ADSCs suppressed tumor growth and maintained gel boundaries. Immunohistochemistry confirmed elevated Ki-67 in tumors containing 3D-primed ADSCs, while macrophage infiltration (F4/80⁺) was highest in 2D-primed tumors and lowest in 3D-primed tumors. Conclusions: Dimensional priming fundamentally reprograms ADSC phenotype and alters their stromal–immune interactions, generating a tumor-permissive state that accelerates PDAC progression. These findings identify mechanical cues as critical regulators of stromal plasticity and highlight dimensional priming as a potentially targetable axis within the PDAC microenvironment. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor clinical response to gemcitabine, largely due to intrinsic and acquired mechanisms of chemoresistance. Identifying agents capable of enhancing gemcitabine efficacy without increasing cytotoxicity remains an unmet therapeutic need. Here, we characterise a small drug sensitiser molecule, B12, and evaluate its potential to sensitise PDAC cells to gemcitabine. Methods: Gemcitabine’s dose–response was assessed by MTT assay to determine IC₅₀ values and dose-modifying factor (DMF). Phenotypic consequences of co-treatment were examined using colony formation and wound scratch assays. Mitochondrial membrane potential (JC-1) and apoptosis (Annexin V/PI) were measured using flow cytometry. Transcriptomic profiling was performed using mRNA-seq with differential expression analysis and pathway enrichment (KEGG/GSEA). NF-κB activity was assessed by nuclear and cytoplasmic fractionation of p65, and RT-qPCR validation of NF-κB associated target genes. Results: B12 alone displayed minimal cytotoxicity in the PANC-1 cell line and normal pancreatic ductal HPDE cells, yet shifted the gemcitabine dose–response curve in PANC-1 cells, reducing the IC₅₀ and yielding a dose-modifying factor of 1.39. Functionally, B12 enhanced gemcitabine-induced suppression of colony formation and reduced wound closure relative to gemcitabine alone. The co-treatment also increased both mitochondrial depolarisation and apoptotic cell populations, with increased cell proliferation inhibition over time. Transcriptomic profiling identified a set of B12-associated genes downregulated both in B12-treated and B12 + gemcitabine conditions, including factors linked to growth, survival, inflammation, metabolism, and drug inactivation. Gene set enrichment analysis revealed negative enrichment of NF-κB associated pathways during B12 co-treatment. Consistently, nuclear-cytoplasmic fractionation showed that B12 reduced gemcitabine-induced nuclear accumulation of p65, accompanied by decreased expression of NF-κB associated targets such as BCL2L1, CCL20, SLC2A1, and MAP3K14. Conclusions: In PDAC cell models, B12 enhances gemcitabine cytotoxic response while displaying minimal intrinsic toxicity under the conditions tested. The sensitising phenotype is accompanied by increased apoptotic susceptibility and is associated with reduced NF-κB signalling at the pathway, transcript, and p65 nuclear localisation levels. However, to establish causality, the lack of sensitisation in HPDE cells will require further validation. Full article

Background: Pancreatoduodenectomy (PD) remains the fundamental treatment for periampullary malignancies but is associated with considerable morbidity (20–50%) and mortality (2–7%). Bacteriobilia contributes to unfavourable postoperative outcomes. Current antibiotic prophylaxis recommendations endorse first-generation cephalosporins, which often fail to adequately target pathogens most frequently isolated from bile. To date, no specific guidelines for preoperative targeted antibiotic therapy have been established, although tailoring such strategies to the bile microbiome may improve surgical outcomes. This study aimed to characterize bile microbiology in patients undergoing PD for pancreatic ductal adenocarcinoma (PDAC), evaluating potential antibiotherapy regimens that provide effective coverage against the most frequently isolated pathogens. Methods: A retrospective cohort analysis of 725 patients surgically treated for pancreatic tumours at a high-volume pancreatic surgery center between 2017 and 2022 was performed. To minimize heterogeneity, study was restricted to 138 patients who underwent PD with histopathological confirmed PDAC. Intraoperative bile cultures were assessed. Results: Patients with bacteriobilia likewise experienced worse outcomes: higher 5-year mortality (OR 3.01, p = 0.007), greater overall postoperative pancreatic fistula (POPF) occurrence (OR 2.54, p = 0.044) and wound infections (OR 2.90, p = 0.038). Among bile microbiome the highest susceptibility rates were observed for combination of amoxicillin/clavulanic acid with gentamicin, while the lowest were noted for cephalosporin–metronidazole regimen (93.6% vs. 30.2%, respectively). Conclusions: Bacteriobilia contributes to postoperative complications and serves as a predictor of poorer survival after PD. Standard perioperative antibiotic prophylaxis in PD is insufficient. Based on our findings, perioperative antibiotic therapy with amoxicillin/clavulanic acid and gentamicin combination appears to provide superior coverage and may improve postoperative morbidity and overall survival following PD. Full article

Background and Objectives: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive, heterogeneous, and lethal human malignancies, underscoring the urgent need for novel, targeted therapeutic strategies for neo(adjuvant) individualized treatment. The epidermal growth factor receptor family (ErbB) is directly involved in abnormal cell proliferation and tumor growth. The overexpression and amplification of HER2 and HER3 have emerged as key molecular events in pancreatic ductal adenocarcinoma. The aim of this study was to evaluate these membrane receptors’ overexpression in relation to pTNM staging, perineural and lymphovascular invasion, and tumor volume in order to obtain the immunohistochemical profile and enhance the development of a targeted and personalized therapy. Materials and Methods: An observational analytical cohort study included patients with histopathologically naïve, confirmed PDAC who underwent cephalic pancreatoduodenectomy at a national high-volume referral center between 2017 and 2022. Archived surgical specimens were retrieved and examined using a tissue microarray technique in two separate pathology departments by two independent pathologists. Results: HER2 positivity was found in 25 cases, of which 84% had lymphatic invasion, 50% had vascular invasion, and 84% had perineural invasion. Patients with HER3 positivity had lymphatic invasion (82.5%), perineural invasion (79.4%), and vascular invasion (38.1%). Combined HER2 and HER3 positivity was present in 19 cases, and these patients had 84.2% perineural invasion. Conclusions: HER2 and HER3 overexpression often coexisted with pathological features, such as perineural invasion, in cases of combined HER2 and HER3 positivity. These findings support the involvement of the ErbB receptor family in pancreatic carcinogenesis and suggest their potential as targets for future (neo)adjuvant therapeutic strategies. Full article

Pancreatic cancer (PC) remains a highly lethal malignancy with limited treatment options and poor survival. Targeting DNA damage response (DDR) pathways has emerged as a promising therapeutic strategy, particularly the ATR-CHK1 and ATM-CHK2 axes. Preclinical studies demonstrate that ATR inhibition disrupts replication stress tolerance, impairs homologous recombination, and disables checkpoint control, enhancing cytotoxicity from standard therapies including gemcitabine, FOLFIRINOX, fluoropyrimidines, and radiotherapy. Synergistic effects have also been observed with other DDR-targeted agents, such as PARP and WEE1 inhibitors. Genomic contexts, including ATM deficiency, ARID1A alterations, and oncogene-driven replication stress, refine therapeutic sensitivity, supporting precision patient stratification. Early-phase clinical trials of ATR inhibitors (ART0380, AZD6738, BBI-355) alone or in combination show promising safety, tolerability, and preliminary efficacy. In this review, we summarize current literature on targeting the ATM-CHK2 and ATR-CHK1 pathways in PC, highlighting preclinical evidence, clinical developments, and strategies for biomarker-driven, precision oncology approaches. Full article

KRAS alterations are a hallmark of pancreatic ductal adenocarcinoma (PDAC) found in >90% of tumors. This review examines the historical evolution of the understanding of RAS and its central role in PDAC biology. We summarize the various downstream effectors, feedback loops, and resistance mechanisms that play a pivotal role in PDAC oncogenesis. Our review explores the early development of covalent inhibitors of KRAS G12C and efforts at specific inhibition of other codons and newer approaches of targeted protein degradation. We subsequently summarize the development of panRAS inhibitors and allosteric and switch-region targeting before focusing on rational therapeutic blockade of crosstalk and upstream signaling, with attention to synthetic lethality approaches transitioning from preclinical to early-phase in-human clinical trials. This review elaborates on ongoing KRAS-specific siRNA research and evolving KRAS-directed immunotherapies. We conclude by outlining the current KRAS clinical trial landscape and future areas of investigation. Full article

Intraoperative assessment of pancreatic quality, followed by sampling for the potential isolation of Langerhans islets for subsequent autotransplantation, is currently a key component of post-total pancreatectomy diabetes mellitus treatment. The aim of this study was to quantitatively evaluate pancreatic parenchymal stiffness using optical coherence elastography (OCE) imaging, and to investigate the utility of the OCE method as a potential indicator of islet yield after pancreatectomy. A total of 41 freshly excised human pancreatic specimens, containing pancreatic ductal adenocarcinoma (PDAC) and surrounding non-tumorous tissues post-pancreatectomy, were studied. In this research, the stiffness (Young’s modulus, kPa) and its color-coded 2D distribution were calculated for various pancreatic samples using compression OCE. Stiffness values were compared between intact pancreatic parenchyma (islet-poor and islet-rich) and pancreatic lesion groups (parenchymal fibrosis and/or PDAC invasion). The data were confirmed by histological analysis. In addition, the measured stiffness values for various morphological groups of the pancreatic samples were compared with the number of isolated islets obtained from pancreatic samples after collagenase treatment. The study demonstrated that OCE can effectively distinguish areas of pancreatic lesions and identify intact pancreatic parenchyma containing Langerhans islets. A highly significant increase in mean stiffness (p < 0.0001) was observed in postoperative pancreatic samples exhibiting signs of parenchymal fibrosis or PDAC invasion compared to unaffected, intact pancreatic parenchyma. For the first time, a relationship between stiffness values and the number of isolated pancreatic islets was demonstrated; in particular, the number of isolated islets significantly decreased (≤110 pcs/g) in samples exhibiting stiffness values above 150 kPa and below 75 kPa. The optimal stiffness range for the efficient isolation of islets (≥120 pcs/g) from pancreatic tissue was identified as 75–150 kPa. The study introduces a novel approach for rapid and objective intraoperative assessment of pancreatic tissue quality using real-time OCE data. This technique facilitates the identification of regions affected by pancreatic lesions and supports the selection of intact pancreatic parenchyma, potentially enhancing the accuracy of Langerhans islet yield predictions during surgical resection. Full article

Initially characterized as a component of the extracellular matrix (ECM) in cartilage, cartilage intermediate layer protein 2 (CILP2) is now recognized as a pleiotropic secretory protein with far-reaching roles in physiology and disease. This review synthesizes evidence establishing CILP2 as a key modulator at the nexus of metabolic dysfunction, cancer, and other pathologies. Genomic studies have firmly established the NCAN-CILP2 locus as a hotspot for genetic variants influencing dyslipidemia and cardiovascular risk. Functionally, CILP2 is upregulated by metabolic stress, including high glucose and oxidatively modified LDL (oxLDL), and actively contributes to pathologies such as dyslipidemia, diabetes, and sarcopenia by impairing glucose metabolism and mitochondrial function. Its role extends to fibrosis and neurodevelopment, promoting hypertrophic scar formation and neurogenesis through interactions with ATP citrate lyase (ACLY) and Wnt3a, respectively. More recently, CILP2 has emerged as an oncoprotein, overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma and colorectal cancer. It drives tumor proliferation and metastasis and correlates with tumor microenvironment remodeling through mechanisms involving Akt/EMT signaling and immune infiltration. The dysregulation of CILP2 in patient serum and its correlation with disease severity and poor prognosis highlight it as a promising biomarker and a compelling therapeutic target across a spectrum of human diseases. Full article