Search Results (4,918)

Poly(ADP-ribose) polymerase inhibitors (PARPis) have transformed the treatment landscape of homologous recombination-deficient malignancies, particularly BRCA1/2-mutant breast, ovarian, pancreatic, and prostate cancers. In contrast, clinical studies evaluating PARPis in broadly selected colorectal cancer (CRC) patients have yielded disappointing outcomes despite evidence that a subset of CRCs harbor DNA damage response (DDR) defects and homologous recombination deficiency (HRD)-associated mutational signatures. These observations highlight the need for improved patient stratification and the development of strategies to enhance PARPi sensitivity in CRC. In this review, we integrate CRC-specific evidence with mechanistic and preclinical findings from other malignancies and discuss candidate biomarkers associated with PARPi responsiveness, including TP53, RAD51, and MRE11, and examine their potential utility in identifying CRC patient populations most likely to benefit from PARP inhibition. We further summarize therapeutic approaches aimed at inducing “BRCAness” and sensitizing CRC cells to PARPis through epigenetic modulation, targeting cell-cycle checkpoint regulators, inhibiting growth factor signaling pathways, and exploiting metabolic vulnerabilities. Emerging strategies involving polyamine inhibition and modulation of NAD+ metabolism have been specifically highlighted for their potential role in therapeutic response. Collectively, these approaches provide a framework for investigating mechanistically compelling opportunities to overcome intrinsic and acquired resistance to PARPis and expand the clinical utility of DDR-targeted therapies in CRC. A deeper mechanistic understanding of PARPi response and resistance, in addition to extensive investigations in CRC-specific models and molecularly selected clinical cohorts, will facilitate the development of biomarker-driven combination therapies and improve outcomes for patients with CRC. Full article

The RGD motif (Arg-Gly-Asp) mediates interaction with integrins, governing adhesion and signaling. Integrin αvβ6, an RGD-binding integrin, has gained attention as a therapeutic and diagnostic target because its expression is restricted in normal tissues yet markedly upregulated in pancreatic and colorectal cancer, where it is linked to poor prognosis. Although sequence identities across both subunits of examined integrin subtypes range from approximately 40% to 55%, structural analyses show that all integrins are highly similar, with an RMSD of less than 1.3 Å. This similarity underlies a conserved mechanism in which arginine and aspartate interact with the α-subunit and the β-subunit metal ion–dependent adhesion site (MIDAS), respectively, stabilizing ligand engagement. In line with this, αvβ6 follows the same recognition principle; however, its unique β6-specificity-determining loop provides an extra binding interface, enhancing affinity toward particular ligands. Herein, this perspective highlights the structural features of RGD-binding integrins, their interaction with linear and cyclic RGD-peptides, and approaches for improving specificity to αvβ6. Beyond the RGD motif, linker design, including spacer length, bioconjugation chemistry, and stimuli-responsive cleavable motifs with self-immolative spacers, balances plasma stability with tumor-specific, traceless payload release, determining the pharmacological behavior of cyclic RGD–nanoparticle conjugates and their adaptation to future delivery and radiotracer platforms. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant tumor requiring novel therapeutic approaches. Electroporation (EP)-based strategies are promising tools for local tumor control and enhanced drug delivery. However, cellular responses and protocols optimization remain poorly investigated in PDAC. Here, we investigated the effects of variable microsecond pulsed electric fields (PEFs) on PANC-1 and MIA PaCa-2 PDAC cells. Immediate responses were assessed via membrane permeabilization and cell death. Delayed effects were evaluated through viability, growth, cell cycle and expression of stress markers. Immediate cell death occurred above specific thresholds in PANC-1 and MIA PaCa-2 cells (16 pulses at 1 kV/cm and 30 pulses at 2.5 kV/cm, respectively), suggesting differential sensitivity to PEFs. Delayed analyses confirmed differences in both viability (−19.3% vs. −46.4% with 4 pulses, 1 kV/cm, 48 h) and growth (−30.3% vs. −57.6% with 4 pulses, 1 kV/cm, 48 h). An opposite modulation of the S-phase population was also observed at 48 h (+7.4% with 20 pulses at 1 kV/cm and −9.2% with 8 pulses at 1 kV/cm for PANC-1 and MIA PaCa-2, respectively). Both cell lines showed similar regulations of apoptosis-associated and autophagy-related markers. Overall, PEFs elicited parameter- and cell-specific responses, supporting fine-tuned EP protocols for pancreatic cancer therapy. Full article

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer with low five-year overall survival rates of ~10% from diagnosis. The immune ‘cold’ tumor microenvironment (TME) of PDAC is a key contributor to tumor progression, featuring immunosuppression in conjunction with a reactive stroma. The immune composition of the TME is highly tumor-promoting, with the presence of immunosuppressive cells and the absence of effector and cytotoxic immune cells. Further to this, the active stroma region of the tumors contains transformed fibroblasts which communicate with tumor and immune cells to further enhance immunosuppression. Fundamental cellular processes such as T cell exhaustion, metabolic signaling, epigenetic modifications, and a series of genetic mutations can all contribute to PDAC progression and poor patient outcomes. This review describes the key mechanisms behind immune dysregulation in PDAC, highlighting the importance of this area and the essential research that is necessary. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, partly because its dense, heterogeneous stroma restricts drug delivery, promotes immune exclusion, and supports therapeutic resistance. Stromal targeting has, therefore, evolved from broad depletion towards biomarker-guided reprogramming and normalization strategies that aim to restore vascular function, improve intratumoral drug penetration, and enhance antitumor immunity. This review summarizes evidence on stromal biomarkers with prognostic or predictive value, including tumor–stroma ratio, fibrosis burden, cancer-associated fibroblast states, extracellular matrix stiffness, vascular accessibility, and spatial immune features. It also examines emerging therapeutic approaches to reprogram the PDAC stroma, such as repurposed drugs, immune–stromal modulators, metabolic interventions, and advanced delivery systems. Emphasis is placed on clinically or translationally supported strategies, including CXCR4, CD40, CD73, vitamin D receptor agonism, matrix remodeling, and biomarker-driven stratification. Overall, PDAC stroma is a dynamic therapeutic target, requiring composite biomarkers and rational combinations with chemotherapy, immunotherapy, and delivery-enhancing strategies. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) can cause pancreatic immune-related adverse events ranging from isolated pancreatic enzyme elevation to severe acute pancreatitis. This study aimed to describe the clinical presentation, diagnostic classification, management, and outcomes of ICI-related pancreatic injury in patients with lung cancer. Methods: We conducted a retrospective, single-center case series of six patients with lung cancer who developed pancreatic injury during or after ICI treatment between January 2016 and December 2024. Clinical characteristics, laboratory and imaging findings, toxicity grade, management, and outcomes were extracted from the available medical records and analyzed descriptively. Results: The median time from ICI initiation to pancreatic injury was 8.6 months (range, 2.3–16.4 months). The recorded Common Terminology Criteria for Adverse Events (CTCAE) severity grade was 2 in two patients, 3 in one patient, and 4 in three patients; pancreatic enzyme elevations were evaluated separately from clinical pancreatic adverse-event severity. Five patients required hospitalization and received supportive care, including intravenous fluids and corticosteroids. One patient received mycophenolate mofetil, and one developed acute necrotizing pancreatitis requiring intensive care, endoscopic procedures, and repeated surgical interventions. Two patients died during follow-up. In one patient, death followed a prolonged course of severe necrotizing pancreatitis complicated by infected necrosis and multiorgan failure; in the second patient, the available retrospective records did not permit reliable attribution of the cause of death to pancreatic toxicity. Immunotherapy was resumed in two patients; recurrent pancreatic enzyme elevation occurred after rechallenge, but recurrent clinically overt pancreatitis was not documented. Conclusions: ICI-related pancreatic injury has a heterogeneous clinical presentation. Pancreatic enzyme elevation alone should not be considered equivalent to acute pancreatitis. Diagnostic classification requires integration of symptoms, biochemical findings, imaging, and exclusion of alternative etiologies. Management should be individualized, and severe cases may require early multidisciplinary involvement. The benefits of corticosteroids and routine pancreatic enzyme monitoring remain uncertain. Full article

Background/Objectives: Adrenomedullin (AM) is a circulating peptide involved in tumor progression, angiogenesis, and fibrosis. However, its clinical utility as a biomarker in gastrointestinal cancers remains unclear. Methods: This single-center prospective observational study included patients with unresectable advanced gastrointestinal cancers (esophageal, gastric, colorectal, biliary tract, and pancreatic cancers) and healthy volunteers. Plasma AM levels were measured before the initiation of systemic chemotherapy in patients with cancer and at the time of enrollment in healthy volunteers. Results: In the unadjusted analyses, plasma mature and total AM levels were significantly higher in the cancer group than in healthy volunteers. Age was significantly associated with both mature and total AM levels, whereas sex did not show a significant association. After adjustment for age, between-group differences in mature and total AM levels were not statistically significant. Among patients with pancreatic cancer, plasma mature and total AM levels were significantly higher in stage IV than in stage III disease. Conclusions: Higher plasma AM levels were observed in the cancer group than in healthy controls in the unadjusted analyses; however, these differences were not statistically significant after adjustment for age. A stage-related difference was observed in pancreatic cancer. These findings should be considered hypothesis-generating and require validation in larger studies with appropriately matched control groups. Full article

Background and Objectives: Metastatic pancreatic adenocarcinoma is related to poor prognosis and is frequently accompanied by malnutrition, inflammation, and immune dysregulation. The Controlling Nutritional Status (CONUT) score is a composite laboratory-based index that may reflect aspects of nutritional and immune status. This study aimed to evaluate the association between pretreatment CONUT score and overall survival (OS) in patients with metastatic pancreatic adenocarcinoma receiving first-line systemic chemotherapy. Materials and Methods: In this retrospective analysis, a total of 156 patients diagnosed with metastatic pancreatic adenocarcinoma between January 2017 and July 2024 and treated with first-line systemic chemotherapy were included. Based on the conventional CONUT classification, patients were categorized a priori into normal-CONUT (scores 0–1) and elevated-CONUT (scores ≥ 2) groups, with CONUT additionally evaluated as a continuous score. OS was estimated using the Kaplan–Meier method. Univariable and multivariable Cox regression analyses were performed to evaluate the association between the CONUT score, selected clinical factors, and overall survival. Results: The cohort demonstrated a median OS of 9.1 months (95% CI: 6.6–11.6). OS was significantly better among individuals classified in normal CONUT group relative to elevated CONUT group (14.1 vs. 6.5 months, respectively, p <0.001). Higher continuous CONUT scores were also associated with shorter OS (HR 1.23 (1.14–1.32), p < 0.001). In multivariable analysis, an elevated CONUT score (HR, 2.40 (1.63–3.52); p <0.001), liver metastases (HR 1.99 (1.31–3.02); p = 0.001), and the presence of comorbidity (HR, 1.88 (1.28–2.75); p = 0.001) remained significantly associated with shorter OS. Conclusions: An elevated pretreatment CONUT score was associated with shorter overall survival in this selected chemotherapy-treated cohort. As a readily available laboratory-based index, CONUT may provide additional prognostic information; however, prospective studies are needed to determine whether it adds value beyond established clinical factors. Full article

The natural history of pancreatic neuroendocrine tumors (NETs) can span decades of slow progression, but it is unpredictable, with a more aggressive course also being common. The two clinical biomarkers currently used to define the grade of a tumor, the Ki67 index and the mitotic index, are not able to fully capture the course of individual patients. This creates an unmet need to discover better prognostic biomarkers to inform therapeutic decisions, as well as therapies with overall survival benefit. Two genomic series of pancreatic NETs were examined to discover sub-sets with divergent characteristics. Primary data were downloaded from the cBioportal cancer genomics portal and analyzed at the individual sample level. Pancreatic NET patients without MEN1/DAXX/ATRX mutations were younger than NET patients with any of these mutations. Pancreatic NETs had consistently low tumor mutation burden but were heterogeneous in their Fraction Genome Altered (FGA), a metric of chromosomal instability (CIN), with one group presenting high FGA and another possessing low to intermediate FGA. FGA did not correlate with Ki67, but high FGA was most prevalent in cases with mutations in MEN1 and DAXX or ATRX. TSC2 mutations were significantly more prevalent in the group with high FGA. Full article

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with limited improvements in long-term survival despite significant progress in systemic therapy. This review focuses predominantly on pancreatic ductal adenocarcinoma (PDAC), the most common and best-studied pancreatic malignancy, while referencing other pancreatic neoplasms only where directly relevant to intrapancreatic fat biology. Obesity has emerged as a major modifiable risk factor for PDAC. In addition, increasing attention has focused on ectopic fat depots, particularly intrapancreatic fat, as potential mediators linking metabolic disease to pancreatic carcinogenesis. This narrative review summarizes the classification and epidemiology of PDAC, the relationship between obesity and pancreatic cancer risk, the biology of intrapancreatic fat, as well as putative mechanisms by which intrapancreatic fat may promote pancreatic carcinogenesis. In addition, we will review current diagnostic approaches, therapeutic and preventive considerations, and key unanswered questions for future research on the relevance of intrapancreatic fat deposits. Collectively, available evidence supports intrapancreatic fat as a biologically plausible and potential mediator of pancreatic cancer risk, warranting further prospective investigation. Full article

In pancreatic ductal adenocarcinoma (PDAC), clinicians often ask whether young age is associated with more aggressive disease or patients more likely to tolerate curative-intent multimodality treatment. The prognostic meaning of age after surgery remains uncertain. We analyzed a retrospective multicenter surgical cohort of patients with resected non-metastatic PDAC. Candidate clinical variables were evaluated in univariable Cox models. The prespecified primary multivariable model included age, sex, N status, T stage, and CA19-9 status. Adjuvant therapy was evaluated in a sensitivity model. The cohort included 696 surgical patients; 70 (10.1%) were aged < 55 years. Median overall survival was 34.4 months in patients aged < 55 years versus 22.0 months in those aged ≥ 55 years (log-rank p = 0.019). In the primary multivariable model, age < 55 years remained independently favorable (HR 0.66, 95% CI 0.49–0.89; p = 0.007). Elevated CA19-9 value independently predicted worse survival (HR 1.39, 95% CI 1.13–1.71; p = 0.002). The sensitivity model confirmed favorable associations for young age and not elevated CA19-9 value. In surgically managed PDAC patients, young age and normal CA19-9 value carried independent favorable prognostic information. Prognosis was also shaped by nodal status, T stage, and receipt of adjuvant therapy. Full article

Malignant distal biliary obstruction (MDBO) is most commonly managed by endoscopic retrograde cholangiopancreatography (ERCP) with self-expandable metal stent placement. When ERCP fails or is not feasible, endoscopic ultrasound-guided biliary drainage (EUS-BD) has increasingly replaced percutaneous transhepatic biliary drainage in expert centers. Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has emerged as an indirect route for biliary decompression when the cystic duct is patent. This comprehensive narrative review focuses on the anatomical rationale, patient selection, procedural technique, comparative positioning, clinical outcomes, adverse events, and unresolved issues of EUS-GBD in MDBO. The supporting evidence is predominantly observational. Published meta-analyses report technical success generally exceeding 90%, pooled clinical success of approximately 82–89%, and overall adverse event rates of approximately 10–14%; these estimates vary with study selection, outcome definitions, assessment time points, and predominantly observational study designs. Comparative studies suggest efficacy and safety similar to EUS-guided choledochoduodenostomy after failed ERCP in anatomically selected patients, although nonrandomized allocation and confounding by indication remain major limitations. A prospective study has demonstrated feasibility as primary palliation, but this strategy cannot yet be considered standard of care. Prophylactic EUS-GBD to prevent post-stenting cholecystitis represents a separate indication and should not be conflated with EUS-GBD for biliary decompression. The key determinant of physiological success is unobstructed communication between the gallbladder and the central biliary tree; therefore, cystic duct patency, tumor relationship to the cystic duct take-off, gallbladder distension, and the absence of extensive gallbladder involvement must be assessed before intervention. EUS-GBD is best positioned as a rescue option after failed ERCP when direct EUS-BD is technically impossible, unsafe, or unsuccessful. Prospective randomized trials, standardized outcome definitions, comparative cost-effectiveness analyses, and dedicated long-term stent management protocols are needed before broader adoption. Full article

Background: Pancreatoduodenectomy (PD) is a complex surgical procedure with substantial postoperative morbidity and mortality. Postoperative outcomes following PD are typically determined by measuring preoperative liver function in the form of serum albumin and bilirubin levels. In this study, the prognostic value of the preoperative ALBI grade was compared with that of albumin and bilirubin alone in predicting postoperative complications and short-term mortality after PD. Methods: This retrospective cohort study included 1149 patients who underwent partial or total PD between 2014 and 2017 at a high-volume surgical center. The preoperative ALBI grade (I–III) was calculated in these patients as well as the preoperative levels of bilirubin and albumin. The associations between ALBI grade, albumin and bilirubin levels with postoperative complications and 30- and 90-day mortality were analyzed using univariate and multivariable logistic regression models. The predictive performance of the ALBI grade and albumin and bilirubin levels was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis. Results: Higher ALBI grades were significantly associated with worse perioperative outcomes, including increased incidence of liver perfusion failure (42.4%) and postpancreatectomy hemorrhage (15.2%). In a pre-specified reduced multivariable model adjusted for BMI, ASA physical status as well as surgical complexity, ALBI grade III remained associated with 30- and 90-day mortality (OR 6.21; 95% CI, 1.62–23.78; p = 0.008 and OR 8.97; 95% CI, 2.91–27.62; p < 0.001) but was attenuated compared to univariate analyses. Seven of the 8 patients with ASA grade IV physical status were in ALBI grade III and accounted for 5 of the 6 30-day and 6 of the 8 90-day deaths in this group; in a sensitivity analysis excluding these patients, the association between ALBI grade III and 30-day mortality was no longer statistically significant, and the univariable association with 90-day mortality was also attenuated to non-significance, although the BMI-adjusted 90-day estimate remained significant (OR 5.02; 95% CI, 1.07–23.54; p = 0.041). ROC analysis showed that the ALBI score (AUC, 0.74 and 0.74) did not outperform albumin alone (AUC, 0.69 and 0.70) in predicting 30- and 90-day mortality (DeLong p = 0.21–0.24), although both outperformed bilirubin alone (AUC, 0.54–0.56). Conclusions: Preoperative ALBI grade III is associated with short-term morbidity and mortality after PD, but this association is confounded in part by baseline surgical risk (ASA physical status), and the ALBI score does not outperform albumin alone as a predictor of mortality. As a simple, readily available composite marker, the ALBI grade may still help flag patients who warrant closer perioperative surveillance, although this retrospective study does not establish that correcting albumin or bilirubin levels before surgery improves outcomes. Full article

Cancer remains a leading cause of global mortality, entailing the exploration of novel therapeutic agents from natural sources. This study evaluated the in vitro anti-cancer potential of essential oils (EOs) extracted from the needles of Pinus sylvestris L. (Scots pine) and Picea abies (L.) H. Karst. (Norway spruce). GC–MS analysis revealed that both EOs are rich in monoterpenes; the primary constituents were α-pinene (35.27%) for Pinus sylvestris sylvestris EO (Pinus EO) and β-pinene (31.40%) for Picea abies EO (Picea EO). Cell viability assay (Alamar Blue) demonstrated that both EOs exert a dose-dependent cytotoxic effect across all tested malignant lines: melanoma (A375), colorectal adenocarcinoma (HT-29), and pancreatic adenocarcinoma (PANC-1). Notably, Pinus EO consistently displayed higher potency toward cancer cells when compared with normal keratinocytes (HaCaT), with the highest selectivity noticed in HT-29 cells. Immunofluorescence analysis revealed morphological changes consistent with apoptosis, such as nuclear condensation, DNA fragmentation, and the disruption of the β-actin cytoskeleton. High-resolution respirometry indicated that the EOs increase LEAK respiration, while also significantly reducing the oxidative phosphorylation (OXPHOS) efficiency. Furthermore, network pharmacology and molecular docking predicted EP300 as a common hub target for both EOs, with β-caryophyllene showing the most favourable predicted binding affinity among the investigated constituents. Overall, these preliminary in vitro and in silico findings support the further investigation of Pinus EO and Picea EO as potential candidates for the development of future adjuvant strategies in cancer therapy. Full article

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor clinical outcomes and limited responsiveness to conventional treatments. Beyond delayed diagnosis, its high mortality is linked to limited treatment choices and resistance to chemotherapy. Neoplastic cells characterized by stem-like features and epithelial–mesenchymal transition (EMT) activation are crucial drivers of drug resistance and metastatic progression. Consequently, targeting these cellular programs could represent a promising therapeutic strategy for PDAC. N-acetyl-L-aspartic acid (NAA) is an endogenous metabolite, mainly localized in the central nervous system, where it facilitates acetate storage for lipid metabolism. Previous studies established its antineoplastic effect in neuroblastoma, promoting a more differentiated phenotype of cancer cells. Here we investigated the effects of NAA on BxPC-3 pancreatic cancer cells using both 2D and 3D models. NAA treatment induced a dose-dependent reduction in cell proliferation and led to a significant downregulation of stemness-associated surface markers, with concomitant upregulation of E-cadherin. Furthermore, NAA significantly enhanced cellular radiosensitization with a reduction in caveolin-1 and increased efficacy of gemcitabine in PDAC cells. Collectively, these results confirmed the anticancer activity of NAA and provide a rationale for further investigation of its synergistic effects with radiotherapy to yield better PDAC treatments. Full article