Search Results (849)

Background: Over 60,000 patients are diagnosed annually with pancreatic cancer in the United States, most with pancreatic ductal adenocarcinoma (PDAC). Despite multimodality treatment, prognosis remains poor, underscoring the need to better define factors associated with improved survival in resectable disease. The aim of this study was to propose “completeness of therapy” in resectable PDAC based on chemotherapy type, relative dose intensity (RDI), duration, and timing of initiation, and to evaluate their association with overall survival (OS). Methods: A systematic review of PubMed identified 34 studies. Hazard ratios (HRs) were extracted and synthesized in forest plots. Outcomes focused on OS in relation to chemotherapy completion (cumulative cycles), time to adjuvant chemotherapy initiation (TTA), RDI, and regimen type. The goal was to conceptualize an evidence-based completeness-of-therapy framework for resected PDAC. Results: Completion of chemotherapy was associated with a 42% reduction in the hazard of death compared with incomplete therapy (HR = 0.58, 95% CI 0.47–0.71, p < 0.01). No significant OS difference was observed for longer TTA within a ≤12-week window after surgery (HR = 1.22, 95% CI 0.95–1.56, p = 0.10). Higher RDI demonstrated a large but non-significant trend toward improved OS (HR = 0.51, p = 0.24). Non-significant trends favoring gemcitabine-based regimens (HR = 0.87, p = 0.26) and FOLFIRINOX (HR = 0.79, p = 0.26) were observed, with FOLFIRINOX suggesting a 21% relative reduction in mortality. Conclusions: Chemotherapy completion is strongly associated with improved OS in resectable PDAC. Initiation of adjuvant therapy within 12 weeks appears sufficient, allowing recovery from surgery. Higher RDI and specific chemotherapy regimens demonstrated numerically favorable hazard ratios; however, these associations were not statistically significant and should be interpreted cautiously. Full article

Background: Gemcitabine, cisplatin and durvalumab or pembrolizumab are standard first-line treatments for advanced or metastatic biliary tract cancer (BTC). Older patients with BTC may be frail or have contraindications to cisplatin. At our institution, oxaliplatin has been used as an alternative to cisplatin. Methods: In this evaluation, we report the safety and efficacy of gemcitabine with oxaliplatin and durvalumab as a first-line treatment of BTC. The primary objective was overall survival (OS). Secondary objectives included time to progression (TTP), disease control rate (DCR), and the incidence of treatment-related toxicities. Results: Twenty-nine patients were included. The majority were Caucasian (97%) and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (97%). Median age was 72 years old. Sixty-six percent had intrahepatic cholangiocarcinoma. Baseline renal insufficiency and/or hearing impairment were the most common reasons for cisplatin contraindication. Median follow-up was 20.6 months. Treatment cycles were every 28 days with durvalumab (1500 mg) given on day 1 and gemcitabine (range 600 mg/m²–1000 mg/m²) plus oxaliplatin (median dose 70 mg/m²) given on days 1 and 15. Median OS was 15.7 months (95% CI: 6.9-NA), median TTP was 6.7 months (95% CI 3.88-NA), and DCR was 76%. Median time on treatment was 3.15 months. Twelve patients (41%) required a dose adjustment, with myelosuppression as the most common toxicity. Conclusions: Oxaliplatin, in combination with durvalumab and gemcitabine, is a suitable platinum substitute for advanced BTC patients when cisplatin is contraindicated. Our analysis showed similar efficacy and no new safety concerns. Given the small sample size, our analysis is hypothesis-generating and calls for a larger prospective analysis. Full article

Drug resistance remains a significant barrier to achieving durable treatment responses. Traditionally, resistance has been attributed to genetic alterations and clonal selection. However, accumulating evidence suggests that early adaptation to therapy is often mediated by non-genetic state transitions. In this review, we propose a conceptual framework in which resistance emerges through therapy-driven molecular evolution in bladder cancer, characterized by three interconnected axes: non-genetic plasticity, metabolic reorganization, and tumor microenvironment remodeling. Using the Gemcitabine-Resistant Cell (GRC) model as a temporal reference system, we describe a stepwise transition from drug-sensitive states dominated by proliferation to survival-optimized resistant states through a growth–survival trade-off. Early adaptive phases are marked by the attenuation of cell-cycle and glycolytic programs, increased epigenetic flexibility, and metabolic rewiring involving mitochondrial and lipid-associated pathways. Later phases involve the reinforcement of resistance through extracellular matrix remodeling, developmental and stress-response signaling, and immunometabolic interactions within the tumor microenvironment, including adenosine- and lipid-associated mediators. Projecting the GRC score onto a clinical bladder cancer cohort further suggests that these evolutionary patterns may also be reflected in patient tumors. Overall, this framework supports a temporally structured view of chemoresistance and highlights opportunities to therapeutically target transitional adaptive states before resistance becomes stabilized. Full article

Lung cancer remains the most prevalent malignancy and the leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. β-Hydroxybutyrate (BHB), the primary circulating ketone body, has shown antitumor activity in other cancers, but its role in non-small cell lung cancer (NSCLC) is not well defined. This study investigated the anticancer and anti-angiogenic effects of BHB alone and in combination with Gemcitabine using in vitro and in vivo approaches. In A549 (adenocarcinoma) and LNM35 (large-cell carcinoma) NSCLC cells, BHB significantly reduced cell number and colony growth in a concentration-dependent manner, with LNM35 cells exhibiting greater sensitivity. Migration of both A549 and LNM35 cells was also markedly inhibited. In endothelial Telo-HAEC cells, BHB exhibited no cytotoxicity but significantly inhibited migration, tube formation, and VEGF-induced spheroid sprouting, indicating anti-angiogenic activity. Combination studies showed that BHB enhanced Gemcitabine-mediated suppression of NSCLC cell number and colony growth, consistent with an additive to synergistic effect. In the chick embryo chorioallantoic membrane model, BHB and Gemcitabine reduced tumor growth individually, while their combination further decreased tumor weight, particularly in LNM35 xenografts, without observable toxicity. These findings provide preclinical evidence that BHB enhances Gemcitabine antitumor activity against NSCLC and reveals its in vitro anti-angiogenic effects. Full article

Carcinosarcoma is a rare and aggressive malignancy characterized by both epithelial and mesenchymal components. It most commonly arises in the uterus, lung, or gastrointestinal tract, whereas occurrence in the oral cavity is exceptionally rare. Here, we report a rare case of an aggressive neoplasm with mixed epithelial and sarcoma-like features that initially presented as a benign-appearing upper lip lesion. A 47-year-old male first presented in March 2025 with a painless upper lip mass that had persisted for two months. The lesion appeared clinically benign, and an excisional biopsy was performed. However, during surgery, intraoperative frozen section analysis revealed features highly suspicious for malignancy. Following surgery, systemic imaging demonstrated multiple hypermetabolic lesions in the lung, colon, liver, pancreas, adrenal glands, and lymph nodes. Biopsies from the lip, colon, and lung revealed a high-grade malignant tumor with variable epithelioid and sarcomatoid features across sampled sites. Immunohistochemistry showed co-expression of cytokeratin and vimentin, supporting mixed epithelial and sarcoma-like features. As no primary tumor was identified despite extensive work-up, the available findings favored an aggressive malignant neoplasm of uncertain primary origin with mixed epithelial and sarcoma-like features, although the final histologic sub-classification remained uncertain due to incomplete original pathology information. The patient subsequently received palliative systemic chemotherapy with an alectinib-based targeted regimen starting in April 2025, but showed progressive disease on follow-up, even with additional second-line gemcitabine/cisplatin and third-line pembrolizumab therapy. The patient ultimately succumbed in September 2025. This case highlights that even relatively subtle-appearing lesions require a high index of suspicion for malignancy, emphasizing the importance of early biopsy and comprehensive systemic evaluation. Carcinosarcoma, though rare, should be considered in the differential diagnosis of aggressive tumors arising in atypical locations. Full article

Pancreatic ductal adenocarcinoma (PDAC) presents unique treatment challenges, often due to the development of anti-cancer drug resistance. Previously, we demonstrated that CRISPR-directed gene ablation disabled the master regulator gene NRF2, a transcription factor known to control drug resistance in squamous cell carcinoma tumor cells, and restored chemosensitivity. In this short study, we evaluated a broad range of CRISPR/Cas9 molecules for their capacity to elicit similar responses in PDAC cells. Synthetic single guide RNAs (sgRNAs) were designed to target multiple functional domains encoded by NRF2. These molecules were delivered to cells via nucleofection, with outcomes analyzed by genotypic, phenotypic, and functional assays. We observed targeting efficiencies ranging from 25% to 100% with a high level of random insertions and deletions (indels). sgRNAs targeting exons 2, 3 and 4 demonstrated a high degree of genotypic, phenotypic and functional outcomes. Targeted disruption of exons 3 and 4 reveals significant loss of cell viability while overcoming drug resistance through the restoration of sensitivity to gemcitabine (>1.75 μM). Our study identifies domain-specific sites within NRF2 that, when disabled, restore sensitivity to gemcitabine, potentiating a more in-depth analysis of this novel augmentative therapeutic approach. Full article

Despite its marked molecular heterogeneity and variable response to gemcitabine-based therapies, pancreatic ductal adenocarcinoma (PDAC) remains poorly understood at the pathway level, particularly across age and treatment contexts. We applied a conversational artificial intelligence framework (AI-HOPE-TP53 and AI-HOPE-PI3K) to analyze clinical and genomic data from 184 PDAC tumors stratified by age and gemcitabine exposure. Pathway-centric analyses were performed and validated using conventional statistical methods. TP53 alterations were more frequent in early-onset compared to late-onset PDAC among gemcitabine-treated patients and showed a similar trend in early-onset untreated cases. In late-onset PDAC without gemcitabine exposure, absence of TP53 alterations was associated with improved overall survival. PI3K alterations were enriched in late-onset gemcitabine-treated tumors. Notably, late-onset patients without PI3K alterations who were not treated with gemcitabine demonstrated significantly improved survival. TP53 and PI3K pathway dependencies in PDAC are context-specific, varying by age and treatment exposure. These findings highlight the value of conversational AI for integrative precision oncology analyses and molecular stratification. Full article

Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy affecting adolescents. FLCs harbor a DNAJB1–PRKACA gene fusion that combines heat shock protein DNAJB1 with the catalytic subunit of protein kinase A. Surgery with systemic therapy provides 5-year survivals of 30–50%, but advanced disease remains largely incurable. Three-dimensional explants from 41 FLC patients were interrogated for drug sensitivity, resistance, and synergy against cytotoxics, targeted agents, and signal transduction inhibitors. Methods: Sterile specimens from histologically confirmed FLC patients were analyzed by Ex Vivo Analysis of Programmed Cell Death (EVA/PCD™) in a CLIA-licensed laboratory. Following mechanical and enzymatic disaggregation, explants underwent 72 h drug exposure. LC₅₀ values were derived from five-point dose–response curves and compared with a database of over 10,000 human tumor analyses. Synergy was assessed by combination index. In parallel, targeted metabolomic profiling was performed in five FLC patients using tandem MS/MS. Results: Forty-one samples were analyzed. Of 24 drugs selected, tumor-cell yields were adequate for testing in 18 (75%). Single-agent activity favored vorinostat, followed by phenformin and 6-diazo-5-oxo-L-norleucine. Combinations favored gemcitabine plus oxaliplatin (GEMOX) and 5-FU plus interferon. Metabolomic analysis identified distinct signature consistent with mitochondrial dysfunction and altered polyamine metabolism. Conclusions: The present findings are exploratory, and hypothesis-generating and should not be interpreted as evidence of clinical efficacy. Prospective clinical validation and mechanistic studies will be required to further define the therapeutic relevance of these observations in fibrolamellar carcinoma. Full article

Background: Aberrant glycosylation is closely associated with tumor progression, changes in the tumor microenvironment, and chemoresistance. This study aimed to identify prognostic sialylation-related genes in bladder cancer and define the role of ST3GAL6 in gemcitabine–cisplatin resistance. Methods: Molecular subtype analysis, prognostic analysis, and risk model construction were performed for sialylation-related genes using transcriptomic data and clinical information from the TCGA database. GC-resistant bladder cancer cell models were established for transcriptomic sequencing and untargeted metabolomic analysis. Cell proliferation and drug sensitivity assays were performed to evaluate the function of ST3GAL6. The regulatory relationship between IGF2BP3, ST3GAL6, and the PI3K pathway was further assessed by combining database analysis with molecular experiments. Results: Sialylation-related molecular patterns were associated with patient prognosis and tumor microenvironment features, particularly fibroblast-related characteristics, in bladder cancer. The key model gene ST3GAL6 was upregulated in bladder cancer tissues and was closely associated with prognosis. In GC-resistant bladder cancer cells, ST3GAL6 expression was significantly increased and accompanied by enhanced sialylation activity. ST3GAL6 promoted bladder cancer cell proliferation and reduced sensitivity to cisplatin and gemcitabine, at least in part through the PI3K-AKT-mTOR pathway. IGF2BP3 was also upregulated in resistant cells, is positively correlated with ST3GAL6, and may help maintain ST3GAL6’s expression by stabilizing its mRNA. Conclusions: Our findings suggest that aberrant sialylation is involved in bladder cancer progression and GC resistance. The IGF2BP3-ST3GAL6-PI3K/AKT/mTOR signaling axis may contribute to this process and may serve as a potential biomarker and therapeutic target in bladder cancer. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited therapeutic options, a high mortality rate, and poor overall survival, necessitating the development of new therapeutic and diagnostic strategies. This study investigated the potential of plasma-derived small extracellular vesicles (sEVs) as a source of molecular biomarkers associated with the treatment response. Methods: Plasma samples were obtained from patients with locally advanced and borderline resectable PDAC at baseline and following neoadjuvant chemotherapy, either FOLFIRINOX (5-FU [fluorouracil], leucovorin, oxaliplatin, and irinotecan) or GEM-ABRAX ( gemcitabine plus nab-paclitaxel), followed by stereotactic body radiation therapy (SBRT). sEVs were isolated from plasma at baseline, after neoadjuvant chemotherapy, and following SBRT, and were characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), nano-flow cytometry, and real-time PCR (RT-PCR). Results: The isolated sEVs exhibited an average size of <200 nm, expressed canonical exosome markers (CD63 and CD9), and exhibited pancreatic cancer (PanC)-associated markers, including cholecystokinin A receptor (CCK-AR) and carbohydrate antigen 19-9 (CA19-9). The sEV cargo included several PanC-associated microRNAs (miRNAs). Notably, the expression profiles of these miRNAs demonstrated interpatient variability, though a subset of miRNAs showed statistically significant changes following treatment. Conclusions: These findings support the feasibility of sEV isolation and molecular profiling from patient plasma and warrant further investigation as a potential source of biomarkers in pancreatic cancer. Full article

Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III β-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC. Full article

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in this in vitro screening study. Materials and Methods: HL-60 cells were treated with gemcitabine, clomipramine, resveratrol, or their combinations at concentrations ranging from 1 to 200 µM. Cell viability was assessed at 24, 48, and 72 h using the trypan blue exclusion method, and results are expressed as a percentage of time-matched untreated controls. Cell proliferation was further evaluated by bromodeoxyuridine (BrdU) immunohistochemical labeling. All experiments were performed in triplicate, and statistical analyses were conducted using one-way analysis of variance (ANOVA) with post hoc comparisons. Results: Gemcitabine markedly reduced HL-60 cell viability at all concentrations and time points (p < 0.001), indicating strong time-dependent cytotoxicity, with a significant drop in BrdU proliferation index at 48 h (p < 0.001). Clomipramine exhibited a biphasic response: high concentrations decreased viability (p < 0.05), while low concentrations allowed partial recovery by 72 h. Resveratrol showed concentration-dependent cytotoxicity, with reduced viability at high concentration and near-control levels at low concentration by 72 h; BrdU indices remained significantly lower than control (p < 0.001). Combination treatments with gemcitabine showed no additive cytotoxic or antiproliferative effects (p > 0.05). A transient enhanced effect was observed in the clomipramine + resveratrol group at 24 h (p < 0.01 vs. clomipramine; p < 0.05 vs. gemcitabine). Conclusions: Gemcitabine, clomipramine, and resveratrol all exhibited inhibitory effects on cell proliferation in HL-60 cell cultures. However, the combination treatments did not show additional cytotoxicity or additive effects. These findings suggest that while each of these compounds individually has the potential to inhibit cell growth, their combined application does not enhance the cytotoxic effects beyond those observed with single treatments. These findings highlight the necessity of a rational approach when considering novel drug combinations. Full article

Background/Objectives: Although intravesical Bacillus Calmette–Guérin (BCG) is an established adjuvant therapy for non-muscle-invasive bladder cancer (NMIBC), chronic global shortages and adverse events (AEs) can occur. Thus, intravesical gemcitabine has been used as an alternative. We compared the long-term oncological outcomes and safety profiles of BCG and gemcitabine in treatment-naïve patients with intermediate- and high-risk NMIBC. Methods: Patients with intermediate- and high-risk NMIBC (n = 477) received adjuvant intravesical induction and maintenance therapy with intravesical BCG (n = 361) or gemcitabine (n = 116) and their data were collected retrospectively. Results: Compared with the gemcitabine group, the BCG group had significantly higher proportions of patients with T1 stage, high-grade tumors, high-risk tumors, and longer median follow-up duration. Over a median 36-month observation period, the BCG group exhibited significantly better recurrence-free survival (RFS) and high-grade RFS (HG-RFS) than the gemcitabine group. In the propensity score–matched high-risk population, BCG also outperformed gemcitabine in RFS and HG-RFS. BCG therapy was identified as a potent protective predictor, reducing the risk of recurrence and high-grade recurrence by 65% and 66%, respectively, in the total cohort, and by 69% and 71%, respectively, in the propensity score-matched high-risk subgroup. No significant differences were observed in the frequency of grade ≥ 3 AEs between BCG and gemcitabine. Conclusions: Intravesical BCG is strongly associated with superior oncological outcomes over gemcitabine in intermediate- and high-risk NMIBC. The results of this study offer pivotal practice-based insights to guide clinical strategies for managing NMIBC. Full article

Background/Objectives: The selection of neoadjuvant therapy for patients with non-metastatic pancreatic adenocarcinoma remains challenging. Methods: We performed a single-institution, retrospective analysis of 79 patients who underwent resection of their pancreatic adenocarcinoma after receiving neoadjuvant therapy. Clinical and pathologic data were collected. Tumor fibrosis was quantified using Masson’s trichrome staining, tumor-infiltrating lymphocytes (TIL) were evaluated by an AI-based analysis of whole-slide H&E images, and immune cell populations were quantified by multiplex immunohistochemistry. Correlation analyses were performed between neoadjuvant treatment regimen, tumor regression, immune phenotypes, and survival. Results: All patients received chemotherapy, 77% FOLFIRINOX and 23% Gemcitabine/nab-paclitaxel (Abraxane). Eighteen percent of patients went on to receive radiation. Tumor regression grade (TRG) correlated with the neoadjuvant regimen. A reduction in tumor markers and the baseline neutrophil-to-lymphocyte ratio (NLR) correlated with overall survival. Among patients with an NLR > 3.3, FOLFIRINOX conferred a survival benefit over Gemcitabine/nab-paclitaxel, and radiation trended towards improved survival. Radiation was associated with increased fibrosis and reduced infiltration of CD8⁺ and regulatory T cells (Tregs). Increased Tregs and PDL1⁺ stromal cells were associated with poor response to neoadjuvant therapy, and NLR > 3.3 correlated with increased Treg infiltration. Conclusions: Our data suggest that patients with a high baseline NLR may benefit from intensified neoadjuvant therapy with FOLFIRINOX and radiation. Combination immunotherapy targeting Tregs and the PD1/PDL1 axis may further improve outcomes. Full article

The combination of gemcitabine (GEM) and olaparib (OLA) shows promise for treating pancreatic cancer, particularly in patients with mutations in the BRCA genes. This work presents the validation of a straightforward, fast, and sensitive chromatographic method for the simultaneous analysis of GEM and OLA, supporting the development of advanced pharmaceutical formulations that combine the two drugs. The efficient chromatographic separation of GEM and OLA was achieved using a C18 column (250 × 4.6 mm, 5 μm) with a mobile phase composed of acetonitrile and water (50:50, v/v), which eluted isocratically at a flow rate of 0.8 mL/min. Determinations were performed using a PDA detector at 243 nm for both drugs. The retention times for GEM and OLA were approximately 3.3 and 4.3 min, respectively. The method was linear (R² > 0.999), with a regression curve in the concentration range of 0.5 to 10.0 μg/mL, demonstrating sensitivity, precision, and accuracy. The recovery rates of the drugs from the pancreatic tissue were higher than 97.0%. The components of a coated liposomal formulation and the pancreatic tissue did not interfere with the analysis, and both drugs demonstrated a low degradation rate under stressful conditions. In conclusion, the validated method was suitable for quantifying GEM and OLA simultaneously, even in a biological matrix, making it feasible to support the development of advanced pharmaceutical formulations that incorporate both drugs, such as liposomes. Full article