Search Results (34,664)

Background and Objectives: FLOT is a highly effective first-line treatment for metastatic gastric cancer and offers a favorable safety profile. Clinical studies investigating the FLOT regimen have reported varying outcomes depending on the infusion duration and have highlighted possible differences in complication rates and the efficacy of neoadjuvant therapy. The choice between 24 h or 48 h infusion durations for fluorouracil can be influenced by several factors, such as the patient’s overall health status, their tolerance to treatment, and the specific treatment protocol determined by the medical team. In this study, we aimed to evaluate the effects of different infusion durations (24 and 48 h) on clinical response, toxicity, and survival in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma. Materials and Methods: This retrospective multicenter study included 113 patients with gastric or gastroesophageal junction adenocarcinoma who received neoadjuvant FLOT chemotherapy (24 h infusion: n = 28; 48 h infusion: n = 85). Propensity score matching (PSM) was performed to balance baseline characteristics, yielding a matched cohort of 90 patients. The primary endpoints were the pathologic complete response (pCR) and toxicity. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). Results: Significant baseline imbalances existed (cT stage p < 0.001). After PSM, the balance improved (cT stage p = 0.009). In the matched cohort, pCR 11.1% (24 h) vs. 12.1% (48 h), p > 0.99. The median DFS was 27.4 mo (24 h) vs. NR (48 h), p = 0.847. The median OS was 32.8 mo in both, p = 0.797. Multivariate analysis (baseline variables) indicates that infusion duration is not prognostic (DFS HR = 0.77, p = 0.453; OS HR = 0.72, p = 0.328). Power was ~10% for a 1% pCR difference. Conclusions: The 24 h infusion protocol was associated with similar outcomes to the 48 h protocol after PSM adjustment. However, residual confounding persists (cT stage p = 0.009 despite PSM), and the combination of this study’s retrospective design and severe underpowering (~10%) precludes definitive conclusions. As a result, the findings are hypothesis-generating. Full article

Background/Objectives: Sentinel lymph node biopsy is central to axillary staging in breast cancer, but conventional mapping often relies on radioisotopes and/or blue dye. Indocyanine green fluorescence has emerged as an alternative, although evidence for its use as a sole tracer in routine practice remains limited. This study evaluated the technical feasibility, lymph node yield, nodal metastasis detection, and short-term clinical outcomes of indocyanine green used as the only tracer for axillary staging in a consecutive single-centre cohort. Methods: This retrospective observational cohort study included 260 patients with histologically confirmed breast cancer who underwent axillary surgery at University Hospital Kaspela between 2024 and 2025 under an institutional protocol using indocyanine green as the sole tracer. Indocyanine green-guided mapping was attempted in all patients. For node-focused statistical analyses, a predefined complete-case–cohort of 230 patients was used. Descriptive analyses assessed axillary procedure distribution, lymph node yield, nodal metastasis, and postoperative outcomes. Exploratory multivariable logistic regression was performed to evaluate predictors of nodal metastasis. Results: Mapping was successful in 259/260 patients (99.6%). In the complete-case–cohort, sentinel lymph node biopsy was performed in 166/230 patients (72.2%), targeted axillary dissection in 4/230 (1.7%), and axillary lymph node dissection in 60/230 (26.1%). Median overall lymph node yield was 4 (IQR 3–7), but this pooled value reflected heterogeneous axillary procedures and should not be interpreted as sentinel node yield alone. In the clinically node-negative upfront SLNB subgroup, median lymph node yield was 4 (IQR 2.75–5), and nodal metastasis was identified in 22/112 patients (19.6%). Overall, nodal metastasis was identified in 58/230 patients (25.2%), with a median of 2 metastatic nodes (IQR 1–3) among nodal-positive cases. Reoperation for axillary lymph node dissection occurred in 14/230 patients (6.1%). In exploratory multivariable analysis, suspicious biopsied-positive nodes (OR 12.85, 95% CI 3.98–41.52), suspicious non-biopsied nodes (OR 15.58, 95% CI 3.44–70.59), and neoadjuvant therapy (OR 0.31, 95% CI 0.11–0.87) were associated with nodal metastasis; these findings should be interpreted cautiously given the expected clinical relationship between preoperative nodal suspicion and nodal positivity, and the limited number of nodal-positive events. Conclusions: Indocyanine green used as a sole tracer demonstrated high technical feasibility within a heterogeneous real-world axillary staging workflow in this single-centre cohort. These findings should be interpreted as implementation-focused feasibility data rather than formal diagnostic validation, given the retrospective design, heterogeneous case mix, and absence of an internal comparator. Full article

Background: Immunotherapy has become an integral part of systemic treatment for cervical cancer (CC). This study assessed the safety profile of cemiplimab and the association between immune-related adverse events (irAEs) and treatment outcomes in patients with persistent, recurrent or metastatic CC. Methods: This ambispective, multicenter, real-world cohort study included 101 patients treated in 13 reference oncology centers as part of the PCCIG-01 study. We evaluated the frequency and severity of irAEs and their association with progression-free survival (PFS) and overall survival (OS). Survival outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazards models, with p < 0.05 considered statistically significant. Results: After a median follow-up of 7.5 months, adverse events occurred in 45 patients (44.6%) and were mostly grade (G) 1–2. IrAEs were observed in 34 patients (33.7%). Endocrine toxicities predominated (n = 24, 58.5% of irAEs), followed by hepatic (n = 5, 12.2%) and gastrointestinal events (n = 4, 9.8%). G3 irAEs occurred in 8 patients (7.9%). Median PFS was 3.9 months (95% CI 2.9–5.6) in patients without irAEs and 10.9 months (95% CI 5.7–16.3) in those with irAEs (p = 0.03). Median OS was 15.3 months (95% CI 8.6–25.9) in patients without irAEs and was not reached in those with irAEs (95% CI 11.6-NR; p = 0.11). The development of irAEs was associated with a 54% reduction in the risk of progression (HR 0.46, 95% CI 0.27–0.80), with no statistically significant impact on OS. Conclusions: In exploratory analyses, the occurrence of irAEs was associated with improved PFS in cemiplimab-treated patients with persistent, recurrent or metastatic CC. Cemiplimab showed a manageable safety profile, with most toxicities being G1–G2. Full article

Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for patients with breast cancer. Breast cancer transcriptomic datasets were retrieved from the Gene Expression Omnibus and processed through standardized normalization procedures. Mutation-driven regulation of SYTL4 expression, treatment response to trastuzumab, cancer hallmark enrichment, and survival associations were evaluated using established bioinformatic tools and enrichment analysis based on integrated cancer hallmark gene sets. Additionally, DNA methylation profiles were analyzed. Herein, it is shown that SYTL4 mRNA expression is significantly (p = 2.01 × 10⁻⁴) diminished in breast cancer bearing BRCA1 mutations, suggesting a mechanistic interplay between BRCA1-driven genomic instability and SYTL4-regulated signaling cascades. Kaplan–Meier survival analysis demonstrated that elevated SYTL4 mRNA expression is significantly associated with improved overall survival in HER2-positive breast cancer patients (HR = 0.72; p = 0.034). Consistently, SYTL4 expression was significantly higher in patients who responded to trastuzumab therapy, supporting its potential as a biomarker of therapeutic response. Epigenetic analysis further revealed significant differential DNA methylation of SYTL4 between tumor and unaffected control tissues (p < 2.2 × 10⁻¹⁶), with region-specific hypomethylation in tumor regulatory regions. KEGG pathway and cancer hallmark enrichment analyses indicated that genes with prominent methylation changes are involved in cytokine signaling, growth factor pathways, and extracellular matrix remodeling, with the strongest associations observed for hallmarks related to genome instability, replicative immortality, resisting cell death, and metabolic reprogramming. In summary, we present that the gene SYTL4 is a prospective biomarker for survival and trastuzumab treatment responsiveness. Our observations posit that SYTL4 expression may signify a biological milieu conducive to sustained HER2 reliance and amplified therapeutic vulnerability. Full article

Nicotinamide adenine dinucleotide (NAD⁺) and its reduced form, NADH, are essential coenzymes that play central roles in cellular redox homeostasis, energy metabolism, DNA repair, and signaling. Cellular NAD⁺ levels are maintained by a dynamic balance between the de novo Preiss–Handler, and salvage synthesis pathways, and consumption by enzymes like sirtuins, PARPs, and CD38. Among these, the nicotinamide Phosphoribosyltransferase (NAMPT)-driven salvage pathway represents the predominant route of NAD+ synthesis. The specific regulation of NAD (NAD⁺ and NADH) levels across distinct subcellular compartments has emerged as a critical determinant of cellular function but it remains poorly understood. Dysregulation of NAD metabolism is a hallmark of aging and various pathologies, including cancer, neurodegenerative disorders, and metabolic diseases, making strategies to modulate NAD levels a promising therapeutic frontier. This review provides the first integrated overview of NAD concentrations across cellular compartments (cytosol, mitochondria, nucleus, endoplasmic reticulum, Golgi, peroxisomes, and the extracellular space) together with measurement and modulation strategies. We summarize current knowledge on NAD distribution within organelles, address key challenges in accurate quantification, and highlight established and emerging approaches for both global and compartment-specific analysis. Finally, we discuss therapeutic strategies, from NAD⁺ precursor supplementation to enzyme modulators and gene therapy, highlighting both their translational potential and current limitations in treating diverse diseases and prolonging life and health span. 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

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn “cold” tumors into “hot” ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology. Full article

Gold nanoparticles offer a versatile platform for cancer theranostics because their high atomic number can enhance X-ray energy deposition, their plasmonic properties support photothermal and photoacoustic applications, and their surfaces allow drug loading and molecular targeting. However, therapeutic benefit remains heterogeneous because tumor uptake, intratumoral coverage, and subcellular localization determine whether deposited gold can be converted into biologically effective damage. Redox context further shapes this conversion by determining whether AuNP-triggered physical or catalytic events can overcome local buffering and propagate into durable injury. During radiotherapy, AuNPs increase local secondary electron release and ROS formation, which can intensify DNA damage when GSH-dependent peroxide detoxification, thioredoxin-related buffering, and KEAP1-NRF2-regulated antioxidant responses are insufficient to contain the redox burden. In catalytic systems, Au-containing nanozymes can convert endogenous H₂O₂ into highly reactive radicals and may simultaneously deplete glutathione, thereby amplifying mitochondrial dysfunction and lipid peroxidation. During photoactivation, plasmonic heating and photosensitizer coupling further reshape ROS generation in a time-dependent and location-dependent manner. On the diagnostic side, CT or spectral CT can quantify tumor gold burden and coverage, whereas ROS-responsive photoacoustic, SERS, or fluorescence probes can report treatment-related oxidants and verify whether redox activation has occurred within the tumor. Clinical translation will therefore depend on quantification-guided dosing, definition of spatial coverage and activation timing, standardized redox-response readouts, and long-term safety evaluation. Full article

Background/Objectives: CTLA-4 is a key checkpoint of peripheral immune regulation, yet its biology cannot be reduced to inhibitory signaling alone. This review discusses CTLA-4 as a dynamic regulatory pathway shaped by ligand handling, intracellular trafficking, recycling, and cell-type-specific function, and examines how these features link molecular mechanism to human disease and therapy. Methods: We synthesized the structural, mechanistic, translational, and clinical literature spanning CTLA-4 molecular biology, cell-type-specific function, inborn errors of immunity, polygenic autoimmunity, transplantation, cancer immunotherapy, and immune-related adverse events. Results: CTLA-4 function depends on surface availability, trans-endocytosis of CD80/CD86, and tight control of endosomal trafficking. These features help explain why CTLA-4 haploinsufficiency, LRBA deficiency, and DEF6 deficiency converge clinically despite different upstream lesions, and why subtler CTLA-4 variation contributes to polygenic autoimmunity. Therapeutic studies also provide mechanistic insight. Abatacept can partly replace pathway function in monogenic disease, whereas belatacept highlights the limits of ligand blockade when endogenous coinhibition is also lost. In oncology, anti-CTLA-4 antibodies act through a more complex interplay involving checkpoint blockade, Fc biology, intratumoral Treg depletion, and receptor recycling. Emerging next-generation agents aim to retain antitumor activity while reducing systemic toxicity through more selective use of these mechanisms. Conclusions: Rather than a static inhibitory receptor, CTLA-4 is better viewed as a context-dependent regulatory pathway whose function depends on trafficking, surface availability, and cellular context. This perspective links molecular mechanism to clinical phenotype and supports more precise CTLA-4-targeted therapy. Full article

Epithelial ovarian cancer (EOC) poses a challenge owing to its high rate of recurrence and drug resistance, resulting in a 5-year survival rate of 30% in advanced stages. To elucidate the molecular mechanisms underlying EOC recurrence, we analyzed transcriptome data from patients with EOC and identified elevated USP19, a deubiquitinating enzyme, as being elevated in patients without recurrence in our previous study. Single-cell RNA sequencing analysis revealed that increased USP19 expression in epithelial cells is associated with activation of apoptotic pathways, suggesting that USP19 may inhibit EOC recurrence through deubiquitination of its binding proteins. Using the protein–protein interaction database, we identified DnaJC7 as a binding partner of USP19 and confirmed their interaction experimentally. USP19-mediated deubiquitination of DnaJC7 increases its protein stability. Notably, upregulation of USP19 and DnaJC7 disrupted the interaction between p53 and MDM2, and knockdown of USP19 and DnaJC7 resulted in decreased p53 expression following cisplatin treatment. These findings highlight the therapeutic potential of enhancing the USP19-DnaJC7 axis to stabilize p53 and improve cisplatin efficacy. Promoting USP19-mediated deubiquitination by stabilizing DnaJC7 may offer a novel combination strategy to enhance the efficacy of cisplatin-based cancer therapy. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited effective therapies. Two-dimensional (2D) in vitro models poorly recapitulate tumor microenvironment (TME) interactions, impeding the translational relevance of TNBC immunotherapy research. Three-dimensional patient-derived tumor organoids (3D PDTOs) have emerged as advanced preclinical models that better mimic tumor–immune interactions. The objective of this systematic review was to assess the landscape of 3D PDTO adoption in TNBC research and evaluate their application in addressing key bottlenecks in TNBC immunotherapy. We retrieved 394 studies published between 2015 and 2025 from the PubMed and ClinicalTrials.gov databases. Of those, 153 studies were included in the review. Fifty-eight (58) TNBC-specific studies met the inclusion criteria, including explicit mention of 3D PDTOs in the title or abstract, with confirmation in the Methods and Results sections. Studies were excluded if they used non-patient-derived tumor organoids or referred to other 3D models as 3D PDTOs. Data were collected from January 2025 through December 2025. Eligible studies were screened in three (3) tiers, grouped by relevant themes and graphed in Excel. We present an overview of the adoption of 3D PDTOs in TNBC research, highlighting the most common application trends within this scope. We also discuss the potential impact of artificial intelligence (AI) and regulatory guidance from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) pertinent to the adoption of organoids as human-relevant models to improve translational outcomes. Overall, this review provides actionable insights for leveraging 3D PDTOs to advance translational TNBC research and precision oncology. Full article

Background and Objectives: Perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is the standard of care for resectable gastric and gastroesophageal junction adenocarcinoma; however, up to 50% of patients develop metastatic recurrence. These patients have prior exposure to platinum and taxane agents, and optimal first-line treatment in the metastatic setting remains undefined. This study aimed to characterize real-world treatment patterns and outcomes in patients progressing after perioperative FLOT, focusing on relapse timing and HER2 status. Materials and Methods: This retrospective, multicenter cohort study included 296 patients from 31 centers across Türkiye, stratified into early relapse (≤6 months, n = 114) and late relapse (>6 months, n = 182) groups. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Median PFS and OS for the entire cohort were 6 and 9 months, respectively. Early relapsers had significantly shorter median PFS (4 vs. 6 months, p = 0.029) and OS (8 vs. 12 months, p = 0.047); however, early relapse timing did not retain independent prognostic significance on multivariable analysis. No significant difference in PFS or OS was observed between cytotoxic chemotherapy regimens in either relapse group. HER2 positivity was the only independent predictor of improved PFS on multivariable Cox analysis (HR 0.48, 95% CI 0.29–0.81; p = 0.006). In the late relapse group, trastuzumab-based chemotherapy achieved a median PFS of 14 months and OS of 18 months, significantly superior to all cytotoxic regimens (PFS p = 0.007; OS p = 0.029). Conclusions: In patients progressing after perioperative FLOT, cytotoxic chemotherapy regimen selection did not demonstrate a statistically significant survival difference in this retrospective cohort, regardless of relapse timing. HER2 positivity is the dominant predictive biomarker, and trastuzumab-based therapy suggests a potential survival benefit that warrants prospective validation. Comprehensive biomarker profiling at metastatic diagnosis and prospective trials designed for this post-FLOT population are needed to establish evidence-based treatment standards. Full article

Objectives: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. Methods: The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. Results: Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis—manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. Conclusions: Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC. Full article

Manganese-based nanomaterials have been novel multifunctional platforms in tumor immunotherapy because of their tunable multivalent states, biocompatibility, and multi-stimulus responsiveness. Current cancer treatments are insufficient and cause severe side effects; therefore, manganese-based nanomaterials are proposed in combination with immunotherapy to mitigate adverse effects. This review outlines the antitumor effects mediated by four key mechanisms: (1) activation of the cGAS-STING immune signaling pathway, (2) direct activation of immune cells, (3) induction of immunogenic cell death (ICD), and (4) modulation of the tumor microenvironment. These approaches are broadly categorized into two types: monotherapy and multimodal combination therapy. Monotherapy encompasses three specific modalities: (1) direct use as a Stimulator of Interferon Genes (STING) agonist, (2) vector-mediated targeted drug delivery, and (3) mediation of chemodynamic therapy to generate reactive oxygen species, thereby inducing ICD. Multimodal combination therapy involves synergistic integration with traditional or emerging treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, and low-level light therapy, as well as multimodal combination treatment methods. It significantly enhances the antitumor efficacy of traditional therapies through immunostimulation, thus achieving synergistic breakthroughs in treatment efficiency and survival rate. Collectively, the multifunctional integration of manganese-based materials is a novel strategy for developing “self-adjuvant” immunotherapeutic platforms and investigating the clinical translation potential. Full article

Natural bioactive compounds present promising avenues for the prevention and therapeutic intervention of cancer. Octacosanol has garnered significant attention for its distinctive biological properties, yet its specific antitumor effects and underlying mechanisms remain unclear. This study systematically evaluated its antitumor effects and elucidated the associated molecular mechanisms. We confirmed that it dose-dependently inhibited A549 cell proliferation in vitro. It also remarkably suppressed cell invasion and migration by downregulating MMP2 and MMP9 expression, an effect that was associated with reduced phosphorylation of JAK3/STAT3 and PI3K/AKT, suggesting a potential regulatory role of these signalling cascades. Meanwhile, it significantly inhibited tumor cell VEGF secretion and VEGF-mediated neoangiogenesis by modulating the PI3K/AKT signaling axis. Mouse experiments demonstrated that octacosanol significantly reduced tumor p-AKT, MMP2, and MMP9 levels, indicating its in vivo anti-metastatic effect. It also remarkably decreased tumor microvessel density, alongside reduced VEGF and vascular endothelial marker CD31 expression, further verifying its potent anti-angiogenic activity. This work provides evidence of octacosanol’s dual anti-metastatic and anti-angiogenic effects in lung cancer and offers novel mechanistic insights into its activity against this highly prevalent malignancy. These findings establish a solid foundation for further exploration and development of octacosanol as a promising adjuvant for clinical antitumor therapy. Full article