Programmed death-ligand 1 (PD-L1) expression in Grade Group 1 (GG1) prostate carcinoma biopsies has not been established as a marker of pathological upgrading at radical prostatectomy (RP). This two-center retrospective case-control study included 172 men with GG1 carcinoma in the biopsy closest to RP: all 86 patients upgraded to GG2 and 86 randomly selected non-upgraded controls from 126 eligible GG1 patients. PD-L1 was assessed with the SP263 clone using the combined positive score (CPS), with CPS ≥ 1 predefined before outcome comparison. CPS ≥ 1 occurred in 36/86 upgraded cases (41.9%) and 18/86 controls (20.9%; unadjusted odds ratio [OR], 2.72; 95% confidence interval [CI], 1.39-5.33; p = 0.005). After adjustment for serum prostate-specific antigen, positive-core count, Prostate Imaging Reporting and Data System category, and center, CPS ≥ 1 remained associated with upgrading (adjusted OR, 2.91; 95% CI, 1.47-5.97; p = 0.003). A Firth bias-reduced sensitivity model including digital rectal examination yielded a similar CPS estimate. Biopsy CPS ≥ 1 was associated with biopsy-RP grade discordance, but the study does not establish an optimal cutoff, predictive performance, or clinical utility. Prospective multicenter validation, including active-surveillance outcomes, is required.

Actionable ALK, ROS1, RET, NTRK, and NRG1 fusions define biologically distinct subsets of advanced non-small cell lung cancer (NSCLC), yet real-world data across these rare populations remain limited. We retrospectively evaluated patients with advanced NSCLC treated at Memorial Healthcare System who received genotype-matched fusion-directed therapy; the first fusion-directed agent defined the index treatment, and survival was measured from its initiation. Progression was determined from radiographic reports and treating-oncologist documentation. After patient-level reconciliation, 59 unique patients were included: 29 ALK, 14 ROS1, 11 RET, 3 NTRK, and 2 NRG1. Median follow-up was 47.7 months (95% CI, 28.6-58.7), median progression-free survival was 44.8 months (95% CI, 17.1-not estimable), and median overall survival was not reached. No statistically significant survival differences were detected among ALK, ROS1, and RET subgroups, although limited sample sizes preclude exclusion of clinically meaningful differences. Later-line index therapy was not significantly associated with progression-free survival in exploratory unadjusted analysis. These findings provide descriptive real-world evidence of precision-oncology implementation across actionable fusion-defined NSCLC while underscoring that pooled outcomes should not be interpreted as evidence of equivalent efficacy across molecular subtypes or therapies.

Oral diseases represent a major global health burden, and non-coding RNAs (ncRNAs) have emerged as pivotal regulators in their pathogenesis, offering new avenues for diagnosis and therapy. This review synthesizes current knowledge on ncRNAs-including miRNAs, lncRNAs, and circRNAs-across a spectrum of oral conditions, encompassing periodontitis, oral squamous cell carcinoma, oral submucous fibrosis, oral lichen planus, oral leukoplakia, and chronic orofacial pain. Mechanistically, ncRNAs function through competing endogenous RNA networks, immune-inflammatory cascades, metabolic reprogramming, and fibroblast activation; notably, recent discoveries have revealed that certain circRNAs and lncRNAs encode functional micropeptides, adding an additional layer of regulatory complexity in oral pathology. On the translational front, salivary and circulating ncRNAs have shown promise as non-invasive biomarkers. However, major bottlenecks remain, including insufficient longitudinal validation, marked technical heterogeneity across studies, and delivery challenges specific to the oral microenvironment. By critically evaluating mechanistic insights alongside these translational barriers, this review identifies critical knowledge gaps and proposes prioritized strategies to facilitate the clinical integration of ncRNA-based precision dentistry.

OX40 (TNFRSF4) is a costimulatory T-cell receptor and OX40 agonists are in clinical development, yet its role in small cell lung cancer (SCLC) is still to be characterised. We analysed the discovery cohort (n = 77, 48 events), GSE60052 (n = 79 tumours; 48 with survival), GDSC1+GDSC2 (61 SCLC cell lines, 542 drugs) and human SCLC single-cell atlas (77,143 cells from primary and metastatic sites, 20 donors), using Cox models, FDR-controlled correlation, nested-model comparison and deconvolution. High TNFRSF4 showed a non-significant protective trend (pooled HR = 0.86 per SD, 0.68-1.10, p = 0.23); a nominal cutpoint did not survive correction for cutpoint search (p = 0.25). No drug reached FDR < 0.05 among 658 tests, including platinum agents and etoposide. TNFRSF4 tracked immune infiltration (13-gene score ρ = 0.76, p = 3 × 10^-16) and was detected in 17.6% of T cells versus 1.03% of malignant cells in all 20 donors. OX40 was enriched in the POU2F3/SCLC-P subtype (p = 0.033), persisting after immune adjustment (β = 1.32, p = 0.011) but not replicating independently (p = 0.10). Adding TNFRSF4 to clinical-plus-immune models provided no meaningful discrimination gain (ΔC-index ≤ 0.005). Power was limited to HR ≥ 1.50 harmful or HR ≤ 0.67 protective, so the observed trend is undetectable at this size. Bulk OX40 therefore primarily reflects immune infiltration, and its SCLC-P association is a hypothesis for prospective testing.

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer, yet the molecular predictors of pathological response remain incompletely defined, particularly regarding microRNA (miRNA) dynamics. We investigated paired pre- and post-NAC miRNA expression profiles in relation to molecular subtype, residual cancer burden (RCB), and clinical timing parameters. Seven patients with invasive breast cancer (Luminal A n = 3, Luminal B n = 1, TNBC n = 2, HER2+ n = 1) who received NAC (AC-T or TCHP) were included in this pilot study. Small-RNA sequencing (NovaSeq X Plus, CeGaT GmbH, project S17293) was performed on 14 FFPE specimens (7 pre-NAC core needle biopsies, 7 post-NAC surgical specimens). Differential expression analysis used the paired Wilcoxon signed-rank test with Benjamini-Hochberg correction. Spearman correlations assessed associations between miRNA expression, RCB score, and clinical timing intervals. Candidate miRNAs were subsequently annotated using experimentally validated miRNA-target interactions. After filtering (≥ three counts in ≥ three samples), 759 miRNAs were analysed. No miRNA reached strict significance (padj < 0.05, |log₂FC| > 1.0) after multiple testing correction, consistent with the limited statistical power (n = 7). Under exploratory criteria (p < 0.10, |log₂FC| > 0.5), 156 candidate miRNAs were identified: 70 upregulated and 86 downregulated post-NAC. Leading candidates included hsa-miR-139-3p (+2.60), hsa-miR-139-5p (+2.36), and hsa-miR-1323 (+1.55) as upregulated, and hsa-miR-429 (-2.53), hsa-miR-141-3p (-1.79), and hsa-miR-1277-5p (-1.25) as downregulated post-NAC. The single patient achieving the lowest residual disease burden (P3, Luminal B, RCB-I, score 1.32) displayed a distinct pre-treatment miRNA profile, separating from all other pre-NAC specimens on principal component analysis and characterised by higher baseline hsa-miR-139-3p/-5p and lower baseline hsa-miR-429 and hsa-miR-141-3p expression, suggesting that baseline miRNA expression patterns may contribute to differential chemotherapy response. RCB score showed a non-significant positive trend with post-NAC Ki-67 (ρ = +0.71, p = 0.07). This pilot study identifies NAC-modulated candidate miRNAs in breast cancer and establishes a paired FFPE-based small-RNA-sequencing workflow applicable in routine clinical settings. The distinct pre-treatment profile of the single best responder generates the testable hypothesis that baseline expression of tumour suppressor miRNAs of the miR-139 family, together with low miR-200-family expression, may track chemosensitivity. As no candidate reached statistical significance after multiple testing correction and none has been validated in an independent cohort or by an orthogonal method, all findings are exploratory and hypothesis-generating. The results support larger prospective validation studies examining miRNA signatures as predictive biomarkers of NAC response across breast cancer molecular subtypes.

Phosphorylated ACC (pACC), a downstream effector of the LKB1/AMPK pathway, may support tumor bioenergetics and exert a tumor-promoting role in glioblastoma (GBM). In the randomized REGOMA trial, pACC expression was associated with improved overall survival (OS) in GBM patients treated with regorafenib, but its validity in large cohorts is unclear. This study aimed to characterize pACC and phosphorylated AMPK (pAMPK) expression in a real-world GBM cohort and to assess their prognostic and predictive value in patients receiving second-line regorafenib or fotemustine/lomustine. In this retrospective, multicenter translational study, pACC and pAMPK were assessed by immunohistochemistry on FFPE tumor sections from 174 IDH-wild-type GBM patients treated with regorafenib (n = 84) or fotemustine/lomustine (n = 90). Staining was performed with a validated anti-pACC monoclonal antibody and quantified by digital pathology. Survival analyses included univariable and multivariable Cox proportional hazards models, with interaction testing. pACC and pAMPK were expressed in 85.6% and 95.4% of samples, respectively, with heterogeneous spatial patterns. Neither marker was significantly associated with OS in the univariable analyses, and neither retained independent prognostic value in multivariable analysis. Regorafenib was associated with significantly longer OS than alkylating agents (10.4 vs. 6.3 months; p = 0.0021). However, the treatment-by-pACC interaction test was not statistically significant (adjusted p = 0.610), providing no formal evidence of a differential treatment effect by pACC status. Although pACC-positive expression was enriched among patients experiencing longer overall survival under regorafenib, formal treatment-by-biomarker interaction was non-significant. These exploratory findings indicate that pACC is not an established predictive biomarker and warrant prospectively powered evaluation.

Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are surrogate markers of the systemic immune-inflammatory response proposed as perioperative prognostic biomarkers in epithelial ovarian cancer (EOC), yet their performance across subgroups remains unexamined. In 373 EOC patients undergoing primary cytoreductive surgery, postoperative day-1 changes (ΔSII, ΔNLR, ΔPLR) were compared for overall survival (OS) and progression-free survival (PFS) across 10 subgroups, and a Clinical-Inflammatory Risk Score (CIRS) combining inflammation with stage and residual disease was developed. Individual markers showed modest discrimination (area under the curve [AUC] 0.579-0.615); the marker with the highest AUC varied by context, with ΔPLR ranking first most often, notably in non-serous tumors, though none was statistically superior. Seeking a molecular counterpart, two public transcriptomic cohorts were re-analyzed: VWF was consistently higher in clear cell than serous carcinoma, whereas IL6-STAT3-related differences were cohort-dependent. The CIRS achieved AUCs of 0.752 (OS) and 0.764 (PFS), a six-fold mortality gradient (7.2% vs. 44.4%), and remained independently associated with OS and PFS (hazard ratio 2.55 and 2.24 per standard deviation), though discrimination was not significantly better than stage and residual disease alone. These biomarkers show subgroup-dependent prognostic value, and the CIRS provides an exploratory risk-stratification framework warranting prospective validation.

Paclitaxel (PTX) remains a major component of treatment for solid tumors, but its clinical performance is limited by poor aqueous solubility, solvent-associated toxicity, heterogeneous tumor exposure, and multifactorial drug resistance. This narrative review examines PTX nanomedicines from a molecular pharmacology perspective, focusing on how carrier design interacts with resistance pathways, tumor microenvironment signals, and intracellular drug trafficking. We outline resistance mechanisms involving ATP-binding cassette subfamily B member 1 (ABCB1)/P-glycoprotein (P-gp)-mediated efflux, microtubule remodeling, apoptosis-related signaling, epigenetic regulation, extracellular matrix deposition, hypoxia, and redox imbalance. We evaluate albumin-bound formulations, liposomes, polymeric micelles, stimuli-responsive carriers, biomimetic systems, carrier-free prodrug assemblies, and multidrug co-delivery platforms according to the molecular and biological barriers they address. Particular attention is given to pH-, redox-, enzyme-, and hypoxia-responsive release; tissue penetration and subcellular localization; and co-delivery of PTX with chemosensitizers, nucleic acids, or pathway-directed agents. Molecular simulation and machine learning are considered as tools for formulation optimization and biomarker-guided patient stratification. These approaches can coordinate drug exposure and resistance modulation in preclinical models, but clinical benefits remain inconsistent. Translation will require reproducible formulations, clinically predictive models, direct measurement of intratumoral drug levels, and validated biomarkers linking molecular delivery mechanisms to patient outcomes.

Disulfiram (DSF), long used as an aversive agent in alcohol dependence therapy, has recently regained attention as a promising candidate for oncological drug repurposing. After administration, DSF is rapidly reduced to diethyldithiocarbamate (DDC), which, in the presence of Cu²⁺, forms the complex Cu(DDC)₂. This compound acts as a strong inducer of oxidative stress, an inhibitor of the ubiquitin-proteasome system, and a suppressor of endogenous hydrogen sulfide (H₂S) synthesis. DSF also modifies protein and non-protein thiol groups, disrupting cancer cell metabolism and promoting apoptosis. Despite robust preclinical evidence, clinical translation remains limited. Key obstacles include DSF's rapid metabolism, insufficient availability of free copper ions in humans, and the lack of predictive biomarkers capable of identifying responsive patients. Another challenge is DSF's low oral bioavailability, which prevents the drug from reaching tumor tissue at therapeutically effective concentrations. Consequently, current research focuses on advanced nanocarrier systems designed to protect DSF from premature degradation and ensure its controlled release within the tumor microenvironment. This review summarizes the multifaceted anticancer mechanisms of DSF and discusses biological and pharmacological factors underlying the discrepancies between experimental findings and clinical outcomes.

Oral squamous cell carcinoma (OSCC) prognosis remains limited by TNM staging alone. We conducted a systematic review and meta-analysis to evaluate preoperative neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte (LMR) ratios as prognostic markers. We searched PubMed/MEDLINE, Scopus, Base, Google Scholar and ScienceDirect from inception to 30 May 2026. Eligible studies reported preoperative ratios and survival outcomes, namely, overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), in surgically treated OSCC. Risk of bias was assessed with the QUIPS tool. Random-effects meta-analyses of multivariate hazard ratios (HRs) were primary; univariate data, heterogeneity, prediction intervals, sensitivity and subgroup analyses were also performed. Thirty-nine studies (12,153 patients; mostly East Asian retrospective cohorts) were included. Elevated NLR predicted worse overall survival (HR 1.51, 95% CI 1.32-1.73) and disease-specific survival (HR 2.00, 1.58-2.54). NLR also showed a significant association with DFS (HR = 1.47, 95% CI: 1.21-1.78), though the prediction interval crossed unity. PLR and LMR showed weaker, less consistent associations. Evidence was limited by predominant retrospective design, geographic concentration and variable cut-offs. Preoperative NLR is a reproducible, inexpensive prognostic biomarker that may complement TNM staging; standardized thresholds require prospective validation. The review was registered in PROSPERO; no specific funding was received.