Search Results (98)

Oral squamous cell carcinoma (OSCC) frequently develops within chronically injured oral mucosa and may be preceded by clinically recognizable oral potentially malignant disorders (OPMDs), which provide an important window for cancer interception. This review examines how etiological exposures, persistent inflammation, and lesion-specific epithelial–stromal–immune interactions cooperate during the transition from mucosal injury to dysplasia, carcinoma in situ, and invasive OSCC. Major carcinogenic exposures, including tobacco, alcohol, and areca nut, are considered together with context-dependent contributors such as microbial dysbiosis, viral infection, and immune-mediated epithelial injury. At the molecular level, inflammation-driven oral carcinogenesis involves cytokine and chemokine amplification, oxidative and nitrosative stress, NF-κB and STAT3 activation, the COX-2/PGE₂ axis, genomic instability, field cancerization, epithelial–stromal crosstalk, angiogenesis, immune dysregulation, and epigenetic and non-coding RNA-mediated reprogramming. Emerging tools such as molecular risk assessment, liquid biopsy, optical imaging, spatially resolved profiling, and artificial intelligence-assisted models may improve identification of high-risk lesions, although most biomarkers require further prospective validation. Prevention should therefore integrate exposure control, biopsy-based diagnosis, local treatment when indicated, long-term surveillance, and trial-based precision strategies according to lesion risk, intervention window, and safety profile. This review supports a shift from lesion-centered management toward risk-adapted precision prevention in inflammation-driven oral carcinogenesis. Full article

Background/Objectives: Oral potentially malignant disorders (OPMDs) require accurate risk stratification to identify patients at the highest risk for severe oral epithelial dysplasia (OED) or oral squamous cell carcinoma (OSCC). We developed and internally validated the oral cancer numerical index (OCNI), a quantitative risk score derived from clinical features and deep learning-based brush cytology measurements. Methods: This retrospective model development and internal validation study was conducted using data from the multicenter Grand Opportunity study. Prospectively recruited subjects with OPMD with complete data were divided at the subject level into a training set (n = 384) and a holdout test set (n = 164) using a 70:30 diagnosis-stratified split. The primary endpoint was severe OED or OSCC versus benign diagnoses, and mild and moderate OED. Predictors included age, sex, tobacco history, lesion color, lesion size, multiple lesions, ulcerative morphology, and the percentages of differentiated squamous epithelial and small round cells derived from deep learning-based cytology. Prespecified rule-out and rule-in thresholds were selected in the training set to target 90% sensitivity and 90% specificity, respectively, and then applied to the holdout test set. Results: At the prespecified rule-out threshold (OCNI ≤ 37.6), sensitivity was 92% and negative predictive value was 97%. At the rule-in threshold (OCNI > 60.0), specificity was 89% and positive predictive value was 67%. Calibration was good in the holdout set (intercept, −0.07; slope, 1.13; Hosmer–Lemeshow p = 0.36), and OCNI increased significantly with worsening histopathologic severity. Conclusions: OCNI provided an objective, clinically interpretable estimate of risk for severe OED or OSCC, with strong rule-out and rule-in performance and good calibration. These findings support further external validation of OCNI as an adjunctive tool for oral lesion risk stratification. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy. The identification and management of precursor lesions, particularly the increasingly common intraductal papillary mucinous neoplasms (IPMNs), pose a significant challenge, creating a profound clinical dilemma between intercepting pancreatic ductal adenocarcinoma and avoiding surgical overtreatment. This literature review aims to synthesize the latest evidence to facilitate a transition from purely morphology-based surveillance toward a biologically informed risk stratification paradigm. This approach could provide a personalized risk-stratification algorithm that optimizes therapeutic management and enables timely intervention for pancreatic cancer. By using PubMed, Embase, Scopus, and Web of Science, we analyzed and summarized key findings from recent literature (2020–2025), including cohort studies, mechanistic analyses, evidence-based guidelines, and systematic reviews on cyst fluid biomarkers (CEA panels, DNA/RNA sequencing), and emerging AI applications. Prospective and multicenter studies consistently report that NOD is independently associated with high-risk stigmata, cyst progression, and malignant transformation. Mechanistic research suggests a bidirectional interplay between the evolving neoplasia and pancreatic endocrine dysfunction. Updated guidelines underscore the need for more precise diagnostic algorithms. Recent work demonstrates that advanced cyst fluid markers—CEA panels, DNA/RNA sequencing, and multi-omic signatures—significantly improve diagnostic accuracy. Furthermore, explainable AI models show encouraging performance in predicting malignancy and assisting patient triage. Risk stratification in PCLs is shifting from morphology-based assessment toward integrated, multimodal approaches combining clinical, endocrine, imaging, molecular, and computational data. Recent evidence positions new-onset diabetes as a clinically accessible and biologically plausible marker of high-risk IPMNs. Similarly, molecular assays and AI-enhanced analytics provide an additional layer of diagnostic precision. The development of personalized risk prediction algorithms could improve early detection of malignancy while reducing unnecessary surgical resections. Full article

Background: Preoperative side-specific identification of extracapsular extension (ECE) is important for selecting an appropriate nerve-sparing strategy at radical prostatectomy. Patients with multiparametric magnetic resonance imaging (mpMRI)-defined capsular contact represent a clinically challenging subgroup because contact raises concern for ECE but does not uniformly indicate extraprostatic disease. We aimed to develop a side-specific nomogram for individualized ECE prediction and perform preliminary internal validation in this selected population. Materials and Methods: We retrospectively analyzed 323 prostate lobes from 286 patients with biopsy-proven, non-metastatic prostate cancer and mpMRI-defined capsular contact who underwent robot-assisted radical prostatectomy between 2015 and 2021 at a single institution. The dataset was randomly split into training (70%) and testing (30%) cohorts. Three multivariable logistic-regression models were developed and compared. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC-ROC), calibration by intercept and slope, and clinical utility by decision curve analysis. A nomogram was derived from the best-performing model in the internal split-sample comparison. Results: Side-specific ECE was present in 110/323 lobes (34.1%). Among the candidate models, the forward-selection model showed the most favorable apparent performance, with an AUC-ROC of 0.85 in training and 0.83 in testing, together with good test-set calibration (intercept 0.24; slope 0.97). The final model included a capsular contact length ≥10 mm, percentage tumor involvement in positive biopsy cores, number of positive biopsy cores, and index lesion size. At a 10% predicted risk threshold, 32% of lobes were classified as low risk, with an observed ECE rate of about 5%. Conclusions: We developed a side-specific nomogram tailored to patients with mpMRI-defined capsular contact and performed preliminary internal validation. The model may aid preoperative side-specific risk assessment relevant to nerve-sparing planning, but external validation and assessment of clinical impact are required before clinical adoption. Full article

Background/Objectives: Early identification of breast cancer patients who are likely or unlikely to benefit from neoadjuvant chemotherapy (NAC) remains clinically important because ineffective treatment may delay definitive surgery and expose patients to unnecessary toxicity. Quantitative ultrasound (QUS) radiomics offers a contrast-free and repeatable method for extracting tissue-sensitive imaging biomarkers from raw ultrasound data. This study aimed to evaluate whether baseline QUS radiomic features and early treatment-induced changes could predict a pathologic response to NAC in a real-world single-center cohort. Methods: We designed a prospective observational study including 96 consecutive women with biopsy-proven stage II–III breast cancer treated with NAC at Victor Babes University of Medicine and Pharmacy Timisoara. All patients underwent standardized QUS examinations before treatment and again at week 2. The response was defined pathologically at surgery as residual cancer burden class 0/I versus II/III. Clinical, histopathologic, and QUS variables were compared between responders and non-responders. Group comparisons used Student’s t test, Mann–Whitney U test, chi-square testing, and Fisher’s exact test where appropriate. Multivariable logistic regression was used to identify independent predictors of response. Model discrimination was summarized using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Forty-three patients (44.8%) were classified as responders and 53 (55.2%) as non-responders. Responders had higher baseline Ki-67 values (47.8 ± 13.1% vs. 41.9 ± 13.0%, p = 0.033), lower baseline homogeneity (0.3 ± 0.1 vs. 0.4 ± 0.1, p = 0.010), and higher peritumoral heterogeneity (0.9 ± 0.1 vs. 0.8 ± 0.2, p = 0.027). At week 2, responders showed larger increases in mid-band fit (3.0 ± 0.8 vs. 1.2 ± 0.8 dB, p < 0.001), greater entropy change (0.7 ± 0.2 vs. 0.2 ± 0.2, p < 0.001), more pronounced spectral intercept reduction (−3.5 ± 1.4 vs. −1.2 ± 1.3, p < 0.001), and greater tumor shrinkage (−24.3 ± 7.0% vs. −11.1 ± 5.7%, p < 0.001). In multivariable analysis, Δ MBF and Δ entropy remained independent predictors of pathologic response. The combined clinical-plus-QUS model achieved an AUC of 0.89. Conclusions: Baseline microstructural heterogeneity and very early QUS-derived treatment changes were strongly associated with the pathologic response to NAC. These findings support the potential role of QUS radiomics as a low-cost, repeatable early-response biomarker in breast cancer. Full article

Drug resistance is a major cause of treatment failure in breast cancer, yet mutation-centered models do not fully explain delayed resistance, reversible tolerance, or re-sensitization after treatment interruption. Here, we synthesize recent findings in drug-tolerant persister (DTP) biology, clonal evolution, and tumor ecosystem dynamics to propose a breast cancer-focused Resistance Continuum as a conceptual framework for organizing the transition from initial therapy to stable resistance across ER-positive, HER2-positive, and triple-negative disease. Here, we synthesize recent findings in drug-tolerant persister (DTP) biology, clonal evolution, and tumor ecosystem dynamics to propose a breast cancer-focused Resistance Continuum as a conceptual framework for organizing the transition from initial therapy to stable resistance across ER-positive, HER2-positive, and triple-negative disease. This framework describes a canonical, but not universal, trajectory spanning treatment-naïve heterogeneity, pre-adaptive priming, reversible DTP states, cycling persisters, and genetically stabilized resistant clones. We discuss how epigenetic and metabolic plasticity may sustain persistence, and we present epigenetic memory as an emerging hypothesis linking repeated non-genetic persistence to facilitated resistance in selected contexts. We also compare subtype-specific features of DTP biology, outline a multi-omics roadmap for interrogating the continuum, and highlight therapeutic opportunities for resistance interception. Overall, the Resistance Continuum is intended as a working scaffold to integrate current evidence and guide future mechanistic and translational studies. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Transforming growth factor-β (TGF-β) signaling plays a central role in lung tissue homeostasis, coordinating epithelial repair, immune resolution, and stromal remodeling following injury. However, persistent or dysregulated TGF-β activation is a hallmark of both idiopathic pulmonary fibrosis (IPF) and lung cancer, two devastating pulmonary diseases that are traditionally studied as distinct entities. Emerging evidence suggests that this dichotomous view may obscure shared pathogenic mechanisms driven by aberrant TGF-β signaling dynamics. In this review, we synthesize experimental, translational, and clinical findings to propose a unifying framework in which IPF and lung cancer represent endpoints along a shared TGF-β–driven pathological continuum. We highlight how the duration and intensity of TGF-β signaling determine divergent cellular outcomes across epithelial cells, fibroblasts, and immune compartments—ranging from physiological wound repair to irreversible fibrotic remodeling and the establishment of a pro-tumorigenic niche. Particular emphasis is placed on the temporal transition from acute injury responses to chronic signaling states that promote epithelial plasticity, fibroblast fixation, immune suppression, and genomic instability. By integrating fibrosis and tumorigenesis into a single pathophysiological model, this review reframes TGF-β signaling as a time-dependent disease modifier rather than a disease-specific factor. This perspective provides a conceptual basis for therapeutic strategies targeting TGF-β signaling windows to intercept disease progression before irreversible fibrosis or malignant transformation occurs. Full article

Background: Erectile dysfunction is a common late effect of prostate radiotherapy. Hydrogel spacers aim to reduce radiation exposure to nearby structures by increasing the distance between the prostate and surrounding tissues, potentially preserving sexual function. Methods: In this retrospective cohort study of 117 prostate cancer patients who received hydrogel spacers, we compared pre- and post-insertion radiation dose and anatomical positioning of erectile structures using paired t-tests. Longitudinal sexual function, assessed via EPIC scores, was modeled using linear mixed-effects regression with natural splines (df = 3), incorporating random intercepts and slopes to account for within-subject variability. Results: Spacer insertion significantly reduced radiation dose to the left and right neurovascular bundles (mean reductions: 1.66 Gy, 95% CI: 1.32–2.00; and 1.64 Gy, 95% CI: 1.28–2.01, respectively; p < 0.01) and the right perineal artery (1.33 Gy, 95% CI: 0.57–2.09; p < 0.01). No significant dose changes were observed for the penile bulb or left perineal artery, nor in anatomical distances. However, spatial displacement was confirmed by significant overlap and integrated volume changes. Longitudinal modeling showed a significant decline in sexual function between 12 and ≥36 months post-treatment (Spline 2: β = –12.72, 95% CI: −18.52–−6.92 and Spline 3: β = –6.68, 95% CI: −10.96–−2.40; p < 0.01). Conclusions: Hydrogel spacer insertion was associated with significant reductions in radiation dose to erectile structures, most notably the neurovascular bundles and the right perineal artery. However, longitudinal analyses revealed no corresponding preservation of sexual function. These findings suggest that while hydrogel spacers effectively reduce radiation exposure to key anatomical structures, their clinical benefit for maintaining erectile function remains uncertain. Full article

Algal carotenoids play a promising role in handling chronic diseases due to their diverse bioactive properties, including anti-inflammatory, antioxidant, and anticancer effects. This study assesses the activity of the antioxidant xanthophyll diatoxanthin (Dt), derived from marine diatoms, against triple-negative breast cancer (TNBC) cells using in vitro models, gene expression evaluation, and explores its role in potentiating the cytotoxic effect of chemotherapy. Dt exhibited selective activity against MDA-MB-231 and BT-549 TNBC cells at concentrations ≥12.5 ng/mL, with maximal effects observed at 25 ng/mL while sparing human umbilical vein endothelial cells (HUVECs) at these doses. When combined with doxorubicin (0.1–0.5 μM), Dt enhanced the anti-tumor efficacy in both TNBC cell lines, further reducing cell viability compared with doxorubicin alone (p < 0.05–0.001). Dt also exerted its activity in inhibiting migration and chemotaxis by approximately 30–50% compared with the controls (p < 0.01) and suppressing 3D-tumor spheroid growth at day 12 (up to >50% reduction, p < 0.001). Notably, secretome analysis revealed Dt-induced changes in inflammatory, oxidative and angiogenic mediators, highlighting its ability to modulate the TNBC microenvironment. Dt also downregulated key pro-survival, pro-angiogenic and pro-tumorigenic genes in both TNBC cell lines, supporting its role in disrupting oncogenic pathways. Angiogenesis-related genes were significantly reduced. Dt also decreased the expression of angiogenic mediators in HUVECs, supporting Dt’s role in inhibiting tumor vascularization. Results on gene expression regulation were also confirmed by RNA-Seq analysis. These findings pose Dt as a promising chemopreventing candidate in the challenging fight against TNBC, a well-known type of cancer that is aggressive and resistant to conventional therapies, targeting critical pathways for tumor survival, such as inflammation, angiogenesis, tumor cell growth, and cell migration. Given its selective activity against TNBC cells, ability to enhance chemotherapy efficacy, and modulation of the tumor microenvironment, Dt holds promise as a complementary drug for cancer prevention and interception. Future studies should focus on validating these effects in vivo and exploring Dt’s potential in combinatorial treatment strategies for cancer. Full article

Background & Objectives: Quantitative ultrasound (QUS) radiomics extracts microstructure-sensitive spectral features from radiofrequency data and may provide contrast-free, early indicators of neoadjuvant chemotherapy (NAC) response in breast cancer. This review synthesized open access human studies evaluating QUS radiomics for a priori prediction and early on-treatment monitoring. Methods: Following PRISMA-2020, we included English, free full-text clinical studies of biopsy-proven breast cancer receiving NAC that reported QUS spectral parameters (mid-band fit, spectral slope/intercept) ± textures/derivatives and machine learning models against clinical/pathologic response. Data on design, RF acquisition/normalization, features, validation, and performance (area under the curve (AUC), accuracy, sensitivity/specificity, balanced accuracy) were extracted. Results: Twelve cohorts were included. A priori baseline models achieved accuracies of 76–88% with AUCs 0.68–0.90; examples include 87% accuracy in a multi-institutional study, 82% accuracy/AUC 0.86 using texture-derivatives, 86% balanced accuracy with transfer learning, 88% accuracy/AUC 0.86 with deep learning, and AUC 0.90 in a hybrid QUS and molecular-subtype model. Early monitoring improved discrimination: week-1 results ranged from AUC 0.81 to 1.00 and accuracy 70 to 100%, noting that the upper bound was reported in a small cohort using combined QUS and diffuse optical spectroscopy features, while week 4 typically peaked (AUC 0.87–0.91; accuracy 80–86% in observational cohorts), and one series reported week-8 accuracy of 93%. Across reporting cohorts, mean AUC increased with a 0.05 absolute gain. A randomized feasibility study reported prospective week-4 model accuracy of 98% and demonstrated decision impact. Conclusions: QUS radiomics provides informative a priori prediction and strengthens by weeks 1–4 of NAC, supporting adaptive treatment windows without contrast or radiation. Standardized radiofrequency (RF) access, normalization, region of interest (ROI)/margin definitions, and external validation are priorities for clinical translation. Full article

Strong communication is central to the translation of breast cancer screening availability into uptake. This experiment tests the role of design features of screening advertisements in directing visual attention in screening-eligible women (≥40 years). To this end, a within-subjects eye-tracking experiment (N = 30) was conducted in which women viewed six static public service advertisements. Predefined Areas of Interest (AOIs), Text, Image/Visual, Symbol, Logo, Website/CTA, and Source/Authority—were annotated, and three standard measures were calculated: Time to First Fixation (TTFF), Fixation Count (FC), and Fixation Duration (FD). Analyses combined descriptive summaries with subgroup analyses using nonparametric methods and generalized linear mixed models (GLMMs) employing participant-level random intercepts. Within each category of stimuli, detected differences were small in magnitude yet trended towards few revisits in each category for the FC mode; TTFF and FD showed no significant differences across categories. Viewing data from the perspective of Areas of Interest (AOIs) highlighted pronounced individual differences. Narratives/efficacy text and dense icon/text callouts prolonged processing times, although institutional logos and abstract/anatomical symbols generally received brief treatment except when coupled with action-oriented communication triggers. TTFF timing also tended toward individual areas of interest aligned with the Scan-Then-Read strategy, in which smaller labels/sources/CTAs are exploited first in comparison with larger headlines/statistical text. Practically, screening messages should co-locate access and credibility information in early-attention areas and employ brief, fluent efficacy text to hold gaze. The study adds PSA-specific eye-tracking evidence for breast cancer screening and provides immediately testable design recommendations for programs in Greece and the EU. Full article

Bone metastases remain a leading cause of morbidity and mortality in patients with advanced breast, prostate, and lung cancers. A striking clinical feature of bone metastasis is the ability of disseminated tumor cells (DTCs) to persist in a dormant state for years or even decades before reawakening to drive overt disease. While the molecular and microenvironmental cues that induce and maintain dormancy have been increasingly studied, the mechanisms governing dormancy escape remain poorly defined yet are critical for preventing relapse. In this review, we synthesize emerging evidence on how the bone microenvironment orchestrates the transition of dormant tumor cells into proliferative lesions. We discuss how osteoclast-mediated bone resorption liberates growth factors such as TGF-β and IGF-1, fueling reactivation; how loss of osteoblast-mediated quiescence signals disrupts the endosteal niche; and how bone marrow adipocytes provide metabolic support through lipid transfer and adipokine secretion. We highlight the role of immune surveillance in maintaining dormancy and how immunosuppressive myeloid populations, regulatory T cells, and inflammatory triggers, such as neutrophil extracellular traps, promote escape. Additional emphasis is placed on extracellular matrix remodeling, mechanotransduction, angiogenic switching, and systemic factors, including aging, hormonal changes, and sympathetic nervous system activation. We also review epigenetic and metabolic reprogramming events within dormant cells that enable reactivation. Finally, we evaluate therapeutic strategies to sustain dormancy or prevent reawakening, including osteoclast-targeted therapies, immune-modulating approaches, and epigenetic or metabolic interventions. By integrating these insights, we identify key knowledge gaps and propose future directions to intercept dormancy escape and delay or prevent metastatic relapse in bone. Full article