Abstract: Background: Prostate cancer remains a major cause of cancer morbidity and mortality among men in the United States. Differences in diagnosis and survival across racial and socioeconomic groups continue to raise concern in clinical and public health research. Population based datasets provide an opportunity to examine patterns of advanced disease and survival outcomes across diverse demographic groups. Objective: This study evaluated racial and socioeconomic disparities in cancer-specific survival among patients with metastatic prostate cancer using a national population-based dataset. Methods: A retrospective population-based study was conducted using data from the Surveillance, Epidemiology, and End Results program. Patients diagnosed with malignant prostate cancer between 2004 and 2020 with distant stage disease were included. The final analytic sample consisted of 54,062 patients. Variables included race and ethnicity, age group, metastatic sites at diagnosis, treatment variables, and median household income. Descriptive analyses compared characteristics by cancer specific death using chi square tests for categorical variables and t tests for continuous variables. Survival patterns were examined using Kaplan Meier methods and log rank tests. Multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios for factors associated with cancer specific mortality. Results: Cancer specific mortality differed across racial and socioeconomic groups. Higher mortality was observed among non-Hispanic Black patients(aHR=1.15,95% CI: 1.00 to 1.31, p =0.046) and non-Hispanic American Indian or Alaska Native patients(aHR=1.15, 95% CI :1.10 to 1.20, p < 0.001) compared with non-Hispanic White patients, while Hispanic and non-Hispanic Asian or Pacific Islander patients showed lower mortality risk. Older age groups demonstrated higher mortality. Liver, lung, and brain metastases were associated with increased risk of prostate cancer death. Patients in higher income groups showed lower mortality compared with patients in lower income groups (aHR=0.83, 95% CI : 0.80 to 0.87, p < 0.001). Conclusion: This study highlights persistent racial and socioeconomic differences in cancer specific survival among patients with advanced prostate cancer in the United States. These findings support continued efforts to address disparities in early detection, access to care, and treatment pathways. Future research should further explore clinical and structural factors that influence survival differences across population groups.

Abstract: Radiotherapy (RT) achieves excellent local control (LC) in early-stage glottic cancer (ESGC); however, treatment-related edema or necrosis may necessitate tracheostomy and adversely affect quality of life. We compared tracheostomy rates and oncologic outcomes between whole-larynx radiotherapy (WLRT) and vocal cord–only radiotherapy (VC-RT) in patients with ESGC. We retrospectively analyzed 247 patients with Tis–T2 glottic cancer treated with definitive RT (2007–2023) at two Middle Eastern centers. Patients received WLRT (n = 166) or VC-RT (n = 81). The primary endpoint was a tracheostomy rate (TR) ≥6 months after RT for non-recurrent airway compromise. Secondary endpoints included 3-year local failure (LF) and overall survival (OS). TR and LF rates were analyzed using cumulative incidence with death as a competing risk, while OS was estimated using the Kaplan–Meier method. The median age was 59 years; 97.6% of patients were male and 78.9% were smokers. The median follow-up was 45.3 months. VC-RT patients more frequently had cT2 disease (22.2% vs. 5.4%, p < 0.001) and received accelerated fractionation (19.8% vs. 7.2%, p = 0.0069). Overall, 20 of 247 patients (8%) required tracheostomy without recurrence. Edema-related tracheostomy occurred more frequently after WLRT (0% vs. 14.2% for VC-RT; p < 0.001). Tracheostomy was reversed in 8/20 patients (40%) after a median of 13.4 months. The 3-year LF rates were 7.6% with VC-RT and 11.6% with WLRT (p = 0.18), and OS was 93.3% and 89.5% (p = 0.16), respectively. VC-RT reduces the risk of tracheostomy without compromising oncologic outcomes.

Abstract: Uveal melanomas (UMs) metastasize at a high frequency, and metastatic UMs are associated with very poor clinical outcomes. Consequently, there is considerable interest in the genetics and biochemistry of UM and how these insights may lead to novel and effective approaches for treating UM. This work reviews evidence that elevated signaling by the CYSLTR2/Gaq/Ga11 pathway drives UM. This work focuses on the large number of signaling pathways that appear to be activated by the CYSLTR2/Gaq/Ga11 pathway in UM, including pathways not thought to be effectors of canonical CYSLTR2/Gaq/Ga11 signaling. This work reviews evidence suggesting that ERBB receptor tyrosine kinases may mediate CYSLTR2/Gaq/Ga11 signaling in UM, thereby accounting for the non-canonical CYSLTR2/Gaq/Ga11 signaling observed in UM. Thus, this work describes novel targets for UM therapy.

Abstract: Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of GTV-to-CTV margin with survival, patterns of failure, and its interaction with MGMT promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: < 1.5 cm and equal to 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (< 1.5 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or patterns of failure, with overlapping recurrence distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no interaction between margin and MGMT status was detected. Conclusions: Reduction of the GTV-to-CTV margin to ≤1.2 cm was not associated with worse survival or unfavorable recurrence patterns, consistently across MGMT subgroups. These findings support the oncological adequacy of margins of approximately 15 mm and provide a rationale for exploring further margin reduction, potentially independent of MGMT status. Prospective validation is warranted.

Abstract: The effectiveness of modern cancer therapy is significantly limited by rapid tumor adaptation, multiple drug resistance mechanisms, and the formation of an immunosuppressive microenvironment supported by M2 phenotype macrophages and latent viral infections. In this paper, we present an innovative binary therapeutic system designed to overcome these fundamental barriers.The first component of the system, MoLRx (mixture of antisense oligoRNA), is based on technology that converts the entire pool of eukaryotic RNAs from baker's yeast into antisense oligonucleotide structures via chemical modification of nucleotide bases (exo- and endo-cyclic). Due to the hyperactivated macropinocytosis characteristic of most solid tumors, MoLRx selectively penetrates cancer cells and forms stable hydrogen-ion bonds with the entire pool of cellular RNAs (mRNA, tRNA, rRNA). The absence of RNA repair mechanisms makes this multi-target approach resistant to tumor mutational adaptation and effectively blocks protein synthesis.The second component, Lipo-Liasten, is a liposomal penta-muryl peptide that acts on the tumor microenvironment, inducing macrophages to shift from the pro-tumor M2 phenotype to the pro-inflammatory and anti-tumor M1 phenotype. This leads to the reactivation of NK cells and the removal of the immunological block created by T-suppressors.The combined use of MoLRx and Lipo-liasten produces a synergistic effect: inhibiting tumor cell proliferation and restoring systemic antitumor immunity. The proposed strategy allows effective treatment of resistant and metastatic forms of cancer, while avoiding the development of tumor lysis syndrome and typical mechanisms of drug escape.

Abstract: Conventional chemotherapy remains limited by incorrect targeting and excessive toxicity to the entire organism and clinical evidence suggests that not one in every 10 anticancer agents gets to the tumour site but the remainder of the concentration is incorporated in normal tissue. These limitations reduce the effectiveness of therapy and increase the risk of serious side effects, particularly in deep-rooted in-depth cancers. The paper discusses AI-based robotic targeted drug delivery technology capable of improving cancer treatment through smart localisation, controlled motion, and adaptive drug delivery.A qualitative thematic analysis approach was used to examine the latest developments in the field of artificial intelligence, medical robotics, and delivery systems based on nanotechnology. The pertinent research in the field of engineering, oncology and intelligent healthcare systems was reviewed to determine the main technological themes that influence the accuracy, safety and clinical feasibility of treatment. The talk focused on the integration of the tumour sensing algorithms, carrier robotic arms, controlled release mechanisms and real-time monitoring in a closed-loop therapeutic framework.The findings indicate that AI, robotics, and nano-scale delivery could increase the accuracy of localisation by more than 25 times compared to the conventional delivery and reduce off-target drug delivery. However, reliability, regulation and cost issues are also present due to the greater complexity of the system.This research has merits as it suggests a system architecture of the intelligent drug delivery and the need to conduct future studies to determine the safety validation, energy-efficient computation, and clinically scalable robots to enable the feasibility of practical application in precise oncology.

Abstract: Background/Objectives: Financial toxicity (FT) is increasingly recognised as a critical dimension of the cancer care continuum, reflecting both objective financial burden and subjective financial distress arising from cancer-related care. This scoping review mapped and synthesised the literature on FT in a focused subset of head and neck cancers (HNC), namely malignancies of the oral cavity, oropharynx, nasopharynx, sinonasal tract, and major and minor salivary glands. Methods: A scoping review was conducted to identify and synthesise studies addressing FT in the selected HNC subsites above. Searches were undertaken in MEDLINE, Embase, Scopus, Web of Science, CINAHL, EconLit, and Global Index Medicus for English-language studies published between 1 January 2015 and 1 January 2025. Eligible studies included adult patients and reported patient-level FT outcomes, including direct costs, indirect costs, out-of-pocket expenditure, financial hardship, financial distress, employment disruption, or related economic strain. Findings were synthesised narratively and organised thematically. Results: Twenty-five studies published between 2015 and 2025 were included. The evidence base was dominated by cross-sectional and retrospective designs, with limited prospective follow-up and very little intervention-focused research. FT was conceptualised heterogeneously across studies, spanning direct expenditure, indirect and non-medical costs, subjective financial distress, and coping-related consequences. Questionnaire-based approaches were used in 13 studies, but only a smaller subset employed FT-specific instruments such as COST. Across the literature, FT was consistently associated with lower income, weaker financial protection, employment disruption, rural residence in some settings, and more intensive treatment. Reported downstream associations included poorer quality of life, psychological distress, care alteration, and work-related burden, although evidence for treatment delay or survival effects was more limited and should be interpreted cautiously. Conclusions: In this focused HNC subset, FT appears multidimensional, socially patterned, and clinically relevant. However, the literature remains methodologically fragmented, with inconsistent measurement and sparse longitudinal evidence. Future work should prioritise validated and tumour-sensitive assessment strategies, prospective study designs, and evaluation of mitigation interventions that address both direct and indirect burden across the cancer continuum.

Abstract: After decades of in vivo isotope tracing, human solid tumors have not been shown to derive the majority of their carbon from circulating glucose. Despite this, glucose uptake by tumors continues to be widely interpreted as evidence of glucose dependence for growth. In contrast, mounting clinical and metabolic evidence indicates that glucose and glutamine are consumed primarily as regulatory and competitive substrates rather than as dominant carbon sources, with tumor biomass supplied largely by lactate, glutamine, and host-derived amino acids and lipids.Cachexia is commonly described as a secondary complication of advanced cancer, yet this metabolic behavior suggests it functions instead as a tumor-maintained systemic state that favors malignant survival at the expense of host tissues. By consuming glucose and glutamine at high rates, tumors restructure host metabolism, suppress immune function through substrate deprivation, and induce a catabolic shift that mobilizes host tissues as the tumor’s true nutrient reservoir. Dietary deprivation strategies therefore fail in solid tumors not because tumors adapt to starvation, but because restriction accelerates host metabolic collapse rather than depriving the tumor.Central to this argument is a newly proposed construct: homeostatic deception via dissociated catabolic ketosis, a tumor-orchestrated state in which physiological ketogenesis is genuinely present but decoupled from its normal protein-sparing function. Circulating ketones satisfy central energy-sensing mechanisms, silencing counter-regulatory alarms while unrestrained muscle proteolysis and lipolysis proceed. The resulting catabolic loop supplies tumors with substrates released from host tissues while the host’s regulatory systems interpret the state as normal adaptive fasting. Cachexia persists as long as the tumor driver remains active and reverses primarily when tumor burden and inflammatory signaling are controlled. A case of metastatic NSCLC, with photographic documentation, serves as the observational origin of this framework (Johnson CL, 2026, https://doi.org/10.5281/zenodo.18988466). This manuscript integrates metabolic tracing, immunometabolism, and clinical observation to propose a mechanistic hypothesis reframing cachexia as a tumor-maintained state. The framework identifies multiple targets for companion therapeutic intervention and explains the failure of diet-based strategies.

Abstract: From the perspective of evolutionary oncology, cancer represents a unicellularized cell system consisting of a self-renewing, oxygen-sensitive stemgermline and an oxygen-resistant somatic tumor bulk cell population generated through germ-to-soma transition processes and somatic proliferation. In this configuration, cancer shows limited analogy to the multicellular organization of its host but displays deep evolutionary homology with the unicellular systems of parasitic amoebae, reflecting its origin in the common ancestor of Amoebozoans and Metazoans. The hypoxic stemgermline is the central driver of cancer’s cell system. Because its genome is highly vulnerable to hyperoxia, it requires continuous protection and, when necessary, replacement through reconstituted sublines. The non-genetic mechanisms underlying cancer drug resistance are interpreted here as ancestral survival programs that originated in the common ancestor approximately one billion years ago during two major evolutionary oxygen transitions. These programs are reactivated in the unicellularized cancer system to protect genome integrity under environmental and therapeutic stress. Over evolutionary time, these survival mechanisms evolved into highly robust and resilient networks, which may explain the remarkable persistence of the parasitic cancer cell system despite therapeutic intervention. Survival is maintained through coordinated programs of genome reconstruction and cycles of cellular plasticity that are activated when either the stemgermline or the somatic tumor population is exposed to intra-tumoral stressors or anticancer therapies. By placing cancer drug resistance within this deep evolutionary framework, evolutionary oncology offers a new conceptual basis for understanding cancer resilience and may guide the development of future therapeutic strategies aimed at targeting these ancient survival programs.

Abstract: Background/Objectives: Histologic regression in primary cutaneous melanoma has shown inconsistent prognostic associations, and its relevance to immune checkpoint inhibitor (ICI) outcomes in patients who later develop recurrent or metastatic disease remains unclear. Methods: This retrospective single-center cohort included 81 patients with resected stage I–III cutaneous melanoma who later developed recurrent or metastatic disease and received ICIs. Histologic regression was classified as present or absent based on primary pathology reports. Objective response rate (ORR) and disease control rate (DCR) were assessed according to RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) from ICI initiation were estimated using Kaplan–Meier analysis and evaluated with prespecified multivariable Cox models. Results: Histologic regression was identified in 24 patients (29.6%). Baseline characteristics were largely comparable between groups, although regression was more frequent in male patients (83.3% vs 59.6%; p = 0.039). ORR was numerically higher in the regression-present group (58.3% vs 43.9%; p = 0.330), and DCR was also higher (87.5% vs 66.7%; p = 0.061). Median PFS was significantly longer in patients with regression (39.3 vs 17.8 months; log-rank p = 0.044). In multivariable analysis, regression remained independently associated with longer PFS (adjusted HR, 0.43; 95% CI, 0.19–0.94; p = 0.035), whereas no independent association with OS was observed (adjusted HR, 0.54; 95% CI, 0.28–1.06; p = 0.071). Conclusions: In patients with recurrent or metastatic melanoma treated with ICIs, primary tumor histologic regression was independently associated with prolonged PFS but not OS. These findings suggest a potential link between regression and early immune-mediated disease control, while its impact on long-term survival remains uncertain.

Abstract: Background: Current surveillance strategies after treatment of endometrial cancer remain largely based on clinical stage and histological grade, reflecting a pre-molecular understanding of disease behavior. However, molecular classification has revealed profound biological heterogeneity across endometrial cancer subtypes, including differences in recurrence patterns, prognosis, and treatment responsiveness. Despite this progress, surveillance strategies have not yet been systematically adapted to molecular risk stratification. Objective: To propose a biology-driven surveillance framework for endometrial cancer that integrates molecular subtype, clinicopathological risk factors, and recurrence phenotype. Methods: This narrative review and conceptual framework synthesizes evidence from cohort studies, molecular classification analyses, international guidelines, and literature addressing recurrence patterns and treatment responsiveness across molecular subtypes of endometrial cancer. Results: We propose a three-tier surveillance model stratifying patients into low-, intermediate-, and high-risk groups. The framework integrates molecular subtype with clinicopathological modifiers and expected recurrence phenotype. Within the no specific molecular profile (NSMP) subtype, CTNNB1 mutation status is incorporated as a primary modifier, assigning CTNNB1-mutated tumors to the intermediate-risk group regardless of estrogen receptor (ER) status. In CTNNB1 wild-type NSMP tumors, ER expression functions as a secondary modifier, allowing identification of a biologically low-risk subgroup. L1CAM expression is considered a high-risk modifier within NSMP. The framework also accounts for differences in therapeutic modifiability of recurrence, including the role of immunotherapy in mismatch repair-deficient tumors. Conclusions: Uniform post-treatment surveillance does not reflect the biological diversity of endometrial cancer. The proposed framework provides a biologically grounded approach to surveillance that aligns follow-up intensity with recurrence phenotype and therapeutic opportunities. This model may serve as a conceptual basis for prospective studies evaluating personalized surveillance strategies in endometrial cancer.

Abstract: Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetric cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, paclitaxel-containing regimens have shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma of the lung and undifferentiated carcinoma of the pancreas. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.

Abstract: Acquired resistance to EGFR tyrosine kinase inhibitors remains a principal barrier to durable remission in non-small cell lung cancer (NSCLC). Using a time-resolved protein interaction network analysis of isogenic Gefitinib-sensitive and resistant NSCLC cells, we show that network entropy increases progressively under drug treatment in both phenotypes, while small-world topology is lost, consistent with Gefitinib's dismantling of EGFR-centered signaling hubs. Eigenvector entropy alone distinguished the resistant phenotype at baseline, reflecting a pre-established, robustly buffered network state. Co-expression network analysis revealed a resistance-specific subnetwork in which delta-catenin (CTNND1) serves as the dominant topological bridge between EGFR, VAV3, HIF3A, and NOTCH2, four nodes independently linked to chemoresistance but not previously connected within a single regulatory network. We propose that HIF1α-driven induction of CTNND1, EGFR-mediated positive feedback, and VAV3-dependent Rho-GTPase activation cooperate to drive actin cytoskeletal remodeling and phenotypic switching. BIRC3 emerged as an independent late-stage apoptotic block exclusive to resistant cells. These findings nominate CTNND1 and VAV3 as candidate co-targets and eigenvector entropy as a systems-level biomarker of Gefitinib resistance.

Abstract: Preoperative sarcopenia has emerged as an important determinant of adverse postoperative and long-term outcomes in patients with resectable non–small cell lung cancer (NSCLC). Its frequent coexistence with systemic inflammation may further worsen survival outcomes. At the same time, neoadjuvant chemotherapy and chemoimmunotherapy have substantially improved pathological response and survival in resectable NSCLC. However, their interaction with host-related factors such as sarcopenia and systemic inflammatory status remains insufficiently characterized. This narrative review aims to synthesize current evidence regarding the interplay between preoperative sarcopenia, systemic inflammation, and neoadjuvant therapy in resectable NSCLC and evaluates their potential combined impact on surgical and oncological outcomes. A narrative synthesis of 20 studies involving patients undergoing lung cancer resection was performed. Sarcopenia was primarily assessed using computed tomography or PET-CT–derived skeletal muscle indices, most commonly the skeletal muscle index, whereas systemic inflammation was evaluated using biochemical inflammatory markers. The available evidence consistently indicates that preoperative sarcopenia is associated with poorer long-term survival, and this adverse effect appears to be amplified in the presence of systemic inflammation. Although neoadjuvant chemoimmunotherapy has improved tumor response and survival outcomes, it may also act as a systemic stressor capable of aggravating muscle loss. Importantly, no study to date has simultaneously evaluated sarcopenia, systemic inflammation, and neoadjuvant therapy within a unified analytical framework. Most available studies focus primarily on sarcopenia, while inflammatory or treatment-related parameters are typically analyzed separately. Overall, while sarcopenia and systemic inflammation are recognized predictors of adverse outcomes in resectable NSCLC, robust evidence integrating them with neoadjuvant therapy is lacking. Clarifying their potential interaction may improve risk stratification and help optimize perioperative management strategies in the era of neoadjuvant therapy.

Abstract: Hepatocellular carcinoma (HCC) is driven by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively sustain tumor growth, immune evasion, and vascular remodeling. Through integrative single-cell transcriptomic analysis of 159,925 cells from tumor and healthy human liver tissues, we delineated the cell-type-specific transcriptional programs underlying immunometabolic reprogramming and mapped the intercellular communication circuits that maintain tumor homeostasis. Malignant hepatocytes activated dual glycolytic and oxidative metabolic programs while suppressing antigen presentation capacity, coupling metabolic plasticity to immune evasion. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand–receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM-integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention.

Abstract: Background: This narrative review evaluates bacterial pathogen dysbiosis support of host risk for oral squamous cel carcinoma (OSCC) mediating environmental exposomes. Objective: Review provides metabolic, enzymatic, and immunologic mechanisms of oral dysbiosis amplifying chemical carcinogenesis and suppressing therapies for cancer. Narrative: Oral dysbiosis engages with endogenous synthesis of tobacco specific N-Nitrosamines (TSNA) and degradation of tobacco leaf’s poly-aromatic hydrocarbons (PAHs), and pollutants creating a reservoir of carcinogenic agent. Bacteria metabolism of essential amino acid tryptophan-tryptamine, PAHs and TSNAs amplifies chemical carcinogenesis risk for OSCC synthesizing ligands for aryl-hydrocarbon receptor (AHR) transcriptional environmental sensing. Lipophilic chemical affinities between bacteria and carcinogen facilitate intercellular aggregations and accumulations in oral epithelium. Gram negative bacteria’s lipopolysaccharide (LPS) and endopeptidases enhance lipophilic peroxidation (e.g., trimethylamine oxide (TMAO), exciting pathogen pattern recognition responses (e.g., DAMP, PAMP) with toll-like receptor expression eliciting NF-KB transcription of cytokines, and pathogen’s epoxide hydrolases of diol epoxides producing DNA adducts, mutations and oxidative stresses. LPS+PAH+TSNA causes lipophilic membrane disruption driving ubiquitination-proteosome and Golgi-trans network’s inappropriate host protein degradation, sorting, and transporting of epithelial proteins. Pathogens adhere to epithelium and release bacterial virulence factors, (cysteine-serine) proteases, and endopeptidases. degrading immunoglobulins, complement, cytokines, and extracellular matrix increasing intracellular transcriptional complex expressions of proto-oncogene/oncogenes. Influence of arginine-polyamine-epigenetics-methylation, and nonessential (cysteine) amino acid, sulphuration suppresses oncology therapies. AHR derived E3 ubiquitin ligase enhances DNA instability, with biomolecular condensates supporting tumor microenvironment (TME). Conclusion: Oral bacterial oncogenesis results in evasion from immune recognition, depressed mucosal tumor immune surveillance, cytotoxicity and therapies.

Abstract: Background/Objectives: Oral squamous cell carcinoma (OSCC) exhibits substantial biological heterogeneity, and current clinicopathological risk stratification incompletely reflects tumor metabolic behavior. Stable isotope ratio mass spectrometry enables quantitative assessment of carbon and nitrogen isotopic composition, potentially capturing cumulative metabolic reprogramming associated with tumor aggressiveness. This study evaluated whether isotopic signatures of tumor tissue and surgical margins are associated with lymph node metastasis and survival outcomes in OSCC. Methods: In this prospective study, 54 consecutive patients undergoing primary surgical treatment for OSCC were enrolled. Paired samples derived from tumor tissue and surgical margins were analyzed using isotope ratio mass spectrometry to determine the relative abundance of nitrogen-15 and carbon-13 isotopes. The primary endpoint was pathological lymph node metastasis. Secondary endpoints included disease-free survival and overall survival. Paired comparisons were performed using Wilcoxon signed-rank tests with false discovery rate correction. Logistic regression models for nodal metastasis were constructed using Firth penalization with bootstrap internal validation, while survival outcomes were evaluated using Cox proportional hazards models with model complexity restricted according to the number of events. Results: Tumor tissues demonstrated significantly lower δ¹³C and δ¹⁵N values and higher nitrogen-to-carbon ratios compared with surgical margins (all adjusted p < 0.05). In multivariable analysis, tumor δ¹⁵N was independently associated with lymph node metastasis and modestly improved model discrimination. However, it was not independently associated with disease-free or overall survival. Exploratory analyses indicated that higher δ¹³C values in surgical margins were independently associated with shorter disease-free survival. Conclusions: These findings suggest that isotope ratio mass spectrometry–based isotopic profiling identifies reproducible metabolic differences between tumor and margin tissues in OSCC. Tumor δ¹⁵N is associated with lymph node metastasis, whereas margin δ¹³C may reflect recurrence risk and potentially capture metabolic field effects. These findings are hypothesis-generating and warrant validation in larger, independent cohorts.

Abstract: Background: High-grade soft tissue sarcoma (STS) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68⁺ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68⁺ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. Methods: Immunohistochemistry scoring of Regnase-1 and CD68⁺ TAMs was performed in 91 patients; OS was assessed by Kaplan–Meier and Cox regression; findings were validated in an independent TCGA-SARC cohort (n = 212). Results: In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate HR = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68⁺ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1–3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. ZC3H12A-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. Conclusions: Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy.

Abstract: The challenge of radioresistance (RR) in radiotherapy (RT) is currently being tackled, on one hand, by introducing into clinical practice new RT equipment with high quality of ionizing beams, high precision of radiation delivery to tumour, and optimization of treatment plans. On the other hand, new therapeutic methods for suppressing RR in tumours of cancer patients are being developed through a combination of RT with chemo-, immuno- and targeted therapies based on molecular diagnostic data. As a result of numerous preclinical and clinical trials of the combination therapy, the main molecular mechanisms, driving an increase in radiosensitivity (RS), were found out, and the key cellular signalling pathways responsible for RR were established. One of the established mechanisms is in adaptation of cancer cells to an elevated level of reactive oxygen species (ROS) by activation of antioxidant systems (AOS) of cellular protection and survival. Considering that RT relies mainly on the production of ROS that damage DNA and cause cancer cell death. Consequently, the activation of the AOS can mitigate the RT effectiveness, and it is assumed that suppression of the AOS and cellular adaptation mechanisms to a high ROS level can increase tumour RS and enhance the effectiveness of radiotherapy. In this review we discussed a role of one of the key components of the cellular AOS being under the control by a transcription factor NRF2 (nuclear erythroid factor 2) which governs the expression of a battery of antioxidant enzymes and protects cells from oxidative stress induced by RT. First, we briefly discussed the molecular function of the redox-sensitive the NRF2 AOS, which is activated in cells following the increased ROS level due to irradiation. Second, we reviewed the experimental and clinical data on activation of the NRF2 AOS in some cancer cells and tumour under ionizing irradiation. Third, we discussed results of numerous experimental and clinical investigations which clearly showed that suppression of the NRF2 AOS leads to an increase in radiosensitivity of various cancers and an enhancement in the effectiveness of RT in cancer patients. These data confirm the potential of combining RT with targeted therapy aiming at the suppression of the NRF2 cytoprotective AOS. Based on multiple experimental and clinical studies, we advocated a role of NRF2 inhibitors as radiosensitizers that promote overcoming radioresistance due to extra ROS accumulation and oxidative stress induction by inhibition of the NRF2-dependent antioxidant responses to radiotherapy.

Abstract: Background: Young women treated for breast cancer may continue to experience sexual and reproductive problems after treatment. These issues are not always addressed in routine follow-up. We evaluated sexual health, quality of life, and fertility-related counselling in breast cancer survivors younger than 40 years. Methods: We performed a single-centre cross-sectional study including 65 women with non-metastatic breast cancer who had completed primary treatment at least 12 months earlier. Patients completed the EORTC QLQ-C30 and SHQ-22 questionnaires and an additional questionnaire on fertility preservation. Results: Overall quality-of-life scores were relatively preserved, although several domains remained affected, especially physical and role functioning, fatigue, and insomnia. Sexual problems were common, particularly low libido, vaginal dryness, treatment-related impairment of sexual life, and limited communication with healthcare professionals. Women receiving endocrine therapy reported poorer physical, emotional, and cognitive functioning, together with a higher symptom burden and more sexual complaints. Thirty-nine patients (60%) reported receiving information on fertility preservation before treatment, but only 11 underwent a fertility preservation procedure. Women who had undergone fertility preservation reported higher sexual activity scores. Conclusions: In this cohort of young breast cancer survivors, sexual difficulties remained frequent more than one year after completion of treatment, even when overall quality-of-life scores appeared relatively preserved. Fertility counselling was also not uniformly reported. These findings suggest that sexual health and reproductive issues should be addressed more consistently during follow-up care, especially in women receiving endocrine therapy.