Machine learning (ML) and deep learning (DL) models applied to electronic health records (EHRs) have substantial potential to improve oncology care across diagnosis, prognosis, treatment selection, and trial recruitment. However, opacity of many high-performing models limits clinician trust, regulatory acceptance, and safe deployment. Explainable artificial intelligence (XAI) methods aim to make model behavior understandable and actionable in clinical contexts. The present perspective summarizes current XAI approaches applied to EHR-based oncology tasks, identifies key challenges in evaluation, reproducibility, clinical utility, and equity, and proposes pragmatic recommendations and research directions to accelerate safe adoption in oncology. Common XAI categories used with EHR data include feature importance/interaction methods, intrinsically interpretable models, attention mechanisms, dimensionality reduction, and knowledge distillation or rule extraction. Tree-based models with SHapley Additive exPlanations (SHAP) explanations dominate recent EHR studies. Other interpretable strategies, such as generalized additive models and rule sets, appear in settings where transparency is prioritized. Gaps include inconsistent reporting, scarce formal evaluation of explanations for clinical utility, limited reproducibility for data and code availability, inadequate external validation, and insufficient consideration of fairness and equity that these issues are particularly important in oncology, where heterogeneity and stakes are high. Overall, integrating XAI with EHR-driven oncology models is promising but underdeveloped, which requires further progress by multi-stakeholder evaluation frameworks, reproducible pipelines, prospective and multicenter validations, and equity-aware design. The field should prioritize clinically meaningful explanations beyond ranking features and study how explanations affect clinician decision-making and patient outcomes.

Glioblastoma (GBM) is a complex condition with a poorly understood pathophysiology and no effective treatment to date. The present article highlights the role of canonical and non-canonical signal transducer and activator of transcription 3 (STAT3) interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the modulation of the mitochondrial melatonergic pathway in GBM microenvironment pathophysiology. The capacity of STAT3 and NF-κB to interact to upregulate the mitochondrial melatonergic pathway is suppressed systemically over the course of aging, thereby attenuating the capacity to achieve inflammation resolution. The suppressed capacity to induce the mitochondrial melatonergic pathway systemically is partly driven by the dramatic 10-fold decrease in pineal melatonin over aging. The attenuation of pineal melatonin in the first half of sleep over aging and aging-accelerating conditions disinhibits the effects of cortisol in the second half of sleep. This decrease in the melatonin/cortisol ratio alters the nature of night-time dampening and resetting in preparation for the coming day by altering cellular and intercellular homeostatic interactions. Aging and aging-accelerating conditions, by impacting the night-time melatonin/cortisol ratio, also suppress the capacity of the vagal nerve to resolve inflammation. This further contributes to systemic changes that influence GBM pathoetiology and ongoing pathophysiology. Aging-associated changes in night-time dampening and resetting provide a novel framework on which many previously disparate bodies of data on GBM pathophysiology can be collated. This has numerous future research, prevention, and treatment implications.

Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior, often resulting in ossicular erosion, hearing loss, labyrinthine fistula, and, rarely, intracranial complications. Surgical excision remains the primary management strategy; however, recurrence is common due to persistent microenvironmental drivers. Recent mechanistic studies-including single-cell transcriptomics, spatial proteomics, and epigenetic profiling-reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation via RANKL and activin A, epithelial plasticity with partial epithelial-to-mesenchymal transition (EMT), and a dysbiotic, biofilm-forming microbiome. Emerging evidence further implicates oxidative stress, RNA and epigenetic modifications, miRNA dysregulation, and immune cell infiltration as central modulators of lesion chronicity and bone resorption. Collectively, these processes establish a self-sustaining pro-osteolytic microenvironment that drives bone erosion and postoperative recurrence. Cholesteatoma recapitulates several features of malignant lesions-hyperproliferation, local invasion, and stromal/immune cell recruitment-yet remains fundamentally benign, lacking metastatic potential and genomic instability. Its aggression is ecological rather than genetic, highlighting the potential for microenvironment-directed, precision-based strategies. Adjunctive approaches may include local delivery of modulatory agents, targeted interference with inflammatory, proteolytic, osteoclastogenic, and microbial axes, and biomarker-guided patient stratification. Preclinical and early-phase experimental studies assessing target engagement, radiologic stabilization, and molecular surrogates of efficacy could inform safer, mechanism-driven interventions that complement surgery, reduce recurrence, and preserve hearing. Integrating molecular pathobiology with clinical strategy positions cholesteatoma as a model for benign yet locally aggressive, microenvironment-driven disease, providing a roadmap for translational therapies with direct relevance to surgical practice.

Background: Docetaxel is a cornerstone chemotherapy for metastatic hormone-sensitive and castration-resistant prostate cancer. Although the standard triweekly regimen is widely used, weekly and biweekly schedules are often employed to improve tolerability, particularly in elderly or frail patients. The comparative efficacy and safety of these dosing strategies remain unclear. This study aimed to systematically compare weekly, biweekly, and triweekly docetaxel regimens using a network meta-analysis.

Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to February 2025. Randomized controlled trials and observational retrospective studies comparing weekly, biweekly, and triweekly docetaxel regimens were included. Outcomes assessed were prostate-specific antigen (PSA) response rate, time to treatment failure or progression, and adverse events. A frequentist random-effects network meta-analysis was conducted using R software.

Results: Eleven studies involving 1,238 patients were included. PSA response rates did not differ significantly among regimens; triweekly docetaxel showed a numerically lower response compared with weekly dosing (RR = 0.79, 95% CI 0.52–1.22;I² = 41.1%). Time to treatment failure was significantly longer with triweekly dosing compared with weekly dosing (mean difference = 10.91 months, 95% CI 6.94–14.87;I² = 96.8%). Biweekly and triweekly regimens were associated with significantly higher hepatotoxicity compared with weekly dosing (RR = 3.71 and RR = 3.21, respectively; I² = 0%). Vomiting was more frequent with triweekly docetaxel (RR = 2.47, 95% CI 1.31–4.63). No significant differences were observed for overall adverse events, hematologic toxicity, neuropathy, fatigue, febrile neutropenia, nausea, anorexia, or diarrhea.

Discussion: Docetaxel dosing schedules show comparable PSA response rates. Triweekly dosing prolongs time to treatment failure but is associated with greater toxicity, whereas weekly dosing offers better tolerability. Treatment decisions should balance efficacy and safety based on individual patient characteristics.

Breast cancer is a leading cause of cancer death in women worldwide. One of the major causes of death from breast cancer is metastatic disease, which results from the malignant cells invading and migrating through blood vessels to distant sites. Several studies have shown that metastasis is facilitated by haemostatic proteins. Breast cancer is characterized by a haemostatic imbalance, which is tilted more to a procoagulant state with resultant thrombotic complications. These elements that are involved in thrombosis also play key roles in different aspects of breast cancer growth, including cancer proliferation and progression, cancer survival, angiogenesis, and metastasis. Some of these elements include platelets, endothelial cells, coagulation factors, and fibrinolytic proteins. There is a close relationship between cancer and many of the haemostatic elements. They are usually increased in metastatic breast cancer and have found use as predictive and prognostic markers. Some have been validated in breast cancer. Due to their seemingly active roles in breast cancer progression, some of the haemostatic proteins are being developed as diagnostic tools in the management of breast cancer. They are equally seen as potential targets for the development of novel therapies in breast cancer or repurposing drugs in current use for the same gain. This review highlights the role haemostatic proteins play in breast cancer progression, and their diagnostic and therapeutic relevance.

Aim: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor survival outcomes. Prognostic models developed in Western cohorts rarely assess algorithmic fairness. This study aimed to develop and internally validate a clinically interpretable Cox survival model for TNBC using baseline diagnostic variables and to evaluate its fairness according to ISO/IEC TR 24027:2021 guidelines in a Middle East and North Africa (MENA) cohort.

Methods: A total of 138 TNBC patients were included after merging two institutional datasets and removing variables with > 25% missingness. Baseline features comprised age, tumor size, lymph node involvement, tumor grade, Ki-67, type of surgery, metastasis at diagnosis, chemotherapy, and radiotherapy. A Cox proportional hazards (CoxPH) model with six clinically established predictors was fitted to reduce overfitting. Model performance was assessed through five-fold stratified cross-validation using Harrell’s concordance index (C-index), receiver operating characteristic area under the curve (AUROC), and calibration curves. Fairness was evaluated using demographic parity, equality of opportunity, predictive equality, and equalized odds metrics following ISO/IEC TR 24027:2021.

Results: During follow-up, 34 patients (24.6%) died. Metastasis at diagnosis, high tumor grade, and radical mastectomy were significantly associated with mortality. The CoxPH model achieved a C-index of 0.80 [SE = 0.04; 95% confidence interval (CI): 0.72–0.87] and an AUROC of 0.81 (95% CI: 0.72–0.90). Calibration plots showed strong agreement between predicted and observed survival probabilities, with a modest overall bias of –8.8%. Fairness assessment revealed small but notable disparities in false-positive rates across age groups and surgical categories, while lymph node status and other variables showed no significant bias.

Conclusions: This study presents a robust and fairness-aware survival prediction model for TNBC using routinely available clinical features. The model demonstrates strong discrimination, good calibration, and quantifiable fairness across patient subgroups, offering a clinically interpretable and ethically aligned tool to support TNBC risk stratification and decision-making in the MENA region.

Aim: Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core NURD remodeling complex ATPase that plays a crucial role as a gene repressor. Its overexpression has been reported in several cancers. In papillary thyroid carcinomas (PTCs), CHD4 is overexpressed and associated with aggressive features of the tumor, such as proliferation, migration, and epithelial-mesenchymal transition (EMT). We previously showed in PTCs that NADPH oxidase NOX4 expression is positively regulated by BRAF^V600E mutation, which is the most aggressive alteration in PTCs. In this retrospective study, we wondered whether there is a link between CHD4 and NOX4 protein expression in malignant thyroid tissues.

Methods: We explored CHD4 protein expression by immunostaining analysis in 86 human thyroid tissues: 44 thyroid tumor tissues [28 classical forms of PTCs (C-PTCs), 13 follicular variants of PTCs (F-PTCs), and three anaplastic thyroid carcinomas (ATCs)] and 42 of their normal adjacent tissues (NATs). The detection ofBRAF^V600E mutation was performed using Sanger sequencing and digital droplet PCR. Statistical analyses were conducted using GraphPad Prism 8 software. Various tests were used to assess the statistical relevance of different correlations, such as the chi-square test, Fisher’s exact test, and the Pearson correlation coefficient. Ap-value of less than 0.05 indicates statistical significance.

Results: The CHD4 protein expression analysis with already published data from our group BRAF^V600E status and NOX4 expression) reveals a highly significant level of CHD4 protein expression in C-PTCs compared to F-PTCs and ATC. Importantly, 70% of C-PTCs-BRAF^V600E overexpress CHD4 at the protein level, confirming the positive correlation between the CHD4 expression and BRAF^V600E mutation. Furthermore, a high level of CHD4 is associated with the presence of capsular breach and vascular emboli, affirming the involvement of CHD4 in thyroid tumor aggressiveness. Interestingly, we showed for the first time, to our knowledge, a positive correlation between CHD4 and NOX4 protein expression in malignant thyroid tissues.

Conclusions: The results of this study suggest that CHD4 could be used as a complementary molecular marker to improve the diagnosis and the management of PTCs-BRAF^V600E.

Aim: Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes.

Methods: 3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels.

Results: 3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30–300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib. Transcriptomic profiling revealed shared upregulation of apoptosis-related BCL2, CASP7, FAS, FASLG, GADD45A) and autophagy-related ATG7, ATG16L1, IRGM, PIK3C3, ULK1) genes in response to TGF-β or upon 3D spheroid formation. 2DG, transient silencing of TGF-β, or galunisertib treatment prevented these increases.

Conclusions: 3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.

Aim: Intravesical Bacillus Calmette–Guérin (BCG) is the standard therapy for non-muscle invasive bladder cancer (NMIBC); however, many patients experience recurrence or progression. We examined how urinary immune signals and the urinary microbiome change across BCG and are related to outcomes.

Methods: In this single-center prospective cohort study, adults with NMIBC underwent transurethral resection of bladder tumor (TURBT), followed by BCG induction. Urine was collected before TURBT, before BCG, after BCG induction, and three months later. Urine sediment mRNA (PD-L1, PD-L2, CD33, and CD204) was quantified using TaqMan ΔCt. The urinary microbiome was profiled using 16S rRNA gene sequencing, and diversity, composition, and taxon balance were evaluated using nonparametric tests, PERMANOVA, repeated-measures correlations, and mixed-effects models. We analyzed the relationship between the urinary microbiome and prognosis.

Results: Twenty-three patients were analyzed; ten recurrences, eight progressions, and three deaths were observed. Relative to baseline, CD33 increased after BCG and after three months; PD-L2 increased immediately after BCG and returned to baseline by three months; PD-L1 and CD204 increased after BCG. Shannon alpha-diversity was unchanged, but total read count was higher at three months, with stable beta-diversity and dispersion. Higher PD-L1 expression was associated with lower Actinobacteria abundance in the bladder cancer microenvironment. A higher post-BCG Firmicutes/Bacteroidetes ratio was associated with worse prognosis, with the clearest signal for progression-free survival (PFS) observed in the univariate Cox models. Higher post-BCG Corynebacterium and Enterobacteriaceae abundance was associated with better PFS.

Conclusions: BCG was associated with higher urinary PD-L1/PD-L2 and myeloid marker transcripts, while overall community structure remained stable. These exploratory data support that pre-BCG microbial features may be related to early response, and post-BCG profiles may reflect durability and survival. Urine immune-microbiome profiling could be a feasible, noninvasive adjunct for monitoring and risk stratification in NMIBC.

Aim: This study aimed to evaluate the real-world efficacy and safety of lorlatinib in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior ALK tyrosine kinase inhibitor (TKI).

Methods: The dataset included 82 subjects with metastatic NSCLC, who received lorlatinib upon compassionate use program or routine treatment between January 2017 and May 2025. All patients involved in this study responded to a prior ALK inhibitor for at least 4 months and switched to the above drug due to disease progression.

Results: The overall objective response rate (ORR) was 64.6%, with the disease control rate (DCR) of 96.3%. Among 65 patients with brain metastases, the intracranial ORR and DCR were 66.2% and 96.9%, respectively. After a median follow-up of 82.7 months, the median progression-free survival (PFS) was 66.7 months (95% CI, 40.5–75.0 months), while the median overall survival (OS) was not reached (NR) (95% CI, NR–NR). Patients who had benefited from prior ALK TKI for more than 12 months achieved significantly longer PFS (NR vs. 34.0 months;p = 0.013) and OS (NR vs. 39.4 months; p = 0.002). Multivariate analysis showed that prior response to ALK TKI of less than 12 months was an independent negative predictor of survival (PFS: p = 0.039, OS: p = 0.027). Treatment-related adverse events (AEs) were reported in 75.6% of patients, with 8.1% experiencing grade 3 or higher toxicity; no treatment-related AEs led to permanent discontinuation of lorlatinib.

Conclusions: This real-world dataset demonstrates an unusually pronounced benefit from lorlatinib in selected patients who progressed on early-generation TKIs, especially in long-term responders to prior therapy. However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance.

Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that typically arise from the pleura but may occur in various extrathoracic sites. Primary intraparenchymal pulmonary SFTs without pleural attachment are exceptionally uncommon and often pose diagnostic and therapeutic challenges. We report the case of a middle-aged female patient presenting with progressive dyspnea and a large mass in the left lower lobe on imaging. Computed tomography revealed a well-circumscribed, hypervascular mass occupying the left lower lobe. Bronchoscopic and percutaneous biopsies were nondiagnostic, and surgical resection was pursued. Intraoperatively, the tumor was found to arise from the lung parenchyma without pleural involvement. Histopathological examination demonstrated a spindle-cell neoplasm with the typical “patternless pattern,” and immunohistochemistry confirmed nuclear STAT6 positivity, establishing the diagnosis of SFT. The postoperative course was uneventful apart from a transient pulmonary embolism, which was successfully treated. The patient was discharged in good condition and is under regular radiologic surveillance. SFTs of the lung are rare and often mimic more common pulmonary tumors radiologically. Histologic confirmation with STAT6 immunohistochemistry is crucial for accurate diagnosis. Complete surgical excision remains the mainstay of treatment. Given the risk of late recurrence-especially in large tumors-long-term imaging follow-up is mandatory. This case highlights the importance of considering SFT in the differential diagnosis of large pulmonary masses, the critical role of STAT6-based histopathologic confirmation, and the necessity for prolonged surveillance even after complete resection.

Background: Targeted radioligand therapy (TRT) is an emerging theranostic modality in oncology. While well established in neuroendocrine and prostate cancers, its role in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) remains investigational. This systematic review summarizes current evidence evaluating TRT in lung cancer.

Methods: A Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided systematic review of PubMed, Embase, and Scopus (2000–November 2025) was conducted. Original studies evaluating TRT in SCLC or NSCLC were included. Primary outcomes were tumor response, disease-control rate, and treatment-related toxicity. Secondary outcomes included progression-free survival, overall survival, and dosimetry. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool.

Results: From 2,453 records, 15 studies were included, reporting 358 lung cancer patients, of whom 105 received TRT. Disease-control rates reached up to 78% in mixed NSCLC/SCLC cohorts. In SCLC, somatostatin receptor-targeted peptide receptor radionuclide therapy demonstrated heterogeneous disease control (0–50%), with [¹⁷⁷Lu]Lu-labeled agents showing more favorable outcomes than [⁹⁰Y]Y-based therapy. The most favorable outcomes were a median progression-free survival of 11.9 months and an overall survival of 16 months in responders. In NSCLC, fibroblast activation protein (FAP)-targeted agents such as [¹⁷⁷Lu]Lu-FAP-2286 demonstrated partial metabolic responses, including a 44.4% response rate and 78% disease control in a mixed cohort. Severe toxicities were infrequent.

Discussion: TRT is a promising but experimental option for advanced lung cancer. Early efficacy signals exist for strong somatostatin receptor (SSTR)-targeted therapy in SCLC and FAP-targeted therapy in NSCLC, but evidence remains limited. Prospective trials with standardized protocols and dosimetry are needed to define TRT’s role in lung cancer treatment.

This commentary discusses the FDA’s drug approvals in 2025, with a particular focus on cancer therapies and the role of companion diagnostics (CDx). Cancer has emerged as the leading therapeutic area, accounting for 35% of all new drug approvals, largely driven by targeted therapies, with kinase inhibitors representing nearly half of these drugs. Many of the drugs have received orphan drug designations and/or have utilized the Accelerated Approval Program. A key finding was the widespread adoption of the drug-diagnostic co-development model, in which a CDx assay is developed along with the drug and used for patient selection in clinical trials. However, a significant challenge is the frequent lack of concurrent drug and CDx assay approvals. The absence of an analytically and clinically validated CDx assay may pose a challenge for healthcare providers in accurately identifying eligible patients, potentially delaying access to appropriate therapy. The FDA’s cancer drug approvals for 2025 highlight an ongoing commitment to precision medicine, with several new targeted treatments, such as antibody-drug conjugates and kinase inhibitors, where CDx assays play an important role in identifying the appropriate patient population.

The treatment paradigm for advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations is undergoing a significant transition. While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have long served as the frontline standard, the emergence of heterogeneous resistance mechanisms requires more robust therapeutic strategies. This review evaluates the clinical impact of the MARIPOSA trial, which demonstrated the superior efficacy of combining the bispecific antibody amivantamab with lazertinib. Beyond improving progression-free and overall survival, this dual-inhibition approach fundamentally alters the clonal evolution of the disease by suppressing common escape routes, such as MET amplifications and secondary EGFR mutations. Furthermore, we explore the diversifying landscape of second-line interventions, including the rise of antibody-drug conjugates (ADCs) like Sac-TMT and patritumab-deruxtecan, dual PD-1/VEGF inhibitors, and novel fourth-generation TKIs. By integrating preclinical insights on drug-tolerant persister cells with late-phase clinical data, this article outlines a future forEGFR-mutant NSCLC management defined by precision sequencing and the proactive mitigation of molecular resistance.

Aim: The aim of this study is to investigate the molecular and functional features underlying the clinical heterogeneity between oligometastatic (OM) and polymetastatic (PM) colon cancer.

Methods: We performed a genotype-phenotype analysis in a homogeneous cohort of 127 patients with metastatic colon cancer (mCC) profiled using the same next-generation sequencing platform (TruSight Oncology^® 500). OM disease was defined as the presence of one to three metastatic lesions per involved organ, involving no more than two organs overall, with all lesions measuring < 70 mm in maximum diameter and no single lesion > 25 mm. Molecular alterations, microsatellite instability (MSI), tumor mutational burden (TMB), and overall survival (OS) were analyzed. Gene Ontology (GO) enrichment and Phenolyzer network analyses were applied to explore functional differences between prognostically distinct molecular subgroups.

Results: OM patients showed a striking survival advantage compared with PM patients [median OS not reached versus 29 months; hazard ratio (HR): 0.20, P < 0.0001], validating the clinical distinction between the two phenotypes. PM disease was significantly enriched for RAS mutations, whereas OM disease was associated with MSI-high status and elevated TMB. Canonical driver alterations were largely shared between groups, and Phenolyzer analysis revealed similar core oncogenic networks centered on adenomatous polyposis coli APC), tumor protein p53 TP53), and epidermal growth factor receptor EGFR). In contrast, GO analysis demonstrated selective enrichment in PM tumors for molecular functions related to ATP binding, nucleotide binding, and protein kinase activity, consistent with enhanced bioenergetic demand and signaling intensity.

Conclusions: These findings support refined biological stratification of mCC and the exploration of personalized, metastasis-directed strategies, potentially incorporating immunological modulation in OM disease.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. Consequently, standard hormone and HER2-targeted therapies are ineffective, necessitating reliance on chemotherapy, immunotherapy, antibody-drug conjugates (ADCs), and poly(ADP-ribose) polymerase (PARP) inhibitors forBRCA-mutated cases. TNBC exhibits rapid growth, a high risk of early recurrence, and disproportionately affects younger women, Black women, and BRCA1 mutation carriers. Standard management typically involves neoadjuvant chemotherapy followed by surgery and potential radiation. However, TNBC treatment remains challenging due to its severe biological heterogeneity, high metastatic potential, and the toxicity associated with systemic therapies. This review discusses the current understanding of TNBC biology, highlighting the urgent need for advanced diagnostics, integrated molecular subtyping, and personalized targeted therapies.

In 2013, more than a decade ago, the “Recalcitrant Cancer Research Act of 2012” was signed into law in the USA. Recalcitrant cancers are among the leading causes of global cancer morbidity and mortality. At the inception of the act, priority was placed on lungs and pancreatic cancers. Despite the tremendous advancement achieved in the research and treatment of said ‘recalcitrant cancers’ in the form of developing novel or modified small molecule and antibody drugs, modest improvement has been recorded for patients’ survival. Also, current mortality and morbidity for recalcitrant cancers keep increasing. Similarly, rare cancers only enjoy very meager research and drug development efforts globally. Consequently, very limited advancement has been made towards therapeutic development targeting rare cancers. Hence, the current situation calls for re-strategizing research efforts and exploring different treatment modalities towards combating recalcitrant and rare cancers. On this note, RNA therapeutics strategy holds a unique and vital prospect because of its propensity to target coding and non-coding RNA transcripts in the biological system. Moreover, RNA therapeutics such as lncRNAs and circRNAs have been established to even modulate protein expressions and biological phenotypic activity through RNA-protein interactions. Therefore, the current review aimed at summarizing existing literature, clinical trials, and elucidating the important prospect of RNA therapeutics in mitigating the recalcitrant and rare cancers menace.

Chemotherapy has profoundly shaped modern oncology, evolving from early cytotoxic approaches to biologically informed strategies. In glioblastoma (GBM), the highly aggressive primary brain tumor, precision medicine does not rely on the identification of a single crucial oncogenic driver but integrates biologically informed stratification strategies to predict treatment response, resistance, and therapy-induced adaptation. This review recapitulates the historical milestones of chemotherapeutic development in neuro-oncology, with particular emphasis on GBM. As the main chemotherapeutic agent currently used in GBM, temozolomide (TMZ) initially represented a major therapeutic breakthrough; however, its clinical use has progressively unveiled the biological and clinical limitations of conventional cytotoxic paradigms. While TMZ exerts antitumor activity through DNA damage–induced apoptosis, accumulating experimental evidence indicates that it may also elicit adaptive responses, ultimately supporting tumor progression and therapy resistance. By integrating historical milestones with recent molecular understanding, this review highlights how improved knowledge of therapy-induced adaptations may inform emerging precision medicine strategies in GBM, underscoring the need for tailored treatments to overcome tumor heterogeneity and adaptive responses.

Endocrine resistance in estrogen receptor-positive (ER+) breast cancer has undergone a fundamental reconceptualization over the past decade. The discovery that activating mutations in the ESR1 gene encoding ERα emerge under aromatase inhibitor (AI) selection pressure and drive ligand-independent receptor activation established a shift from empirical treatment sequencing to molecularly guided intervention. This review provides a synopsis of the structural biology underlying constitutive ER activation, the evolutionary dynamics of ESR1-mutant clones detectable through circulating tumor DNA (ctDNA), and the clinical evidence demonstrating that early molecular detection can trigger therapeutic switches that alter disease trajectory. The regulatory approval of elacestrant for ESR1-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position ESR1 genotyping as a dynamic biomarker with direct therapeutic implications. We examine the integration of oral selective ER degraders (SERDs) into treatment algorithms, the role of co-occurring alterations in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and emerging directions, including machine learning approaches to ctDNA kinetics and adaptive trial designs that treat clonal evolution as an actionable target. The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrentESR1 and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) ESR1 calls from background noise in liquid biopsies.

Background: Breast cancer encompasses heterogeneous pathological and molecular subtypes with distinct aetiologies and clinical outcomes. Although cigarette smoking is an established carcinogenic exposure, its subtype-specific associations and molecular effects in breast cancer remain insufficiently clarified. This systematic review synthesizes epidemiological, molecular, and prognostic evidence on how active cigarette smoking influences the risk of specific breast cancer subtypes.

Methods: We conducted a systematic review, including observational and translational human studies that assessed active cigarette smoking in relation to breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, or by intrinsic molecular classifications. We also included studies evaluating smoking-associated molecular alterations within breast tumors.

Results: Nineteen studies met the eligibility criteria. Epidemiological evidence suggested a possible modest increase in the risk of luminal/ER-positive breast cancer, particularly among women with longer smoking duration, heavier cumulative exposure, or smoking initiation before first full-term pregnancy; however, the pooled meta-analysis for current vs. never smoking was not statistically significant. No meaningful association was identified for triple-negative breast cancer (TNBC), and findings for HER2-positive breast cancer were heterogeneous. Molecular studies were associated with smoking-related changes in promoter DNA methylation, higher overall mutational burden, increased genomic instability, altered immune-cell infiltration within the tumor microenvironment, and conversion of receptor phenotype-especially toward HER2 positivity-suggesting a potential association with more aggressive tumor characteristics. Prognostic studies generally showed poorer overall survival and a higher risk of disease recurrence among smokers.

Discussion: Active cigarette smoking may be associated with a possible modest increase in the risk of luminal/ER-positive breast cancer, while being associated with molecular alterations linked to more aggressive tumor phenotypes and poorer clinical outcomes.

Breast cancer classification and therapeutic decision-making have traditionally relied on the evaluation of estrogen receptor alpha (ERα), PR, and HER2, yet this framework does not fully explain tumor heterogeneity, endocrine resistance, or estrogen responsiveness in ERα-negative contexts. Emerging evidence implicates non-genomic estrogen signaling mediated by membrane-associated receptors such as G protein-coupled estrogen receptor 1 (GPER-1) and ERα36. Acting as interconnected signaling nodes, these receptors activate MAPK/ERK and PI3K/AKT pathways and engage in crosstalk with receptors such as EGFR, promoting proliferation, cellular plasticity, and adaptive responses. Here, we propose an integrative framework based on three axes: endocrine resistance in ERα-positive tumors, estrogen responsiveness in ERα-negative subtypes, and environmental modulation of signaling. Within this model, GPER-1 and ERα36 form a coordinated network that extends beyond genomic mechanisms and converges on shared downstream effectors. These pathways also intersect with post-transcriptional regulation, tumor-microenvironment interactions, and extracellular vesicle-mediated communication, contributing to tumor progression and metastasis. Environmental ligands, such as bisphenol A, may further modulate signaling intensity, reinforcing plasticity and resistance phenotypes. Collectively, GPER-1 and ERα36 emerge as candidate biomarkers with diagnostic and therapeutic relevance. Their integration into multi-omics and functional classification strategies may refine breast cancer stratification and support more precise therapeutic approaches.

Gastrointestinal stromal tumours (GISTs) are the clearest solid-tumour model of precision oncology because diagnosis, prognosis, and treatment are strongly shaped by molecular genotype. The discovery of activating mutations in KIT proto-oncogene receptor tyrosine kinase KIT) and platelet-derived growth factor receptor alpha PDGFRA) transformed management by enabling genotype-directed use of tyrosine kinase inhibitors (TKIs) across localized and advanced disease. This review summarizes how molecular classification informs contemporary GIST care, from diagnostic work-up and risk stratification to neoadjuvant, adjuvant, and metastatic treatment planning. KIT exon 11 mutations generally predict sensitivity to standard-dose imatinib, whereas KIT exon 9 tumours may benefit from dose escalation. PDGFRA D842V confers primary resistance to imatinib but sensitivity to avapritinib, illustrating the clinical value of mutation-specific therapy. We also review KIT/PDGFRA-wild-type GISTs, including succinate dehydrogenase SDH)-deficient, neurofibromin 1 NF1)-associated, B-Raf proto-oncogene BRAF)-mutant, and neurotrophic tyrosine receptor kinase NTRK)-rearranged subtypes, where extended molecular testing is increasingly important. Surgery remains central in localized disease, but operative timing, extent of resection, and use of neoadjuvant therapy should be individualized according to tumour site, rupture risk, technical feasibility, and genotype. In advanced disease, sequential use of imatinib, sunitinib, regorafenib, ripretinib, and selected mutation-specific agents reflects evolving resistance biology and the need for ongoing molecular interpretation. Emerging tools such as broader genomic profiling and liquid biopsy may further refine treatment selection. GIST therefore demonstrates that precision oncology is most effective when molecular diagnostics, surgery, systemic therapy, and multidisciplinary decision-making are integrated across the full disease course.

Aim: The aim of this multicenter study was to assess patient characteristics and short-term survival outcomes of first-line (1L) enfortumab vedotin plus pembrolizumab (EVP) as compared with conventional chemotherapy in locally advanced or metastatic urothelial carcinoma (la/mUC).

Methods: The database included 642 patients with la/mUC diagnosed between January 2008 and December 2025 at 12 collaborating hospitals. Baseline characteristics and follow-up data, including overall and organ-specific objective tumor response according to the RECIST v1.1, progression-free survival, and duration of response, were compared among the 1L regimens. Treatment-related adverse events (TRAEs) were graded according to the CTCAE v5.0 in patients treated with 1L EVP.

Results: The objective response and disease control rate were higher with 1L EVP than with chemotherapy (66% vs. 42% and 83% vs. 68%, respectively). The organ-specific response rate for liver metastatic lesions was 85%. Median progression-free survival (95% confidence interval) for 1L EVP, gemcitabine plus cisplatin, and gemcitabine plus carboplatin was 14.5 months (10.5–not determined), 10.5 months (8.4–13.3), and 9.2 months (6.7–14.2), respectively. In the safety analysis set including 40 patients, all-grade TRAEs occurred in 36 (90%) patients, including grade 1–2 events in 30 (75%) and grade 3–4 toxicities in 6 (15%). Grade 3–4 TRAEs included skin toxicity (7.5%), anorexia (5.0%), anemia (5.0%), gastrointestinal disorders (2.5%), renal dysfunction (2.5%), and interstitial lung disease (2.5%). The median number of administered EV cycles was 4 (range, 1–13), 5 (2–13), and 10 (4–13) in the overall, responder, and complete-response populations, respectively. EV dose modifications and interruptions were frequent in the initial 2 months but rare thereafter.

Conclusions: This multicenter study provides real-world evidence on short-term outcomes and safety with 1L EVP, highlighting its impact on the evolving treatment landscape for la/mUC.

Aim: This study aims to investigate the expression and function of antisense long non-coding RNA (lncRNA) STEAP3-AS1 in breast cancer (BC). Additionally, it explores STEAP3’s regulatory relationship withSTEAP3-AS1 and potential signaling pathways to provide a theoretical foundation for identifying novel therapeutic targets.

Methods: Database prediction and collection of tissue samples were employed alongside a cell proliferation assay and Transwell migration and invasion assay to examine STEAP3-AS1 expression levels in BC tissues and cell lines, as well as its impact on cellular functions. Statistical analyses were performed, including two-tailed Student’s t-test, Mann-Whitney U test and analysis of variance (ANOVA).

Results: Both database and 9 paired clinical tissue sample results demonstrate that STEAP3-AS1 expression was significantly downregulated in BC compared with normal breast tissues P < 0.05). Compared with the estrogen receptor/progesterone receptor (ERPR)-negative (–)/human epidermal growth factor receptor-2 (Her2)-positive (+) subtype, the ERPR(+)/Her2(−) and ERPR(−)/Her2(−) subtypes exhibited a significantly lower expression level of STEAP3-AS1 P < 0.05). Overexpression of STEAP3-AS1 markedly suppressed the proliferation, migration, and invasion capabilities of MDA-MB-231 and MCF-7 cells compared with negative controls P < 0.05). Furthermore, STEAP3-AS1 exhibited a positive synergistic effect with its sense strand STEAP3, inhibiting BC cell migration and invasion.

Conclusions: This study is the first to demonstrate the tumor-suppressive role of STEAP3-AS1 in BC. These findings provide novel insights into the mechanisms underlying BC progression and offer critical theoretical support for the development of new therapeutic strategies.

In recent years, immunotherapy has modified the treatment landscape of advanced and recurrent endometrial cancer (a/rEC), particularly for patients with defective mismatch repair and microsatellite instability-high (dMMR/MSI-H), significantly improving their outcomes. Its success in later treatment lines has led to its investigation and adoption as a first-line therapy, alone or with chemotherapy. However, despite the high and long-lasting efficacy of immune checkpoint inhibitors (ICIs) in dMMR/MSI-H EC, not all patients benefit from this treatment, and reasons underscoring primary resistance in this setting remain poorly understood and are not yet incorporated into clinical decision-making. Additionally, the correlation between ICI response, tumor mutational burden (TMB), and PD-L1 expression, well-documented in other tumors, appears inconsistent in EC. While proficient mismatch repair and microsatellite stable (MMRp/MSS) EC remain an unmet medical need, some patients within this group still respond to ICIs. Although several biomarkers, includingTP53, BRCA, and homologous recombination deficiency (HRD), have been investigated, none have proven to be definitively predictive. This review examines the relevant trials with ICIs as a single agent or in combination in EC and explores the available evidence on potential predictive biomarkers.

Aim: The purpose is to explore the mechanism and new therapeutic strategy of lethal 3 malignant brain tumor like 4 L3MBTL4) gene in pancreatic ductal adenocarcinoma (PDAC).

Methods: Immunoprecipitation, siRNA knockdown, immunohistochemistry, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays, comet assays, and a xenograft mouse model were employed.

Results: L3MBTL4 was methylated in 16.3% (7/43) of intraductal papillary mucinous neoplasms, 19.0% (4/21) of mucinous cystic neoplasm, and 28.2% (84/298) of PDAC, and its expression was regulated by promoter region methylation. L3MBTL4 methylation was significantly associated with tumor differentiation and tumor size. The expression of L3MBTL4 inhibited cell proliferation, colony formation, and induced apoptosis and G1/S phase arrest. L3MBTL4 activated ATM/CHK2 and inhibited NHEJ signaling by interacting with Ku70. Loss of L3MBTL4 increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo.

Conclusions: L3MBTL4 is a new component of NHEJ signaling and epigenetic silencing of L3MBTL4 sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy.

Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2–Keap1 axis to adapt to these conditions, leading to redox plasticity and “Nrf2 addiction” in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc^–, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.

The molecular pathogenesis of oral squamous cell carcinoma (OSCC) is a complex process involving genetic alterations that accumulate over time. The clinical presentation and management of patients vary according to several pathological factors, but lymph node involvement is a key consideration in this context. Accurate lymph node staging in the neck is challenging because metastases may be present at an early stage of oral cancer. This narrative review assesses the evolution of imaging techniques over the last five years, distinguishing between research and established methods in order to address specific clinical questions. Conventional imaging techniques, including ultrasonography, contrast-enhanced computed tomography, contrast-enhanced magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography, are reviewed and compared with several noteworthy developments in optical and fluorescence imaging. In this scenario, various position papers and guidelines strongly suggest using scintigraphy for sentinel node biopsy. However, its use in clinical practice is not widespread. This is a direct result of unrelenting advances in imaging accuracy, treatment options and new diagnostic approaches. All these approaches are considered here, but none emerges as a universal solution. Overall, no single technique currently emerges as a universal solution. The most realistic strategy is an integrated, multidisciplinary pathway. Multimodal imaging integration framework and AI-assisted diagnostic strategy could provide a novel clinical decision-making pathway for cervical lymph node staging in T1–T2 stage OSCC patients.

We aimed to evaluate the suitability of archival ureteroscopic (URS) biopsy specimens for fibroblast growth factor receptor 3 FGFR3) biomarker analysis in upper urinary tract urothelial carcinoma. Thirty-six patients with upper urinary tract urothelial carcinoma who underwent diagnostic URS and radical nephroureterectomy (RNU) were included. Among the 36 RNU-derived tissue specimens, 33 (92%) yielded valid FGFR3 RNA test results; the remaining three (8.3%) showed test failure because of undetectable amplification by reverse transcriptase-polymerase chain reaction. Of the 33 RNU specimens with valid amplification, eight (24%) had FGFR3 alterations. Of these eight specimens, two (25%) were valid for FGFR3 RNA testing; one showed positive concordance with the paired RNU specimen, whereas the other did not. The remaining six specimens (75%) showed test failure. Correlation analysis of FGFR3 immunohistochemical staining scores demonstrated a moderate positive correlation between RNU and paired URS specimens (Spearman’s ρ = 0.47, P = 0.004). Our findings indicate that URS biopsy specimens are unsuitable for FGFR3 RNA testing but may be useful for protein-based biomarker analysis when RNU specimens are unavailable.

Aim: Transurethral laser ablation (TULA) for recurrent bladder cancer is a less invasive treatment method for patients. We report here our initial clinical experience with TULA for recurrent bladder cancer.

Methods: This retrospective study analyzed 48 patients. Twenty-four cases were treated with TULA and another 24 cases were treated with transurethral resection of bladder tumor (TURBT) from Feb 2024 to Mar 2025 at Kochi Medical School Hospital. Intraoperative and postoperative outcomes and recurrence-free survival (RFS) were analyzed between TULA and TURBT.

Results: This study showed that TULA using a 980-nm diode laser was significantly shorter than TURBT in terms of perioperative results: operative time, hospital stay, catheterization, bladder irrigation, and postoperative hospital stay. Regarding the occurrence of complications, TULA was observed to be less prevalent than TURBT in all cases. Kaplan-Meier curves showed that TULA was significantly associated with longer RFS compared to TURBT (hazard ratio 4.739; 95% confidence interval, 1.272–17.65; p = 0.02039).

Conclusions: Our preliminary results showed that TULA for recurrent bladder cancer is feasible and safe.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice.

Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS).

Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events.

Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

Aim: The aim was to determine the transcriptomic features of tumor and stromal cells in direct contact within tumor nodules in luminal and triple-negative breast cancer.

Methods: Spatial transcriptomic profiling was performed using the Visium 10x platform on FFPE tumor tissue sections from 10 patients with luminal breast cancer and 9 patients with triple-negative breast cancer. Manual morphological annotation of spots and evaluation of differentially expressed genes (DEGs) in identified spot clusters were performed using Loupe Browser v8.0.0 (10X Genomics, USA). Activated biological processes were assessed using the Enrichr online resource and the GO Biological Process 2025 database. Ligand-receptor pairs were identified using the CellChat package (v2.0) in R (v4.4.2).

Results: In luminal breast cancer, mixed cluster (tumor cells colocalized with stromal cells) was characterized by overexpression of genes encoding S100A family Ca²⁺-binding proteins S100A4, S100A8, S100A9), matrix metalloproteinases MMP2, MMP7, MMP14), cytokeratins KRT5, KRT7, KRT15, KRT23, KRT81), the mesenchymal marker VIM, and epithelial-mesenchymal transition (EMT)-associated genes ICAM1, PRRX1) compared to tumor-only cluster. In triple-negative breast cancer, mixed cluster showed overexpression ofS100A2, S100A8, S100A9, the epithelial gene KRT6B, the cancer stem cell marker CD44, and NOTCH2, which is associated with negative regulation of EMT. In both breast cancer subtypes, mixed cluster showed transcriptomic enrichment of gene sets associated with regulation of the ERK/MAPK cascade, apoptosis, and cell adhesion and migration. Ligand-receptor pairs associated with cell-cell contact, EMT, and immune response were also detected in colocalized cells, with a broader spectrum of these pairs observed in luminal breast cancer.

Conclusions: This study assessed the transcriptomic characteristics of directly contacting tumor and stromal cells and identified the spectrum of ligand-receptor pairs mediating their interactions. Characterizing the properties of cells at the tumor-stroma interface helps unravel mechanisms of breast cancer progression and identify novel diagnostic markers and therapeutic targets.

Aim: Minimally invasive approaches for radical cystectomy (RC) have been increasingly adopted; however, comparative evidence regarding surgical quality and perioperative outcomes among open (ORC), laparoscopic (LRC), and robot-assisted RC (RARC) remains limited. This study evaluated these three modalities using standardized composite metrics, trifecta and pentafecta, and inverse probability of treatment weighting.

Methods: We retrospectively analyzed 192 patients who underwent RC with ileal conduit or neobladder reconstruction between 2006 and 2023. Inverse probability of treatment weighting was applied using comprehensive clinicopathological covariates. Trifecta and pentafecta achievements, perioperative parameters, and postoperative complications were compared among the ORC n = 110), LRC n = 38), and RARC n = 44) groups.

Results: RARC achieved the most favorable perioperative and surgical outcomes. Specifically, RARC showed significantly higher rates of several trifecta and pentafecta components than ORC, including fewer positive soft tissue surgical margins (0.0% vs. 5.2%,P < 0.01), reduced major complication rates within 90 days (16.1% vs. 44%, P < 0.05), and fewer urinary diversion–related sequelae within 12 months (1.5% vs. 13.5%, P < 0.05). RARC was also associated with significantly lower blood loss than ORC (380 ± 513 mL vs. 2,913 ± 2,997 mL, P < 0.01), as well as lower rates of pelvic abscess, gastrointestinal anastomotic leakage, and obstructive ileus (all P < 0.01) than ORC. In contrast, LRC was not superior to ORC in terms of major complications or diversion-related outcomes. Local pelvic recurrence within 12 months did not differ significantly among the three modalities.

Conclusions: RARC may be a favorable surgical option for reducing perioperative morbidity in patients with high-grade bladder cancer, with comparable 12-month local recurrence rates among surgical approaches.

Tumor heterogeneity and cellular plasticity are major drivers of therapeutic failure across many cancer types. While precision oncology has largely focused on static genomic alterations, growing evidence indicates that tumors behave as dynamic biological systems that continuously adapt during treatment. Tumor cell populations can transition between distinct functional states under therapeutic pressure, including transient drug-tolerant phenotypes that may precede stabilization of genetically or epigenetically resistant clones. These transitions are shaped by mechanisms such as epigenetic reprogramming, stress-response signaling, metabolic rewiring, and microenvironmental interactions. This review synthesizes findings from tumor plasticity, drug-tolerant persister biology, therapy-induced vulnerabilities, clonal evolution, and adaptive therapy to examine how temporal tumor dynamics influence treatment response. Emerging evidence suggests that some tumors may pass through short-lived phases of cellular instability during therapy in which molecular dependencies, stress-response programs, or adaptive survival states are altered before resistance becomes genetically or epigenetically stabilized. However, such transition states should be considered therapeutically actionable only when linked to functional evidence of altered drug sensitivity, pathway dependence, immune susceptibility, or clinical response. Advances in single-cell transcriptomics, epigenomic profiling, serial circulating tumor deoxyribonucleic acid (ctDNA)/cfDNA analysis, multi-omics integration, and dynamic imaging are enabling longitudinal monitoring of tumor state transitions and may facilitate identification of transient biological states preceding stable resistance. Integrating temporal tumor biology with therapeutic sequencing strategies, adaptive treatment schedules, and biomarker-guided monitoring may therefore help test whether specific adaptive states can be therapeutically exploited and may refine precision oncology approaches.

Aim: Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenesE5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity.

Methods: A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method.

Results: Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5-associated with immune evasion-combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients.

Conclusions: These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.

Aim: Oligoprogressive disease (OPD) has emerged as a clinically relevant and common scenario in oncology, reflecting progression in a limited number of metastatic sites while systemic therapy continues to control the majority of disease. Despite its increasing recognition, the definition, diagnostic approach, and management of OPD remain poorly standardized.

Methods: A multidisciplinary expert panel from Kazakhstan and international faculty, including ten medical oncologists, radiation, and surgical oncologists, participated in a structured survey. The questionnaire consisted of 15 items divided into three domains: definition of OPD, diagnostic evaluation, and treatment strategies. Responses were analyzed, and consensus was defined as ≥ 70% agreement, relative agreement as 50–69%, and lack of consensus as < 50%.

Results: Consensus was reached that OPD is defined as progression in a limited number of lesions while other sites remain controlled, regardless of lesion size or localization. No consensus was achieved regarding the maximum number of progressive lesions, with experts divided between “≤ 5 lesions” and “any number amenable to local therapy.” Imaging with CT or PET-CT was considered sufficient. Biopsy and molecular testing were recommended only in selected contexts. Systemic therapy continuation during OPD was endorsed if effective, with strong support for local therapy, particularly stereotactic ablative radiotherapy (SBRT/SABR). Divergence remained regarding the management of repeat OPD.

Conclusions: This Kazakhstan Cancer Society consensus defines the fundamental clinical features of OPD and provides practical recommendations for diagnosis and treatment. Comparison with international guidelines reveals broad alignment on systemic continuation and local therapy, as well as persistent variation regarding lesion number, biopsy, and repeat OPD management.

Aim: Breast cancer remains a major cause of cancer-related mortality in women, particularly in advanced stages where therapeutic options are limited. While immune checkpoint inhibitors (ICIs) have improved outcomes in a subset of patients, many do not respond, highlighting the need for alternative immunotherapeutic strategies. This study evaluated the effect of dendritic cell (DC)-based immunotherapy on tumor growth and on the inflammatory profile of peritoneal myeloid cells in a 4T1 murine breast cancer model.

Methods: BALB/c mice bearing 4T1 breast tumors were treated with bone marrow-derived DC-based immunotherapy. Tumor volume was monitored over time, and CD14⁺ cells obtained from peritoneal lavage were analyzed by flow cytometry for the cytokines IL-12, IL-17, and TNF-α and the transcription factors RORγT and GATA3.

Results: DC-based immunotherapy was associated with a non-significant trend toward reduced tumor volume and a marked suppression of key proinflammatory cytokines: IL-12 ( P < 0.0005), IL-17 ( P < 0.0001), and TNF-α ( P < 0.0001). Expression of the transcription factors RORγT and GATA3, associated with Th17 and Th2 differentiation, was also downregulated ( P < 0.0001). These immunological effects were observed in CD14⁺ myeloid cells from the peritoneal compartment.

Conclusions: DC-based immunotherapy modulates the systemic/peritoneal inflammatory profile and attenuates tumor-promoting inflammation. This strategy may offer therapeutic benefit for patients with breast cancer who are unresponsive to conventional or ICI-based treatments and supports its further evaluation in translational studies.

Breast cancer remains one of the leading causes of cancer-related mortality worldwide, and despite considerable advances in therapeutic strategies, the absence of reliable, minimally invasive diagnostic tools continues to limit early detection and real-time disease monitoring. Liquid biopsy has emerged as a transformative paradigm in oncology, offering the capacity to integrate tumor biology through the analysis of tumor-derived materials that circulate in peripheral blood and other biofluids. This review provides a comprehensive overview of the key analytes employed in liquid biopsy, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), extracellular vesicles (EVs), and protein biomarkers with particular emphasis on their translational relevance in breast cancer. Drawing on landmark clinical trials and foundational molecular studies, we highlight how these biomarkers capture spatial and temporal tumor heterogeneity in ways that conventional tissue biopsy cannot. Finally, we address the technical, clinical, and ethical challenges that still impede widespread adoption of liquid biopsy, and we outline a forward-looking research agenda oriented toward multi-omics integration and point-of-care diagnostics. Taken together, this review underscores the potential of liquid biopsy to complement existing diagnostic standards and improve how we screen for, monitor, and treat breast cancer across disease stages.

Aim: The aim of our study was to evaluate the safety and efficacy of delivering systemic treatments concurrently with whole-brain radiotherapy (WBRT).

Methods: A single-institution, prospective observational study was conducted in Athens, Greece, including 99 patients treated with WBRT for brain metastases from September 2017 until October 2019, and with a follow-up period extending to March 2025. The study endpoints included overall survival (OS) for all causes of death, time to intracranial progression (TTICP), and serious acute toxicities.

Results: The median OS from all causes of death was 6 months [95% confidence interval (CI): 4.7–7.3]. Concomitant systemic therapy reduced the risk of death p = 0.005), and the presence of systemic metastases p = 0.009) increased the risk of death for patients with brain metastases treated with whole brain radiotherapy. The median TTICP was 10 months (95% CI: 3.3–16.6), with a more protracted fractionation and a larger number of brain metastases being prognostic of an increase in the TTICP. Acute severe toxicity was observed in 16.2% of patients, with no statistically significant difference between concurrent and no systemic therapy groups, and with no treatment interruptions in patients treated concurrently.

Conclusions: This study showed that there is no serious toxicity from the combination of systemic therapy with WBRT, and that the OS and the TTICP are not compromised with their concurrent delivery.

Primary bone sarcomas are rare and biologically heterogeneous malignancies for which therapeutic progress remains limited, particularly in metastatic and recurrent disease. Advances in genomic and molecular profiling have revealed substantial inter- and intratumoral heterogeneity across the major subtypes, including osteosarcoma, Ewing sarcoma and chondrosarcoma, challenging conventional histology-driven treatment strategies. Precision medicine approaches are being increasingly explored to better capture this biological complexity and guide individualized therapeutic decision-making. This review examines emerging precision oncology strategies in bone sarcomas, including molecular diagnostics, targeted therapeutic approaches, three-dimensional functional modeling systems, and liquid biopsy technologies for dynamic disease monitoring. Together, these platforms provide biologically informed frameworks for patient-specific treatment and longitudinal assessment of tumor evolution. However, clinical implementation remains limited by genomic complexity, small patient cohorts, and methodological variability across experimental platforms. The integration of multi-layered precision models combining genomic stratification, functional drug sensitivity testing and circulating biomarker monitoring may enable more adaptive and individualized management strategies. Such approaches have the potential to improve therapeutic selection and ultimately advance outcomes for patients with primary bone sarcomas.

Precision oncology has revolutionized cancer care in high-income countries, but its implementation in Latin American low-resource settings faces profound bioethical dilemmas. This study analyzes these challenges through the lens of social justice and equity. An integrative review was conducted following the Whittemore and Knafl framework. A systematic search was performed across PubMed, Scopus, SciELO, and LILACS (2015–2025). Thematic synthesis was applied to integrate empirical data with normative bioethical theories. Four major analytical themes were identified: 1) The innovation paradox and financial toxicity, where prohibitive pricing (exceeding 100,000 USD/year) violates distributive justice and leads to a biological penalty in survival; 2) Infrastructure deficits and epistemic injustice, highlighted by a 9.4% access rate to next-generation sequencing (NGS) and the risks of applying Eurocentric genomic data to admixed LA populations; 3) Research vulnerability, where clinical trials serve as survival strategies, compromising autonomy and informed consent; and 4) The judicialization dilemma, where individual court orders for high-cost drugs threaten systemic sustainability and equity. To prevent a genomic apartheid, Latin America must transition toward genomic sovereignty and frugal precision oncology. Bioethical frameworks in the region must prioritize protection ethics and social justice to ensure that scientific innovation does not exacerbate existing health inequities.

Breast cancer management increasingly hinges on decisions made in “grey zones” where tissue sampling is scarce, and tumour biology evolves under therapeutic pressure. This narrative review synthesises evidence on how whole-body imaging biomarkers and circulating tumour DNA (ctDNA) can support response-adaptive pathways at the interface of surgical and systemic care. Four clinically actionable domains are discussed. (a) 16α-[¹⁸F]fluoro-17β-estradiol ([¹⁸F]FES) positron emission tomography/computed tomography (PET/CT) enables non-invasive, whole-body mapping of functional oestrogen receptor (ER) expression to address receptor discordance, heterogeneous metastases, and selection of endocrine-based strategies. (b) Human epidermal growth factor receptor 2 (HER2)-targeted PET (notably⁸⁹Zr-trastuzumab, with emerging alternatives) provides whole-body receptor assessment to uncover actionable HER2-positive disease despite HER2-negative primaries, informing anti-HER2 treatment selection when repeat biopsy is infeasible. (c) In triple-negative breast cancer treated with immune checkpoint inhibitors,¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT offers quantitative response and whole-body burden assessment but requires immunotherapy-aware interpretation (e.g., confirmation strategies for apparent early progression) to mitigate pseudoprogression and dissociated responses, while simultaneously visualising immune-related adverse events. (d) Pairing early metabolic change on FDG PET/CT with ctDNA kinetics is presented as a biologically complementary approach for response monitoring and risk stratification, with potential to inform trial-embedded response-adaptive hypotheses, with ctDNA offering a rapid systemic trajectory and PET providing lesion-level localisation in heterogeneous or oligoprogressive disease. Overall, these tools add value only when linked to prespecified clinical questions and consensus actions; prospective studies are needed to validate standardised, outcome-improving response-adaptive algorithms that integrate imaging and liquid biopsy. Key implementation challenges include tracer availability, harmonised acquisition/reconstruction, threshold definition, and avoiding overtesting. Near-term impact may be greatest in problem-solving and in trial-embedded decision rules that operationalise biomarker-guided care.

A functional immune system is a key antagonist of cancer cell growth. Cytokines such as interferons (IFNs) promote the onset of inflammation, turn cells into an anti-viral state, and shape the dynamic tumor-immune cell interactome. Recent work illustrates how type I IFNs contribute to the resolution of inflammatory conditions. This involves macrophage-mediated efferocytosis for the clearance of apoptotic cells and the intrinsic capacity of type I IFNs to restrict their own autocrine signaling loops via the IFN-stimulated gene 15 (ISG15) protein. We discuss how this may affect tumor cells and how acetylation-dependent processes can affect the phosphorylation-dependent signaling cascades that augment IFN-dependent gene expression.

Endocrine treatment in combination with CDK4/6 inhibitors represents the mainstay of first-line palliative treatment in HR+/HER2– breast cancer. The treatment landscape after progression on CDK4/6 inhibitors has evolved into a complex and rapidly evolving field, driven by novel endocrine and targeted agents, new combination therapies, and increasing implementation of biomarker-directed approaches. Recent randomized trials have shown that new therapeutic strategies significantly prolong progression-free survival in this setting, with some treatments reaching notable numerical improvements. Translating these options into routine clinical practice remains challenging due to heterogeneous trial designs, lack of head-to-head comparisons, suboptimal comparator treatments, and limited overall survival data. While the increasing implementation of biomarkers holds the potential for more personalized treatments, their clinical utility depends on their mechanistic and contextual biological relevance, methodological reliability of detection, and proven predictive value in clinical trials. Based on the current evidence, optimal treatment selection and sequencing in the post-CDK4/6 inhibitor setting remain insufficiently defined, and optimization of biomarker-guided treatment requires further mechanistic understanding and methodological refinement. This narrative review provides an overview of the most recent randomized clinical trial evidence shaping current clinical practice and discusses persistent uncertainties regarding its implementation in routine care.

With national breast cancer screening programs leading to earlier diagnosis and improved treatments, more women are achieving long-term remission. However, this has resulted in rising rates of cardiotoxicity in breast cancer survivors consequent to their cancer therapies. Anthracyclines, a cornerstone treatment in breast cancer, carry a significant risk of short- and long-term cardiotoxicity through inhibition of topoisomerase II, preventing DNA repair and increasing oxidative stress. This most commonly manifests in the form of left ventricular (LV) systolic dysfunction or heart failure, and in severe cases, death. Many of the other treatments, including taxanes, cyclophosphamide, human epidermal growth factor receptor 2 inhibitors, immunotherapies, hormone therapies, and radiotherapy, also carry a risk of cardiac injury in the form of heart failure, arrhythmias, myocarditis, and pericardial disease. Surveillance has traditionally been performed by monitoring LV ejection fraction by transthoracic echocardiography. However, this has been found to be a late marker of cardiotoxicity, with damage potentially irreversible, and may reflect a missed opportunity for early intervention. Research has focused on identifying cardiac biomarkers and advanced imaging techniques, including strain analysis, to detect subclinical myocardial injury or dysfunction prior to irreversible damage, with LV global longitudinal strain a sensitive marker of subclinical LV systolic dysfunction and superior predictor of future cardiovascular events. Further research is needed to establish standardized guidelines on surveillance and management of this vulnerable patient cohort.