OBJECTIVE: Primary hepatic extraskeletal osteosarcoma (PHOS) is an extremely rare and aggressive malignant tumor originating in the liver with no primary skeletal lesion. Less than 1% of all extraskeletal osteosarcomas occur in the liver, often presenting as a large abdominal mass with poor prognosis. CASE PRESENTATION: We report a rare case of a 64-year-old man diagnosed with a giant PHOS (163×128×160mm) accompanied by pulmonary and lymph node metastases. Multimodal imaging magnetic resonance imaging (MRI), computed tomography (CT), bone scintigraphy, positron emission tomography (PET)/CT demonstrated a heterogeneous hepatic mass with extensive calcifications, rim enhancement, restricted diffusion, and elevated fluorine-18-fluorodeoxyglucose (F-FDG) uptake. Histopathological analysis confirmed the diagnosis, showing atypical mesenchymal cells producing osteoid matrix with strong special AT-rich sequence-binding protein 2 (SATB2) positivity and negative epithelial markers. DISCUSSION: Imaging characteristics and immunohistochemical profiling were crucial in differentiating PHOS from hepatocellular carcinoma and metastatic osteosarcoma. The case supports the metaplasia theory of PHOS pathogenesis and highlights its radiologic-pathologic correlation, especially the "cloud-like" enhancement on imaging corresponding to unmineralized osteoid and vascular proliferation. CONCLUSION: This case highlights the diagnostic challenge and clinical significance of PHOS. Comprehensive imaging and pathological evaluation are essential for accurate diagnosis. Due to its rarity and aggressiveness, PHOS requires individualized management strategies, typically involving surgery and adjuvant therapies despite limited evidence-based guidelines.

Metastasis remains the dominant cause of cancer mortality, yet genetic alteration alone fails to explain the spatial plasticity, immune escape, and therapy resistance characteristic of advanced solid tumours. Here we advance an RNA-centric framework in which exon-mediated activation of transcription starts (EMATS) amplifies transcriptional output, while hierarchical RNA surveillance-nuclear decay and cytoplasmic nonsense-mediated decay (NMD)-determines transcript fate downstream of transcription. In hypoxic tumour cores, EMATS-driven RNA overproduction overwhelms surveillance capacity, causing RNA fate collapse, proteostasis stress, destabilisation of proteasome-HLA coupling, and immune invisibility. In contrast, invasive tumour margins preserve RNA surveillance, maintaining antigen presentation and metastatic signalling. This framework explains immune escape independently of mutation burden or cytokine excess. It reconciles paradoxes in immunotherapy response, and positions RNA fate as a tractable axis for biomarker development and therapeutic stratification.

BACKGROUND: Anal cancer incidence is rising in the United States, now exceeding 10,000 cases annually. Chemoradiation (CRT) is the standard curative-intent treatment for non-metastatic squamous cell carcinoma of the anus (SCCA), with surgery generally reserved for non-responders with persistent or progressive disease. Recent trials have refined management, supporting the assessment of response at 26 weeks before considering surgery. However, contemporary population-level patterns of upfront primary surgery and associated survival trends remain incompletely described. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) registry (2004-2020), we identified adults with newly diagnosed non-metastatic anal squamous cell neoplasms (ICD-O-3 8050-8089). Outcomes were receipt of primary surgery as initial treatment and overall survival. We evaluated temporal trends (Cochran-Armitage), factors associated with primary surgery (multivariable logistic regression), and survival over time (Kaplan-Meier; multivariable Cox proportional hazards modeling). RESULTS: Among 16,718 patients with non-metastatic anal cancer, 33.1% (n = 5,529) underwent primary surgery and 83.7% (n = 13,997) received radiation as part of initial management. Primary surgery declined from 46.0% in 2004 to 28.7% in 2020 (trend p < 0.001), while radiation utilization was relatively stable over time (trend p = 0.106). In adjusted analyses, younger age (<50 vs 60-69 years; OR 1.614), male sex (OR 1.508), and Non-Hispanic Black race (vs Non-Hispanic White; OR 1.178) were associated with higher odds of primary surgery. Tumor factors were strongly associated with surgical use (e.g., T1 vs T2: OR 3.072; higher N stage associated with lower odds). Overall survival improved across diagnosis periods (log-rank p = 0.0002); in adjusted Cox models, diagnosis in 2016-2020 (vs 2004-2007) was associated with lower mortality risk (HR 0.77). CONCLUSIONS: From 2004 to 2020, primary surgery as initial management for non-metastatic anal cancer declined substantially, consistent with increasing adoption of CRT, while overall survival improved over time. Persistent use of upfront surgery in select subgroups warrants further study to clarify indications and ensure guideline-concordant care. IMPLICATIONS FOR PRACTICE: In this population-based study, primary surgery for non-metastatic anal cancer declined substantially over time, while overall survival improved, supporting the continued shift toward CRT-first, sphincter-preserving management. These findings reinforce the importance of guideline-concordant, multidisciplinary care and careful response assessment before considering surgery. Persistent use of upfront surgery in select subgroups suggests a need for closer evaluation of treatment decision-making, patient counseling, and potential barriers to optimal nonsurgical therapy.

PURPOSE: To elucidate the biological heterogeneity of gallbladder cancer (GBC) cells and refine post-operative risk stratification by investigating the expression and downstream signaling of the B7-family immune checkpoint molecules CD276 (B7-H3), VTCN1 (B7-H4), and HHLA2 (B7-H7) at single-cell resolution. METHODS: Single-cell RNA sequencing (scRNA-seq) data from seven primary tumors delineated five epithelial subgroups via non-negative matrix factorization (NMF). The functional association between HHLA2 and RAC1/CDC42-PAK1-Cofilin signaling was validated by lentiviral manipulation, pharmacologic inhibition, and subcutaneous xenografts. A total of 188 surgically treated GBC patients were enrolled for survival modeling. Seven machine-learning survival algorithms were trained on five variables (CD276, VTCN1, HHLA2 expression, tumor size, and differentiation) and compared by C-index, ROC-AUC, and calibration curves. RESULTS: CD276 + and VTCN1 + epithelial cells displayed pro-proliferative profiles, whereas HHLA2 + cells exhibited high EMT and migration signatures. HHLA2 overexpression led to increased RAC1/CDC42-PAK1-Cofilin signaling activity, enhanced proliferation, invasion, and EMT in vitro, and accelerated tumor growth in vivo. These effects were reversed by RAC1, CDC42, or PAK1 inhibitors, as well as by CFL1 knockdown. NMF classified tumor epithelial cells into five functionally distinct subgroups. A gradient-boosting machine (GBM) model integrating expression of the three B7 molecules with tumor size and differentiation achieved superior discrimination and accurate calibration on both the training and validation sets. CONCLUSION: B7-family expression delineates biologically distinct GBC subpopulations; HHLA2 promotes EMT via RAC1/CDC42-PAK1-Cofilin signaling. The GBM model incorporating CD276, VTCN1, and HHLA2 expression with tumor size and differentiation demonstrates potential for enhanced post-operative risk stratification, offering promising candidates for biomarker development and targeted therapeutic interventions.

Metabolic reprogramming and genome instability represent two fundamental hallmarks of cancer. Emerging studies now demonstrate that specific metabolic alterations directly fuel replication stress, DNA damage, and compromised DNA damage response. This underscores that metabolites are not merely passive by-products but active biochemical regulators of genome instability. Perturbation of specific metabolic pathways can preferentially unmask these vulnerabilities for therapeutic targeting. In this review, we propose an integrated framework highlighting metabolism-induced genome instability as a potential therapeutic target. By delineating the metabolic targets that induce genome instability, we provide a comprehensive overview of the complex interplay between metabolic pathways and genome stability. We further highlight that metabolism-induced genome instability can be strategically exploited to potentiate standard-of-care therapies. Collectively, these insights redefine metabolism-induced genome instability as a targetable vulnerability of cancer. This systematic synthesis provides a mechanistic rationale for next-generation therapeutic designs in which metabolic interventions are leveraged to convert genome instability into actionable clinical vulnerabilities.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with late-stage diagnoses predominantly driven by the absence of early clinical symptoms and the inadequate sensitivity of current diagnostic tools, highlighting a critical unmet need in liver cancer management. Circulating extracellular vesicles (EVs), which naturally carry proteins and nucleic acids, serve as both mediators of tumor-specific biology and reporters of early pathophysiological changes, offering a transformative avenue for noninvasive liquid biopsy. This review integrates mechanistic advances in understanding EV-associated proteins involved in HCC pathogenesis with state-of-the-art proteomic methodologies for EV biomarker discovery, validation, and clinical translation. We highlight how functional and mechanistic insights into EV proteins guide the identification of clinically relevant biomarkers and examine recent progress in analytical approaches for isolating and profiling blood-derived EVs in large patient cohorts. Additionally, we discuss the development of high-throughput detection platforms, such as biochip-based assays, which are accelerating the translation of EV protein biomarkers from research to routine clinical practice. Critical challenges, including the lack of standardized analytical workflows, limited demonstration of clinical utility, and the need for multicenter validation, are addressed, with a focus on strategies to ensure robust and reproducible biomarker performance. By bridging mechanistic understanding with analytical innovation and clinical application, we aim to accelerate the deployment of EV proteomics for earlier HCC detection, risk stratification, and treatment monitoring, ultimately advancing precision oncology.

BACKGROUND: Bladder cancer (BCa) remains a major global health challenge with high recurrence and progression rates. Although metabolic reprogramming is recognized as a hallmark of cancer, the molecular mechanisms driving glycolysis in BCa are incompletely understood. ATAD3A, a mitochondrial membrane protein implicated in various malignancies, has not been characterized in BCa. This study aimed to investigate the role of ATAD3A in BCa progression and elucidate the molecular mechanisms linking ATAD3A to tumor metabolism. METHODS: TCGA-BLCA data were analyzed to assess ATAD3A expression and its association with clinical outcomes. Functional assays, including CCK-8, colony formation, EdU incorporation, Transwell migration/invasion, wound healing, and Seahorse metabolic flux analysis (ECAR and OCR), were conducted in BCa cell lines with ATAD3A knockdown or overexpression. Subcutaneous xenograft models were used to evaluate tumor growth in vivo. Quantitative proteomics identified downstream pathways. Mechanistic studies included cycloheximide chase assays, proteasome inhibition, ubiquitination assays, immunofluorescence, and co-immunoprecipitation to explore the regulation of MYC stability by ATAD3A and USP10. RESULTS: ATAD3A was significantly upregulated in BCa and associated with advanced stage and poor prognosis. ATAD3A knockdown suppressed proliferation, migration, invasion, and tumor growth, whereas overexpression enhanced these malignant phenotypes. Proteomics revealed enrichment of glycolysis pathways upon ATAD3A overexpression, and functional assays confirmed ATAD3A-dependent increases in lactate production and glucose uptake. Glycolysis inhibition with 2-DG abolished ATAD3A-driven phenotypes. Mechanistically, ATAD3A stabilized MYC protein without affecting its mRNA levels, prolonging MYC half-life by suppressing ubiquitin-proteasome-mediated degradation. USP10 was identified as a key mediator, directly interacting with MYC and reducing its poly-ubiquitination. Rescue experiments confirmed that USP10 or MYC restoration overcame the suppressive effects of ATAD3A knockdown both in vitro and in vivo. CONCLUSION: Our findings demonstrate that ATAD3A drives BCa progression by promoting USP10-mediated stabilization of MYC and enhancing glycolytic reprogramming. The ATAD3A-USP10-MYC axis represents a potential therapeutic target for BCa.

BACKGROUND: Acute pain syndrome (APS) is a common side effect of paclitaxel therapy. To date, there is no standard of care to prevent APS in patients receiving paclitaxel. Through this study, we aim to assess whether oral duloxetine reduces the incidence of paclitaxel-induced APS (P-APS) as compared to placebo. METHODS: This is a multi-centric, randomized (1:1), double-blind, placebo-controlled, parallel-group superiority trial. A total of 204 patients with breast cancer planned to receive paclitaxel will be randomly assigned to receive either oral duloxetine or a matched placebo for 7 days after paclitaxel infusions for 4 cycles. The primary objective of the study is to compare the proportion of patients who develop P-APS in two groups. Key secondary objectives are to compare the quality of life (using the FACT-B scale), the incidence of peripheral neuropathy, the safety profile, and adherence with duloxetine. Patient-reported outcomes for P-APS and neuropathy will be assessed at the end of each cycle using BPI-SF and EORTC-CIPN20 questionnaires, respectively. DISCUSSION: The DOPA study is designed to evaluate whether oral duloxetine can reduce the occurrence of APS in patients receiving paclitaxel chemotherapy for breast cancer. Limited trials have assessed P-APS prevention using etoricoxib, dexamethasone, and pregabalin, but no pharmacological measure is effective. If the trial successfully meets its primary endpoint, oral duloxetine could become the new standard of care for preventing paclitaxel-induced APS. TRIAL REGISTRATION: Clinical Trials Registry of India - CTRI/2024/10/075636. Registered on 22 October 2024.

X-ray triggered local activation of prodrugs is promising for tumor radio-chemo-immunotherapy. However, the insufficient active drugs within tumors under prescribed X-ray doses lead to poor immunogenic effects. Here, we proposed to develop ClO-responsive nanoprodrug (DOX/S-M) that could persistently release DOX in response to inflammation induced by single-dose X-ray irradiation, thereby maintaining high levels of active DOX in tumors. DOX/S-M, prepared by the self-assembly of DOX-S-mPEG and tumor-targeting amphiphilic polymers (DSPE-PEG-Folate), were stable in normal environments. After X-ray irradiation, DOX/S-M, which was accumulated at the tumor site in a targeted manner for 24 h, underwent collapse and DOX release for 24 h in the presence of a high concentration of ClO produced by the infiltration and activation of inflammatory cells. Consequently, DOX/S-M induced systemical immune responses through activating strong immunogenic cell death (ICD) following X-ray irradiation, exhibiting significant inhibition of both primary and distant tumors. Meanwhile, DOX/S-M showed negligible toxicity to normal tissues. In a word, this work developed an X-ray stimuli prodrug activation strategy for tumor radio-chemo-immunotherapy that utilizes X-ray triggered inflammatory response in tumors for controlled and persistent chemotherapeutic drugs activation, providing valuable guidance for exploring clinical anti-cancer strategy with low toxicity and high therapeutic efficacy.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy approved in the USA for relapsed or refractory multiple myeloma (RRMM) as early as following first relapse, based on pivotal CARTITUDE-1 (≥ 4 prior lines of therapy [LOT]) and CARTITUDE-4 (1-3 prior LOT) trials, which reported high response rates and prolonged survival. In CARTITUDE-1 and CARTITUDE-4, rates of all-grade parkinsonism were 6% and < 1%, respectively, while rates of cranial nerve palsy were 3% and 9%, respectively. This study aimed to characterize new-onset nonimmune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic events (NEs) among patients with RRMM receiving cilta-cel after 1-3 or ≥ 4 prior LOT. METHODS: This retrospective study used two real-world data sources: open and closed insurance claims from the Komodo Research Database (February 2021-November 2024), and electronic medical records from Loopback Analytics (February 2021-December 2024). New-onset non-ICANS NEs, including parkinsonism, cranial nerve palsy, and Guillain-Barré syndrome, were assessed from cilta-cel infusion until the end of clinical activity, death, or end of data availability. Analyses were conducted separately by database and stratified by LOT. RESULTS: In patients with 1-3 prior LOT (Komodo: 124; Loopback: 79), over a median follow-up of 3.4-3.5 months, cranial nerve palsy occurred in 5.6% and 5.1% in Komodo and Loopback, respectively, with no parkinsonism or Guillain-Barré syndrome observed. In patients with ≥ 4 prior LOT (Komodo: 524; Loopback: 191), over a median follow-up of 13.2-13.3 months, parkinsonism occurred in 1.0% in both databases, cranial nerve palsy in 4.6% and 1.0%, and Guillain-Barré syndrome in 0.2% and 0.5% in Komodo and Loopback, respectively. CONCLUSIONS: In this real-world study, rates of non-ICANS NEs post-cilta-cel infusion across two databases were comparable to or lower than prior trials or real-world studies, reinforcing the favorable risk-benefit profile of cilta-cel in routine practice. Graphical Abstract available for this article.

Homozygous loss of the 9p21 locus encompassing CDKN2A, CDKN2B, and MTAP is the most frequent copy number alteration across tumor types, making it a promising target for precision medicine strategies. To explore drug vulnerabilities exposed by this loss, we generated 9p21 locus isogenic bladder cancer (BLCA) cell models to perform a multiparametric drug screen, testing 2,349 compounds. We identified cytarabine and methotrexate as significantly more effective in the 9p21 compromised BLCA cells. Analysis of morphological alterations further supported a genotype-specific activity of nucleoside analogs, nominating gemcitabine as a drug with greater efficacy in this context. To further exploit MTAP loss, we explored drug combinations targeting MTAP synthetic lethal partners, PRMT5 and MAT2A. Synergy between cytarabine and inhibitors of PRMT5 (MRTX1719) and MAT2A (AG-270) was mediated by a differential activation of DNA damage and replication stress markers, suggesting an exploitable vulnerability. In fact, rational drug combinations with ATR/CHK1 pathway inhibitors increased efficacy while maintaining 9p21-specificity. Finally, we confirmed the effectiveness of these combinations in cell models of pancreatic adenocarcinoma and pleural mesothelioma, two tumor types with high prevalence of MTAP loss and, most notably, in bladder cancer patient-derived organoids, underscoring the strong translational potential of our findings.