The World Health Organization introduced substantial revisions in the 2020 fifth edition of the classification system for bone and soft-tissue tumors, reorganizing what were previously called the Ewing sarcoma family of tumors or Ewing-like sarcomas into a new category of "undifferentiated small round cell sarcomas" based on molecular genetic characteristics. This reclassification established four distinct entities: Ewing sarcoma (ES), CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and sarcoma with EWSR1-non-ETS fusion genes. Each subtype may demonstrate specific clinical, pathologic, and imaging features, with different treatment responses and prognoses. ES primarily affects children and young adults, with characteristic "moth-eaten" lytic bone destruction, aggressive periosteal reactions, and extensive surrounding soft-tissue masses. CIC-rearranged sarcomas typically manifest as well-circumscribed lobulated soft-tissue masses with extensive internal necrosis and hemorrhage but no calcification. Sarcomas with BCOR genetic alterations commonly occur in adolescent boys as osteolytic or sclerotic lesions in the long bones or the pelvis, often with calcification in the extraosseous component. Sarcomas with EWSR1-non-ETS fusion genes may manifest as osteolytic lesions with cortical expansion and saucer-like surface erosion in long bone diaphyses. Radiologic recognition of CIC-rearranged sarcomas enables oncologists to anticipate their aggressive nature and poor response to standard ES treatments, which may necessitate more intensive initial surgical interventions. In comparison, identifying BCOR-CCNB3 sarcomas through imaging allows clinicians to inform patients of their potentially more favorable outcomes compared with those of ES while still applying appropriate comprehensive treatment approaches. The authors provide an overview of the clinical features, pathologic findings, imaging characteristics, differential diagnosis, and treatment outcomes of each entity. ©RSNA, 2026.

Neocentromeres are newly formed chromosomal regions that can replace the function of traditional centromeres and are well documented in human clinical studies. However, their occurrence in neoplasia, including acute leukemia, appears to be rare. We analyzed complex karyotypes in bone marrow cells from 113 patients with acute myeloid leukemia and one patient with acute lymphoblastic leukemia using centromeric/multicentromeric fluorescence in situ hybridization and identified four cases (3.5%) with derivative chromosomes exhibiting newly formed constrictions. Three of these patients had secondary leukemia following preexisting hematological disorders, suggesting a potential role for neocentromeres in disease progression. In all four cases, neocentromeres were detected on derivative chromosome 11. To our knowledge, this is the first report of neocentromeres derived from this chromosome in acute leukemia. All four patients in our study died; however, all exhibited complex karyotypes, which are independently associated with poor prognosis and an aggressive disease course. Neocentromeres are a rare but potentially important source of genomic instability in malignant diseases. Generally, the formation of a new constriction allows mitotic rescue of acentric chromosomes, preventing their loss. An increase in genomic alterations in tumor cells predicts a more aggressive disease course and adverse outcomes. Due to limited data, the prognostic significance of neocentromeres remains unclear. Further rigorous investigation is required to deepen our understanding of the mechanisms underlying neocentromere formation and their implications in cancer.

Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment.

The extracellular matrix (ECM) is a highly organised and dynamic regulator of tissue structural integrity and biochemical signalling, and its dysregulation is a hallmark of fibrosis and cancer. Recent evidence highlights the critical role of epigenetic mechanisms in controlling ECM-related gene expression and remodelling activity. This review integrates recent advances in understanding how epigenetic mechanisms govern ECM composition, remodelling, and mechanotransduction, and how reciprocal ECM-derived signals reshape the epigenetic landscape. Growing evidence links DNA methylation, histone modifications, and non-coding RNAs to the regulation of key ECM components, matrix-modifying enzymes, and stiffness-associated signalling pathways, including TGF-β, Wnt, and PI3K/Akt are summarised in this review. The bidirectional feedback between altered ECM mechanics and epigenetic enzyme activity is emphasised, showing how matrix stiffening and aberrant epigenetic programming cooperatively drive pathological tissue remodelling and tumour progression. This review summarises findings from in vitro systems, animal models, and human disease studies that illustrate the functional consequences of ECM-epigenetic crosstalk. The emerging therapeutic approaches targeting the ECM-epigenetic axis, including epigenetic modulators and ECM-directed interventions, outline current challenges and future directions for restoring matrix homeostasis in disease. Together, this review provides an integrated framework for understanding the bidirectional ECM-epigenetic interactions and their translational relevance in molecular biomedicine.

Leptomeningeal disease (LMD) is a devastating complication of advanced solid tumors with limited prognostic and response-assessment tools. Because LMD molecular evolution is frequently compartmentalized behind CNS barriers, cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) may provide CNS-specific molecular readouts of disease activity. We evaluated whether baseline CSF ctDNA profiles and longitudinal ctDNA kinetics associate with survival in LMD.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen and progesterone receptors and HER2 amplification. Representing 10-15% of breast cancer cases, TNBC disproportionately affects Black and pre-menopausal women and is associated with poorer outcomes. With chemotherapy as the primary systemic treatment option, achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is a key prognostic factor. However, TNBC biological heterogeneity complicates treatment response prediction. This study aimed to identify transcriptomic biomarkers predictive of NAC response in TNBC patients and evaluate machine-learning models for response classification.

Anti-PD-1 treatment has shown clinical benefit in malignant cancers. However, EGFR-mutant (EGFR-MT) lung adenocarcinoma, an immune-cold tumor, shows poor response to this immunotherapy. This scenario is associated with elevated levels of B7-H4, an immune checkpoint demonstrating CD8+ T cell inhibition activity. Our previous study has revealed that deubiquitinase USP2a could stabilize B7-H4 protein. Therefore, we further explore whether USP2a inhibition could remodel immune-cold microenvironment in this study. First, we confirmed that USP2a inhibitors effectively promoted proteasomal degradation of B7-H4 through blocking its deubiquitination process. To rule out the possiblity that USP2a might directly inhibit EGFR MT endocytosis so as to inhibit B7-H4 expression,we investigated the effect of USP2a inhibitor ML364 on EGFR mutants protein levels. It showed that ML364 did not inhibit EGFR mutant protein levels. ML364 could directly inhibit tumor cell proliferation in vitro. In immune-deficient nude mice ML364 inhibited tumor growth through inhibiting USP2a substrates Cyclin D1 and MDM2. In immune-competent C57BL/6 mouse model, ML364 could downregulate B7-H4 level thereby repress tumor growth through remodeling immune-cold microenvironment. Finally, we proved that ML364 could sensitize tumor to anti-PD-1 therapy in immune-competent mice. Immunohistochemical staining analysis showed that ML364 could inhibit B7-H4 expression, thereby enhanced Qa-1b (homolog of HLA-E in mouse) expression and CD8+ T cell infiltration. This study proved that inhibition USP2a could suppress tumor growth through two mechanisms: directly inhibiting tumor cell proliferation and remodel immune-cold microenvironment. Therefore, inhibiting USP2a could sensitize tumor to anti-PD-1 therapy.

Gliomas are primary brain tumors that develop from glial cells within the central nervous system and are among the deadliest human cancers. Glioblastoma (GBM) is the most malignant form of glioma. NLRX1 is an innate immune pattern recognition receptor that exhibits tumor-suppressive or tumor-promoting effects that may be cancer type- and context-dependent, aided by differences in the microenvironment. Here, we report that NLRX1 is differentially expressed in microglia, astrocytes, GBM cell lines, and glioma patient tissues. siRNA-mediated silencing of NLRX1 induces metabolic stress in GBM cells, as observed by an increased number of tunneling nanotubes (TNTs) formation between GBM cells and decreased expression of autophagy markers. Moreover, silencing of NLRX1 decreases the ability of the GBM cell lines, LN-229 and LN-18, to proliferate and migrate. si-NLRX1 GBM cells exhibit attenuated ability to generate 3D spheroids. In summary, our findings indicate that NLRX1 positively regulates GBM pathophysiology by supporting GBM cell metabolism, proliferation, migration, and anchorage-independent growth. We believe our understanding of NLRX1 in GBM pathophysiology paves the way for potential development of GBM-targeting therapeutics that may delay disease progression and/or improve survival.

Genetic testing for gene variants associated with hereditary cancers can help with cancer prevention, early detection, and treatment. However, testing has not been well integrated into primary care settings where its preventative impact can be realized. To explore patient-level barriers and facilitators throughout the genetic testing process in primary care settings, we conducted a thematic analysis of semi-structured interviews with 31 patients within the Early Detection of Genetic Risk (EDGE) study who had not completed the risk assessment (n = 2), had completed the risk assessment but were ineligible (n = 8), had declined testing (n = 10), and had completed testing (n = 11). Interviewees were broadly interested in genetic testing. Those who did not complete the risk assessment cited limited access to technology, exacerbated by health and financial struggles. Several interviewees who completed the risk assessment but were deemed ineligible for testing indicated that their lack of knowledge about biological relatives prevented complete responses to the risk assessment. Those who opted out of testing cited concerns over privacy, insurance discrimination, and potential psychological burden. Notably, the majority who declined testing were unsure if they would refuse again in the future, and three went on to request genetic testing after being invited to complete an interview. Those who changed their minds about testing stated changes in life circumstances (such as obtaining life insurance) that facilitated openness to testing. Patients who completed testing shared similar concerns to those who declined but were motivated by their familial cancer history and believed genetic testing could lead to preventative options. A key finding of this study was that patient readiness for testing changed over relatively brief follow-up times. These results highlight the need for practicable approaches to re-offering genetic testing to individuals over time.

Malignant and non-malignant cells within the tumor microenvironment (TME) actively secrete extracellular vesicles (EVs) that may mediate intercellular communication or enter the blood stream. Circulating EVs in Diffuse Large B-Cell Lymphoma (DLBCL) patients are a promising source of liquid biopsy biomarkers; however, whether different cellular components of the TME preferentially secrete small (S-) and/or large (L-) EVs is still unknown. With an established density-gradient separation protocol and tunable resistive pulse sensing analysis, we demonstrate that DLBCL cells in culture produce 100-1000-fold higher numbers of S-EVs (50-200 nm) compared with L-EVs (200-1000 nm) and very large EVs (>1000 nm). In contrast, the plasma from DLBCL patients contains comparable concentrations of S- and L-EVs, consistent with various cellular origins. Small RNA sequencing showed minor differences in miRNA content between plasma S- and L-EVs; however, messenger RNA sequencing revealed stark differences in cargo between EV-size subtypes and between healthy donors and patients. Deconvolution analysis with single-cell sequencing data from 17 DLBCL tumor tissues as reference using the Statescope algorithm indicated that circulating S-EVs from malignant cells outnumber the L-EVs. In contrast, TME macrophage-, T cell-, and natural killer-derived L-EVs outnumber S-EVs. Together, these findings suggest that circulating S- and L-EVs can originate from distinct cellular compartments within the DLBCL TME, representing complementary biological information. These observations have important implications for the development of EV-based liquid biopsy strategies.

Acute lymphoblastic leukemia (ALL) mainly affects children, though it also occurs in adults. About 25% of adults with ALL have the more aggressive Philadelphia chromosome-positive (Ph+) subtype. Standard treatment includes tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or corticosteroids, which have greatly enhanced survival rates over the past 2 decades. Ponatinib, a third-generation TKI demonstrated greater efficacy compared with imatinib, a first-generation TKI, in the PhALLCON trial.

BackgroundLung cancer remains one of the leading causes of cancer-related mortality worldwide. Holocytochrome c synthase (HCCS), a mitochondrial enzyme involved in apoptosis and energy metabolism, has been implicated in tumorigenesis; however, its role in lung cancer is not well defined.AimThis study aimed to elucidate the prognostic and therapeutic potential of HCCS in lung cancer through integrative bioinformatics analyses.MethodsTranscriptomic, methylation, and clinical data from TCGA were analyzed using TNMplot, UALCAN, and TIMER2.0 to evaluate HCCS expression, promoter methylation, immune infiltration, and prognostic relevance in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Meta-analysis of 18 independent cohorts from LUNG CANCER EXPLORER and four GEO datasets validated expression patterns, while Kaplan-Meier analysis assessed survival outcomes.ResultsHCCS was significantly upregulated in LUAD and LUSC and showed promoter hypermethylation in LUAD. Meta-analysis and external validation confirmed its overexpression. Patients with low HCCS expression exhibited poorer overall survival, suggesting a potential tumor-suppressive effect. HCCS expression positively correlated with immune cell infiltration and co-expressed genes enriched in mitochondrial and apoptotic pathways.ConclusionHCCS may serve as a prognostic and therapeutic biomarker in lung cancer, linking mitochondrial regulation, epigenetic modification, and immune interactions.

ObjectiveTo evaluate the efficacy and safety of radiotherapy plus immune checkpoint inhibitors versus radiotherapy plus chemotherapy in driver gene-negative patients with non-small cell lung cancer and brain metastases.MethodsThis single-center retrospective cohort study (Strengthening the Reporting of Observational Studies in Epidemiology-compliant) enrolled 60 consecutive driver gene-negative patients with non-small cell lung cancer and brain metastases (29 radiotherapy plus immune checkpoint inhibitors, 31 radiotherapy plus chemotherapy) treated between June 2018 and December 2023, with follow-up until July 2025. Survival, tumor response, and immune-related adverse events were analyzed using Kaplan-Meier methods, Cox models, and chi-square tests. The study was approved by the Institutional Review Board and used deidentified data.ResultsRadiotherapy plus immune checkpoint inhibitors significantly prolonged median overall survival (586 vs. 509 days, p = 0.0208) and progression-free survival (494 vs. 383 days, p = 0.0127) as well as improved objective response rate (34.48% vs. 19.35%, p = 0.0394) and disease control rate (75.86% vs. 51.61%, p = 0.0265) compared with radiotherapy plus chemotherapy. Favorable prognostic factors included age <60 years, Eastern Cooperative Oncology Group Performance Status <2, programmed death-ligand 1 tumor proportion score ≥50%, and absence of extracranial metastasis. Radiotherapy plus immune checkpoint inhibitors-related immune-related adverse events (24.14%) were mostly grades 1-2, with no grade ≥4 events.ConclusionsRadiotherapy plus immune checkpoint inhibitors may confer survival benefits and favorable safety in driver gene-negative patients with non-small cell lung cancer and brain metastases. However, caution is warranted in interpreting these findings, which require validation in large-scale prospective studies.

Asialoglycoprotein receptor 1 regulates the inflammatory response in granulosa cells associated with polycystic ovary syndrome. In the granulosa cells of individuals with polycystic ovary syndrome, elevated levels of asialoglycoprotein receptor 1 may activate the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which in turn enhances the expression of prostaglandin-endoperoxide synthase 2. Abstract This study evaluated whether asialoglycoprotein receptor 1 (ASGR1) can regulate the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) in granulosa cells (GCs) in polycystic ovary syndrome (PCOS). The expression levels of ASGR1 in GCs and PCOS mice ovaries were assessed; to determine the in vivo role of ASGR1, it was overexpressed in the ovaries of female mice via adeno-associated virus injection, and RNA-sequencing analysis revealed that ASGR1 upregulated prostaglandin-endoperoxide synthase 2 (PTGS2). Western blot confirmed the levels of activated ERK1/2 after ASGR1 overexpression, and ERK1/2 agonists and inhibitors were used to validate the downstream effects on PTGS2. Results showed that the expression level of ASGR1 in GCs and ovaries of women and mice with PCOS was significantly elevated. In vitro cell culture results demonstrated that ASGR1 significantly upregulated the ERK1/2 pathway and increased PTGS2 expression in KGN cells. Moreover, through the use of agonists, small interfering RNA, inhibitors, and overexpression strategies, it was identified that the ERK1/2 signaling pathway mediates the ASGR1-induced elevated expression of PTGS2. It was concluded that the agonist effect of ASGR1 on PTGS2 in GCs in PCOS is mediated by the ERK1/2 pathway, and these findings provide new insights into the pathogenesis of PCOS-associated inflammation.

The Protein Phosphatase Methylesterase 1 (PPME1) is a methylesterase specific to phosphatase 2A, a tumor suppressor, and plays a key role in tumor development. Its impact on pan-cancer diagnosis, prognosis, and immune regulation is still uncertain.

Pancreatic ductal adenocarcinoma (PDAC) continues to pose a significant clinical challenge due to its high mortality rate and limited treatment efficacy. The role of disulfidptosis, a recently discovered mode of regulatory cell death, in pancreatic cancer progression and tumor immunity remains poorly understood.

Originally reported as an oncogene and currently known to be a major "genome guardian", the p53 protein remains one of the most explored transcription factors, exhibiting variety of functions both within transcription regulation and beyond. Given that p53 dysfunction contributes to the majority of human cancers, understanding its regulatory mechanisms and therapeutic potential remains a primary research focus. This review addresses the key aspects of p53 regulation and functionality, analyses its role in tumor evolution, and provides a comprehensive analysis of current and emerging therapeutic strategies targeting the p53, with particular emphasis on immunotherapy approaches.

Breast cancer is one of the leading causes of mortality worldwide. The tumor microenvironment plays a critical role in cancer progression. This microenvironment is composed of various cells embedded in the extracellular matrix (ECM). Laminin-111, a major ECM glycoprotein, produces bioactive peptides that influence tumor biology. We have shown that the laminin-derived peptide C16 (KAFDITYVRLKF), located in the short arm of the γ1 chain, regulates migration, invasion, and invadopodia formation in different cancer cells. Our findings suggest that the regulatory mechanisms underlying the effects of C16 are associated with β1 integrin. This prompted us to investigate the interaction between the C16 peptide and β1 integrin in breast cancer cells. We found that breast cancer cells bind to C16 peptide, and this attachment is inhibited by β1 integrin depletion via siRNA. Cellular localization of the C16 peptide was analyzed using transmission electron microscopy (TEM) and time-lapse fluorescence microscopy. TEM revealed that nanogold-conjugated C16 decorated the cell membrane and was localized in intracellular vesicles, indicating peptide endocytosis. Time-lapse confocal microscopy showed that C16 was internalized by breast cancer cells within 2 h of incubation, with this process increasing over time. Based on these observations, we hypothesized that the peptide is endocytosed and directed to the endosome-lysosome pathway for degradation. Time-lapse imaging demonstrated that part of the internalized peptide colocalized with lysosomes in breast cancer cells. This suggests that C16 may be involved in integrin recycling. Furthermore, rhodamine-labeled C16 colocalized with activated β1 integrins. Flow cytometry analysis showed that C16 increased β1 integrin activation starting at 1 h of treatment. In summary, our results suggest that after interacting with the cell membrane and activating β1 integrins, breast cancer cells internalize peptide C16, which plays a role in β1 integrin turnover.

Mycotoxins are toxic secondary metabolites produced predominantly by fungal genera, such as Aspergillus, Fusarium, and Penicillium, and represent major foodborne contaminants responsible for chronic human exposure worldwide. While aflatoxin B1 (AFB1) is a well-established hepatocarcinogen, increasing evidence indicates that multiple mycotoxins contribute to tumorigenesis across diverse organ systems through shared biochemical and molecular mechanisms. At the molecular level, mycotoxins undergo cytochrome P450-mediated bioactivation, generating reactive intermediates that induce DNA adduct formation, oxidative stress, genomic instability, and disruption of redox homeostasis. These events converge on dysregulation of key signaling pathways governing cell-cycle control, apoptosis, immune surveillance, and epigenetic regulation, including aberrant DNA methylation, histone modification, and non-coding RNA expression. Importantly, emerging data support a "dual-hit" paradigm in which mycotoxin exposure synergizes with oncogenic viral infections, such as hepatitis B virus (HBV), human papillomavirus (HPV), and Epstein-Barr virus (EBV), amplifying genotoxic stress, immune evasion, and epigenetic instability. This review synthesizes current mechanistic insights into mycotoxin-induced carcinogenesis, emphasizing molecular toxicological endpoints that link exposure to cancer risk. In addition, advances in biosensing, detoxification, and preventive strategies are discussed, highlighting the need for mechanism-driven interventions to mitigate mycotoxin-associated carcinogenicity and its public health burden.

M2-like macrophages and CD8+T cells are key immune components that influence tumor behavior and treatment response. Ubiquitin-specific protease 32 (USP32) is established as a key oncogenic factor in gastric cancer (GC). This study aimed to investigate the role of USP32 in regulating M2 macrophage polarization and CD8+T cell dysfunction in GC. Macrophages derived from THP1 cells (THP1-M0) or CD8+T cells were co-cultured with transfected AGS and HGC-27 GC cells. The proportion of CD206+ M2 macrophages and the apoptosis of CD8+T cells were assessed by flow cytometry. Cell invasion was analyzed by transwell assay. The interaction between USP32 and death-associated protein kinase 1 (DAPK1) was verified by GST pull down and Co-immunoprecipitation (Co-IP) experiments. The effect on tumor growth was tested by subcutaneous xenograft studies. USP32 and DAPK1 were overexpressed in GC tissues and cell lines. Mechanistically, USP32 stabilized DAPK1 protein through deubiquitination. DAPK1 downregulation reversed USP32-mediated enhancement in GC cell invasion, macrophage M2 polarization, and CD8+T cell apoptosis in vitro. USP32 depletion exhibited an in vivo anti-growth effect on AGS subcutaneous xenografts. This study identifies the USP32/DAPK1 cascade as a crucial regulator of M2 macrophage polarization and CD8+T cell apoptosis in GC, providing a novel mechanistic link between post-translational regulation and tumor immune evasion.