Abstract BACKGROUND STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone in patients with recurrent anaplastic astrocytoma (AA). We previously reported an overall survival (OS) and progression free survival (PFS) of the combination in the patients with grade 3 IDH-mutant astrocytoma. Here we report updated OS and PFS outcomes based on additional molecular classification and blinded independent central review (BICR). METHOD Eligibility included: age ≥ 18 years, AA (2016 WHO criteria) with first recurrence ≥ 6 months after radiation, KPS ≥ 70, and no imaging findings consistent with grade 4 glioblastoma. Patients received eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) (Arm A) or lomustine alone (110 mg/m2 Q 6 weeks) (Arm B). Primary endpoint was OS. RESULTS Updated molecular data resulted in re-classification of the 343 AA patients enrolled into 3 WHO 2021 defined tumor subtypes, 196 tumors were IDHmut, CDKN2A/B intact, consistent with diagnosis of astrocytoma, IDHmut, WHO grade 3, 33 tumors had CDKN2A/B loss consistent with astrocytoma, IDHmut, WHO grade 4, 106 tumors were IDHwt consistent with diagnosis of glioblastoma, IDHwt, WHO grade 4. Updated results strengthen initial conclusion that eflornithine plus lomustine resulted in significant survival benefit in the astrocytoma, IDHmut, WHO grade 3 group (mOS 34.9 vs, 23.5 months, HR = 0.64, stratified log rank p =0.0136). PFS with eflornithine was also improved (15.8 vs, 7.2 months, HR = 0.57, stratified log rank p =0.0113). BICR demonstrated a high correlation between investigator and centrally determined PFS (p=0.0305), and high correlation between OS and PFS (p=.0001). CONCLUSION The clinically meaningful OS and PFS benefits observed with eflornithine in the molecularly defined 2021 WHO CNS grade 3 astrocytomas is further confirmed and expanded based on additional molecular classification and BICR of PFS.

Abstract Machine learning-based molecular classifications, particularly those using DNA methylation data, have greatly advanced diagnostics for meningioma, the most common type of primary intracranial tumor. Meningiomas have historically been classified into NF2-mutant and NF2-wild-type groups, while additional mutations and copy-number variations associated with progression risk have been incorporated into WHO grading. Several genome-wide methylation-based classification systems have been proposed. The systems, such as the random forest Brain Tumour Classifier, have been incorporated into diagnostic guidelines. However, while a number of core archetypes are shared among the different classifications, discrepancies on the definition and granularity of subtypes remain an obstacle to their clinical application. Understanding the underlying heterogeneity driving these classifications is therefore crucial. Through an integrated analysis of single-nuclei and spatially resolved transcriptomic data, as well as DNA methylation array data from multiple meningioma cohorts, we identified cell types and epigenetic signatures that are associated with increased aggressiveness in meningiomas. The results demonstrated that incremental changes in the tumor microenvironment (TME), particularly shifts in compositions and epigenetic-transcriptomic signatures in tumor-associated monocytes/macrophages and microglia-like cells, have a decisive impact on epigenetic classifications alongside tumor cells, and significantly affect clinical outcome. Therefore, we refine the previously proposed distinct molecular subtypes with a TME-determined risk continuum model for NF2-mutant meningiomas. Based on these discoveries, we additionally designed an immunohistochemistry-based diagnostic approach, which also captures intra-tumoral heterogeneities.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with chemotherapy resistance and tumor heterogeneity posing significant challenges. The Chromobox (CBX) protein family, crucial epigenetic regulators in tumor progression, has not been systematically characterized in LUAD. This study aimed to develop a CBX-based molecular classification system for LUAD and explore the mechanistic role of the CDX2-CBX3 regulatory axis in tumor progression. Through multiomics analysis of TCGA-LUAD data, four distinct CBX subtypes were identified, each associated with variations in survival, clinical stage, DNA repair pathway activation, and immune cell infiltration. Mechanistic investigations (ChIP-qPCR, luciferase assays, and gain/loss-of-function experiments) confirmed that CDX2 directly upregulates CBX3 transcription via conserved promoter binding. CDX2 overexpression enhanced migration, invasion, and xenograft growth, whereas CBX3 knockdown suppressed these phenotypic changes. In conclusion, this study defines clinically relevant CBX molecular subtypes in LUAD and reveals the CDX2-CBX3 transcriptional cascade as a novel driver of tumor progression, offering potential targets for precision therapy.

Adolescent and young adult (AYA) patients remain underrepresented in neuro-oncology research. Despite being the second most common primary brain tumor in this population, meningiomas have not been studied using age-specific molecular analyses. DNA methylation-based classification and prognostic tools have transformed meningioma care. This study aimed to evaluate the performance of these tools across age groups. We analyzed 1,568 meningiomas with DNA methylation and clinical data, including 18 pediatric patients (<15 years), 195 AYA patients (15-39 years), and 1,355 adult patients (>39 years). Pediatric and AYA (P/AYA) tumors were combined and compared with adult tumors. The performance of established molecular classifiers and recurrence predictors, as well as differences in chromosomal copy number alterations were compared across age groups. While histologic grading was comparable between cohorts, P/AYA tumors displayed significantly fewer aggressive molecular groups and lower frequencies of chromosomal arm losses, including 1p, 6q, and 14q. The adult-trained recurrence predictor failed in the P/AYA population (AUC 0.57), despite similar score distributions. Retraining the model on an age-specific cohort using an identical analytic framework improved performance (AUC 0.79) and enabled effective stratification of progression-free survival (p = 0.00054). Importantly, 1p loss retained prognostic significance within the P/AYA group, supporting its clinical utility. Molecular tools developed in adult-dominant cohorts do not generalize to younger patients due to both biological divergence and exclusion from model development. These findings underscore the need for age-specific molecular frameworks and highlight the imperative of including P/AYA populations in precision neuro-oncology research to ensure lifespan-equitable care.

Endometrial cancer is the sixth most common cancer in women worldwide and the fourth most common cancer in women in the United States. In the United States, its incidence and mortality rates have continued to increase since the late 1990s. Endometrial cancer comprises most uterine corpus carcinomas and represents a heterogeneous group of cancers varying in pathology, histology, molecular biology, immunogenicity, and prognosis. Recently, the advancement of molecular classification and subsequent clinical trials have led to new FDA approvals for the use of immune checkpoint inhibitors in endometrial cancer. However, recurrent and advanced-stage endometrial cancer continues to demonstrate high morbidity and mortality, denoting an unmet need for innovative immunotherapeutic strategies. This review explores current concepts in the endometrial cancer tumor immune microenvironment, comparing antigenicity, immunosurveillance, and immunoregulation among molecular and histologic subtypes and providing insight into which subtypes may be particularly responsive to immunotherapy. Novel immunotherapeutic strategies targeting cancer antigens, emerging immune checkpoints, immunomodulatory cytokines, and tumor-infiltrating immune cells are described, and corresponding clinical trials are presented. Integrated approaches such as immunogenic modulation, which enhances tumor susceptibility to immune attack, and immune subset conditioning, which modifies suppressive immune components within the tumor immune microenvironment, are presented as promising avenues to render "cold" tumors responsive. Together, the immunotherapies reviewed here offer potential strategies for treating patients with advanced or refractory endometrial cancer.

Endometrial carcinoma (EC) molecular subtypes are critical for risk assessment and treatment guidance, with strong prognostic implications. To investigate associations between EC molecular subtypes and high-risk pathological factors to optimize individualized therapy. Multicenter retrospective cohort study. Retrospective analysis of 292 EC cases classified via the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) into four subtypes: POLE ultramutant (POLE-mut), mismatch repair deficient (MMRd), p53 abnormal (p53 abn), and p53 wild-type (p53 wt). Associations with clinicopathological parameters were assessed using chi-square tests and logistic regression. Among the 292 patients, the distribution of molecular subtypes was as follows: POLE-mut (6.8%), MMRd (21.2%), p53 abn (14.4%), and p53 wt (57.5%). Molecular subtypes correlated significantly with International Federation of Gynecology and Obstetrics (FIGO) stage (p < 0.001), poor/undifferentiated histology (p < 0.001), and lymphovascular space invasion (LVSI) (p = 0.001). The POLE-mut and p53 wt were predominantly enriched in stage I disease (90.0% and 80.4%, respectively). In contrast, the majority of p53 abn were classified as stage II (81.0%). The MMRd subtype was distributed across all stages. Advanced stages (III-IV) were most frequently observed in the p53 abn and MMRd subtypes. p53 abn showed the highest rate of poor/undifferentiated histology (61.9%). MMRd comprised the largest proportion of LVSI-positive cases (39.1%). Multivariate analysis identified MMRd as an independent predictor of LVSI (p = 0.001), while both MMRd (p = 0.009) and p53 abn (p < 0.001) independently predicted poor/undifferentiated histology. EC molecular subtypes stratify clinicopathological risk and predict tumor behavior, highlighting their potential utility in informing individualized management. These findings suggest possible roles ranging from treatment de-escalation (POLE‑mut) to treatment intensification (p53‑abn), although further prospective studies are needed before routine clinical implementation.

High-grade gliomas (HGGs), including glioblastoma and diffuse midline glioma, highlight one of the most aggressive brain tumors in adults and children with dismal prognosis despite intensive treatment regimens. Recently, epigenetic dysregulation has emerged as a fundamental hallmark of HGG biology, and the epigenetic alterations contribute not only to the molecular classification of HGGs but also to their malignant functional biology. Another notable feature of epigenetic dysregulation in HGGs is its influence on intratumoral heterogeneity, via possible modification of the neuron-glioma network in the brain. In this review, we aim to compile recent advances in our understanding of epigenetic dysregulation in HGGs, focusing on key mechanisms such as DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs. Furthermore, we will update our knowledge on the unexpected biology of glioma interaction with neuronal components from a standpoint of epigenetic heterogeneity. By discussing the epigenetic landscape of HGGs, we aim to provide a framework for future research and therapeutic innovation in the management of these devastating tumors.

Bladder cancer is a prevalent and costly malignancy characterized by significant heterogeneity in presentation and clinical outcomes. This study aimed to classify the molecular subtypes of bladder cancer using immunohistochemistry (IHC) and to evaluate the prognosis, treatment responsiveness, and clinical utility of IHC-based subtype classification. We retrospectively reviewed the data of 84 patients with bladder cancer who underwent radical cystectomy. Immunohistochemistry was performed using the markers CK5/6, CK14, CK20, GATA3, and UPK2. Molecular subtypes were identified through hierarchical clustering, and statistical analyses were conducted to evaluate cancer-specific survival (CSS) and recurrence-free survival (RFS). Among the 68 patients included in the final analysis, 52 were classified as luminal type and 16 as basal type. The 5-year CSS and RFS were 76.2% and 64.2%, respectively. Among patients who received platinum-based neoadjuvant chemotherapy, those with the luminal subtype showed significantly better RFS than those with the basal subtype (P=0.016, HR 5.27, 95%CI 1.15-24.1). However, no significant difference in CSS was observed between the luminal and basal subtypes. Molecular subtypes can be inferred using common immunohistochemical markers, providing a practical approach for personalized treatment strategies. Further prospective studies are needed to validate these findings.

Radiotherapy remains crucial to the management of gynecologic cancers. This review highlights recent advances in radiation delivery, integration with systemic therapies, and the evolving role of radiotherapy across definitive, adjuvant, recurrent, and palliative settings. Trials in cervical cancer have established survival gains with novel systemic combinations, while adaptive and standardized radiation protocols continue to improve precision and outcomes. In endometrial cancer, molecular classification is informing adjuvant therapy selection and driving subtype-specific clinical trials. Expanding use of stereotactic body radiotherapy and proton therapy in ovarian and recurrent disease demonstrates feasibility and durable control. Efforts in reirradiation, palliative care, and survivorship underscore the need for safe dose escalation, symptom management, and long-term quality of life research. Persistent disparities and rising costs emphasize the importance of value-based and equitable care delivery. Emerging imaging and adaptive techniques are making radiation for gynecologic cancers more precise and individualized. Advances in brachytherapy, stereotactic approaches, and proton therapy are refining delivery, while integration with systemic and molecularly guided strategies is broadening therapeutic impact. Ongoing priorities include reducing disparities, improving survivorship, and translating technological progress into accessible, patient-centered care.

MSK-impact heme accurately reproduces diffuse large B-cell (DLBCL) dlbclass cluster classification across clinical scenarios, including diagnosis, relapse, and histological transformation

Deciphering clonal progression in MDS via longitudinal sequencing

Circulating CD161high CD8 T cells at leukapheresis are associated with reduced risk of progression at 12 months (PFS12) in large B-cell lymphoma treated by axicabtagene ciloleucel: Results from the Phase 2 alycante study (LYSA)

The classification of endometrial cancer (EC) has diverged from traditional histologic features based on microscopic appearance to objective molecular characterization. Molecular characterization of EC is pivotal to inform prognosis and to guide therapeutic recommendations. First described by the Cancer Genome Atlas, molecular profiling was later revised by the Proactive Molecular Risk Classifier for Endometrial Cancer and TransPORTEC algorithms to create clinically applicable and relatively easy-to-implement molecular classification systems. Since 2020, the World Health Organization recommended molecular classification of EC into four distinct prognostic subtypes: ECs with polymerase ε (POLE) pathogenic mutations assessed by gene sequencing, mismatch repair deficiency determined by immunohistochemistry or microsatellite instability assay, and p53 abnormalities determined by immunohistochemistry or next-generation sequencing. The final molecular subtype without any of these defining features is called "no specific molecular profile" (NSMP). This is further stratified by estrogen receptor (ER) immunohistochemistry status. Patients with cancers identified as POLE pathogenic mutations have the best prognosis with almost no recurrence or death events, followed by those with strong ER-positive NSMP cancers. Mismatch repair deficiency ECs have intermediate prognosis, whereas p53 abnormalities and ER-negative NSMP have the worst prognosis. Other molecular and pathologic biomarkers of interest include tumor mutational burden, human epidermal growth factor receptor 2, L1 cell adhesion molecule, β-catenin ( CTNNB1 ), and lymph vascular space invasion, which may have prognostic and predictive implications. The current guidelines will continue to evolve; however, at minimum, it is recommended that all patients undergo testing for mismatch repair, p53, and ER, and POLE testing may be prioritized in select circumstances. Molecular classification provides the critical framework to deliver effective, personalized, high-quality care and informs clinical trial design. Molecular assessment ensures consistent diagnosis and provides prognostic information and predictive data to guide appropriate management.

Molecular classification of nonurothelial histologic subtypes of bladder cancer.

Prognostic value of positive peritoneal cytology in FIGO 2009 stage IA grade 1 endometrioid endometrial cancer.

Prevalence of Atypical and Subclonal p53 Immunohistochemistry Expression in Mismatch Repair Deficient and/or POLE-Mutant Endometrial Carcinomas with TP53 Mutation.

Immature granulocytes as novel blood-based biomarkers forbrain tumours: Aprospective case-control study.

Small nucleic acid therapeutics: delivery breakthroughs, clinical translation, and future paradigms in precision medicine.

Beyond the number-Age as a prognostic indicator in endometrial cancer.

A public data-based molecular classification of small cell lung cancer by neuroactive signaling networks unveils distinct microenvironment landscapes and immunotherapy-related prognostic biomarkers