An 18-year-old Hispanic male with an unremarkable medical history presented with a 1-month history of progressive, intermittent headaches, nausea, and diplopia. Upon seeking care, a head CT revealed a solid right frontal lesion and a large, complex cystic parieto-occipital lesion exerting significant mass effect on surrounding structures. The patient initially underwent a left parietal craniotomy for tumor resection, followed by resolution of his neurological symptoms. However, surveillance imaging 1 month later identified a known left atrial cardiac mass and new intracranial embolic infarcts, alongside a 6-cm recurrence at the primary resection site. The patient subsequently underwent a sternotomy for resection of the primary cardiac sarcoma and reconstruction of the left atrium. Shortly after, a second craniotomy was required for resection due to rapid cystic recurrence of the brain metastasis causing midline shift and new focal neurological deficits. Following successful gross-total re-resection, the patient underwent hypofractionated Gamma Knife radiosurgery. He is also undergoing chemotherapy. Six-week follow-up imaging confirmed a positive response to treatments, showing no new metastatic growth and a reduction in the size of existing lesions. This case highlights the aggressive nature of primary cardiac sarcoma and the necessity of multimodal, repeat surgical intervention for CNS involvement.

Glioblastomas remain the most lethal primary brain tumour in adults, with targeted therapies delivering only limited benefit despite deep molecular characterization. Several targeted drugs have received regulatory approval for low-grade gliomas, although progress in glioblastomas remains constrained by, among other aspects, extensive intratumoural heterogeneity, pathway redundancy, cellular plasticity and limited drug delivery to the central nervous system. Some of these challenges might be mitigated through strategies that enhance blood-brain penetration, including focused ultrasonography, convection-enhanced delivery, efflux avoidance and chemical modifications. Improved tumour profiling through multiregional sampling, prioritization of truncal dependencies and the development of novel therapeutic modalities, such as antibody-drug conjugates and theranostics, might also further improve outcomes. In this Review, we summarize the therapeutic landscape of targeted therapies in glioblastomas, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities. We also examine emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry. Furthermore, we highlight tumour heterogeneity and extrachromosomal DNA dynamics as key drivers of oncogene amplification and therapeutic resistance as well as the roles of novel clinical trial designs and liquid biopsy-based monitoring strategies. Lastly, we discuss pathway-based glioblastoma classification and master kinase mapping as methods for aligning drugs with functional tumour states.

Primary adrenal high-grade undifferentiated pleomorphic sarcoma (UPS) is an exceptionally rare malignant mesenchymal neoplasm, and presentation with brain metastasis as the initial manifestation is even more uncommon. This report highlights the diagnostic evaluation and multidisciplinary management of a patient presenting with an undifferentiated brain metastasis accompanied by an adrenal mass. A 75-year-old woman presented with speech disturbance, cognitive slowing, memory decline, gait instability, and right-sided weakness. Brain computed tomography and contrast-enhanced magnetic resonance imaging revealed a left frontal lesion with multiple intracerebral nodules. Positron emission tomography/computed tomography further demonstrated a left adrenal lesion and additional metastatic foci. Owing to symptomatic mass effect, the brain lesion was surgically resected. Initial pathology suggested a poorly differentiated malignant tumor, and the tumor origin remained uncertain after the first immunohistochemical assessment. Subsequent multidisciplinary review, serial adrenal imaging, adrenal core needle biopsy, and comparative pathologic evaluation progressively redirected the diagnosis toward a high-grade undifferentiated sarcoma, morphologically consistent with UPS. The patient subsequently received postoperative brain radiotherapy, anthracycline-based chemotherapy, additional systemic therapy, and local treatment for progressive metastatic disease. Despite multimodal management, the tumor rapidly progressed with thigh metastasis, bilateral adrenal involvement, skeletal dissemination, and bilateral pathologic femoral fractures. The patient ultimately died of intracerebral hemorrhage. This case expands the clinical spectrum of primary adrenal UPS and underscores the importance of dynamic diagnostic reassessment, multisite tissue sampling, extended immunohistochemical evaluation, and multidisciplinary collaboration when evaluating undifferentiated brain metastases associated with an adrenal mass.

Preoperative risk stratification in neurosurgery typically uses body mass index (BMI), albumin, or frailty as single-marker predictors. We assessed whether a composite phenotype predicts outcomes after cranial neuro-oncologic surgery and whether effects differ by tumor histology. A retrospective analysis of 27,057 patients undergoing craniotomy for meningioma, malignant glioma, or brain metastasis was performed using the American College of Surgeons National Surgical Quality Improvement Program database (2016-2023). The composite phenotype incorporated BMI and serum albumin: adequately nourished, obese-replete, sarcopenic-obese, and cachectic-malnourished. Outcomes included major 30-day morbidity, 30-day mortality, failure to rescue (FTR), and non-home discharge. Associations were estimated using inverse probability of treatment weighting (IPTW), histology-stratified analyses, and interaction testing. Compared with adequately nourished patients, sarcopenic-obese and cachectic-malnourished phenotypes conferred elevated odds of major 30-day morbidity (IPTW odds ratio [OR] 1.47 and 1.60, respectively) and 30-day mortality (OR 2.28 and 1.96). Obese-replete showed no mortality increase (OR 1.06) and reduced FTR (OR 0.76), most pronounced in the metastasis cohort (OR 0.58). Phenotype effects differed by histology for mortality (interaction p = 0.044) and non-home discharge (p = 0.009), with sarcopenic obesity conferring a 3.61-fold mortality increase among meningioma patients. The composite phenotype achieved discrimination comparable to but not exceeding serum albumin alone (area under the curve [AUC] 0.75 vs. 0.76 for mortality). A biomarker-defined nutritional phenotype separated distinct high-risk subgroups but did not improve discrimination beyond serum albumin alone, with histology-specific effects. These findings support histology-aware nutritional phenotyping for preoperative risk communication and hypothesis generation rather than superior prediction.

Membrane-associated proteins, including those embedded in exosomal membranes or bound to plasma lipids, are promising disease biomarkers. However, their hydrophobic nature limits detection through conventional proteomic workflows, which primarily capture soluble proteins. In this study, we developed and optimized a lipase-based pretreatment strategy to improve the detection of insoluble membrane proteins in human plasma. Lipase treatment using porcine pancreas-derived enzymes was optimized to 37°C, 3 U, and 1 h, based on overall protein yield and membrane protein enrichment. Sequential application after depletion of high-abundance proteins increased the proportion of membrane proteins from 12%-20%. Using this optimized workflow, we performed data-independent acquisition-based LC-MS/MS analysis of plasma samples from patients with early-stage breast cancer and benign disease (n = 6 each). Notably, 38% of the uniquely detected or enriched proteins in cancer plasma were membrane-associated. Among them, protocadherin 12 (PCDH12) was significantly elevated in the plasma of patients with breast cancer, indicating its potential as a novel diagnostic biomarker. This study highlights the use of lipase-enhanced proteomics for revealing plasma membrane proteins and advancing noninvasive biomarker discovery for cancer.

Myelodysplastic neoplasms (MDS) are clonal blood disorders that cause ineffective hematopoiesis, low blood counts, and a risk of progression to acute myeloid leukemia. Chemotherapy and radiation usually drive these changes, but a small set of medications, including valproic acid (VPA), can also produce reversible myelodysplastic features. We report a case of VPA-induced myelodysplasia in a middle-aged woman with complex neurologic and psychiatric comorbidities. The patient, with a history of paraplegia secondary to traumatic brain injury and epilepsy, was referred for evaluation of pancytopenia and significant weight loss. She had been treated with VPA for seizure prophylaxis for over a year, with dose escalation to 1000 mg three times daily occurring approximately 3 months prior to presentation. Laboratory evaluation revealed pancytopenia. Peripheral smear showed pseudo-Pelger-Huët cells and thrombocytopenia. Bone marrow biopsy demonstrated mild hypocellularity, erythroid hyperplasia, and dysplasia in the megakaryocytic lineage, but cytogenetic and molecular studies were negative for MDS-associated mutations. We promptly stopped VPA and switched her to lacosamide. Supportive care included a PEG tube for nutrition and one packed red cell transfusion for procedure-related anemia. Her blood counts improved within a week of stopping VPA and normalized completely over the following weeks, with no further cytopenia. This case shows why clinicians should recognize drug-induced myelodysplasia as a reversible mimic of primary MDS. VPA's known hematologic toxicity may stem from its histone deacetylase (HDAC) inhibitor activity, which disrupts normal hematopoiesis. Clinicians should consider VPA-induced myelodysplasia in patients on long-term therapy who present with unexplained cytopenias. Stopping the drug early can produce full hematologic recovery and prevent unnecessary interventions.

The prognosis of glioblastoma (GBM) patients remains dismal due to chemoresistance. Repurposing of natural and endogenous compounds, such as the pineal hormone melatonin (MLT) and minor phytocannabinoids like cannabinol (CBN) or cannabigerol (CBG), represents a promising strategy. This study investigates the cytotoxic potential of combining these phytocannabinoids with MLT, evaluating their efficacy both alone and synergistically with temozolomide (TMZ) to overcome drug resistance. To achieve this, cytotoxicity, synergy (Bliss model), and selectivity were evaluated in U87, T98, and U251 GBM lines and normal astrocytes. Mechanisms of damage were characterized via Western blot (γH2AX and PARP-1), flow cytometry using fluorescent dyes/probes (DCFDA, JC-1, MitoBright, BODIPY, PI, and Annexin-V), or the protein marker COX IV and confocal analysis. The results demonstrated that CBN-MLT and CBG-MLT regimens exerted synergistic cytotoxicity while sparing healthy astrocytes. Notably, combining these regimens (U87: MLT 0.3 mg/mL + CBN 25 µM; MLT 0.2 mg/mL + CBG 15 µM. T98: MLT 0.7 mg/mL + CBN 25 µM; MLT 0.6 mg/mL + CBG 30 µM. U251: MLT 0.4 mg/mL + CBN 20 µM; MLT 0.5 mg/mL + CBG 35 µM) with TMZ significantly enhanced chemotherapeutic efficacy, overcoming baseline effects of TMZ in these cell lines. The combinations induced necrotic cell death characterized by severe double-strand DNA damage. This was driven by an early accumulation of intracellular ROS, which triggered mitochondrial depolarization, loss of organelle mass, and lipid peroxidation. CBN combinations consistently triggered more robust biochemical alterations than CBG-based treatments. Taken together, this study provides a strong preclinical basis for utilizing minor cannabinoids combined with MLT in GBM management. Crucially, this co-treatment emerges as a promising approach to potentiate TMZ efficacy, offering a novel and potentially effective therapeutic strategy to counter GBM resilience.

A woman in her early 20s at 30 weeks of gestation presented with elevated blood pressure, transaminitis, progressive dyspnoea, orthopnoea, exertional chest pain and peripheral oedema, raising concern for preeclampsia-associated cardiopulmonary disease or peripartum cardiomyopathy. Transthoracic echocardiography showed preserved left ventricular systolic function, normal left-sided filling pressures, right ventricular dilatation and an estimated right atrial pressure of 15 mmHg; N-terminal pro-brain natriuretic peptide was 57 pg/mL. Cross-sectional imaging revealed a large multi-cystic anterior mediastinal mass occupying the left hemithorax, displacing the heart and abutting/compressing major cardiopulmonary structures. Labour was induced at 34 weeks after clinical stabilisation. Three months postpartum, the patient re-presented with worsening dyspnoea and haemoptysis and underwent complete surgical resection. Pathology confirmed mature cystic teratoma and cardiopulmonary symptoms resolved after resection.