Background Extracranial metastasis of glioblastoma (GBM) is rare (0.4–2%) and associated with poor prognosis. For this report, “early extracranial dissemination” is defined as radiographically and histologically confirmed metastatic disease identified at or within one month of the index GBM diagnosis, distinguishing it from metastasis arising later in the disease course.Case presentation A 65-year-old woman with IDH-wildtype, MGMT-methylated GBM presented with seizures, right hemiplegia, and expressive aphasia. She underwent near-total resection followed by chemoradiotherapy with temozolomide. A suspicious right lower lobe pulmonary lesion was identified on initial staging, and biopsy-confirmed GBM involving mediastinal lymph nodes was established within one month of diagnosis. Despite pulmonary and mediastinal involvement, intracranial hemorrhage, seizures, and venous thromboembolism, she survived 25 months from diagnosis and 24 months following confirmation of metastatic disease.Discussion This case is notable for exceptionally early extracranial dissemination, pulmonary and mediastinal involvement, and prolonged post-metastatic survival. MGMT methylation and sustained temozolomide therapy may have contributed to disease control, although these observations remain hypothesis-generating.Conclusion Early extracranial dissemination may be underrecognized and warrants further investigation through risk-stratified approaches to extracranial surveillance.
BRAF inhibitors have advanced treatment for patients with BRAF-altered high and low-grade glioma (HGG and LGG, respectively). Clinically-available therapies are effective but require selection by mutation type and careful, proactive toxicity management to maximize patient quality of life and treatment duration. While pediatric LGG patients often experience durable responses, adults with LGG and patients with HGG frequently develop treatment resistance and disease progression while on treatment. Strategies to prevent or overcome resistant disease are under active preclinical and clinical investigation. This review serves as a primer to BRAF-altered therapy in glioma, outlines best practices for using available BRAF inhibitors, and highlights emerging therapeutic approaches aimed at improving outcomes in resistant disease. It serves as a forward-looking, practical guide for clinicians treating patients with BRAF-altered glioma.Article highlightsBRAF inhibitors are effective in both pediatric and adult low- and high-grade gliomas (LGG and HGG), but treatment should be tailored to the specific BRAF alteration (Table 1).Dabrafenib combined with trametinib is FDA-approved for BRAF V600E-mutant gliomas, while tovorafenib is approved for pediatric LGGs harboring BRAF V600 mutations or BRAF fusions.Proactive management, including anticipatory guidance and dose reduction for some patients, is essential to mitigate toxicity and avoid treatment interruptions.Tumor progression can occur during treatment interruptions or drug cessation; however, some patients may respond to BRAF inhibitor rechallenge.Emerging strategies focus on combination with other therapies including radiation, autophagy inhibitors, additional targeted agents, and others to overcome acquired resistance.Next-generation BRAF inhibitors—including paradox breakers, dimer disruptors, and protein degraders—are under clinical investigation (Table 2).
INTRODUCTION:Glioblastoma (GBM) is the most aggressive and biologically heterogeneous tumor of the central nervous system, associated with dismal prognosis and frequent recurrence. Amplification of the epidermal growth factor receptor (EGFR) and EGFRvIII mutation are common alterations, yet their prognostic significance remains unclear. This systematic review evaluated whether clinical evidence supports a predictive association between EGFR amplification or EGFRvIII mutation and response to EGFR-targeted therapy in adults with recurrent GBM. METHODS:PubMed, Embase and the Cochrane Library were searched (2010-2025) for studies of adults with recurrent GBM treated with EGFR-targeted therapies, with outcomes stratified by EGFR amplification and/or EGFRvIII. Screening, data extraction and risk-of-bias assessment were performed independently. RESULTS:Twelve studies (565 patients) met inclusion criteria. EGFR amplification was assessed in 11 studies and EGFRvIII in six using FISH, qPCR, RT-PCR, or NGS. Median overall survival ranged from 5.7 to 10.3 months and progression-free survival from 1.7 to 6.0 months, with no consistent survival benefit observed. CONCLUSION:EGFR amplification and EGFRvIII mutation have not demonstrated reliable predictive value for EGFR-targeted therapy in recurrent GBM. The available evidence is largely derived from heterogeneous, single-arm studies, limiting robust assessment of biomarker specific treatment response and therefore these alterations are not recommended to be used to guide off-trial treatment decisions in recurrent GBM.Protocol Registration: www.crd.york.ac.uk/prospero identifier is CRD420251071466.
CASE PRESENTATION:We describe a 62-year-old man with disseminated melanoma (initially staged pT2aN0M0, AJCC stage IB, 8th edition AJCC) who developed multiple brain metastases with hemorrhagic transformation, pulmonary embolism, retrobulbar progression with eyeball herniation, and deep vein thrombosis (DVT). After cerebral edema improved with corticosteroid tapering and the patient became asymptomatic, he started combination immunotherapy with ipilimumab (3 mg/kg q3w × 4) and nivolumab (1 mg/kg q3w × 4). Despite initial benefit, progression led to radiotherapy for retrobulbar lesion and subsequent targeted therapy with encorafenib (450 mg daily) and binimetinib (45 mg twice daily). Shortly after, the patient developed symptomatic left-leg DVT extending to the femoral vein with segmental pulmonary embolism. Given the contraindication to full anticoagulation, mechanical thrombectomy with the Indigo Aspiration System was performed, followed by prophylactic LMWH at reduced therapeutic dose (enoxaparin 1 mg/kg once daily due to recent thrombectomy and hemorrhagic risk from bleeding brain metastases). During targeted therapy, the patient experienced partial regression of brain, liver, and peritoneal metastases, although intracranial hemorrhage recurred later. CONCLUSIONS:This case highlights the value of a multidisciplinary, tailored approach integrating immunotherapy, radiotherapy, targeted therapy, and mechanical thrombectomy with no DVT recurrence observed following thrombectomy at 6-month follow-up.
Abstract:Diffuse pediatric-type high-grade glioma (pHGG), RTK1 subtype, is an uncommon aggressive tumor affecting both children and adults. We describe the case of a 66-year-old woman who presented with a left frontal lobe mass. Following surgical resection, the patient developed herpes simplex virus 2 meningoencephalitis, resulting in death. Histological examination revealed a high-grade glioma demonstrating nuclear pleomorphism, high mitotic activity, vascular proliferation and necrosis. The tumor also exhibited oligodendroglial-like features, nuclear clusters and small true rosette-like structures. Genetic analysis identified partial arm 1p loss and 19q loss, PDGFRA, MYCN and MDM4 amplification, an ATRX mutation and a novel SYN2::PPARG fusion. Homozygous CDKN2A/B deletion was also present. Genomic DNA methylation profiling matched diffuse pediatric-type high-grade glioma, RTK1 subtype, subclass C. This case underscores the importance of utilizing advanced molecular and genomic techniques for accurately diagnosing glial tumors. Further study of the SYN2::PPARG fusion in gliomas could potentially offer insights into its role in glioma biology and possibly help elucidate therapeutic strategies for tumors with PPARG fusions. Article Highlights:We report a case of diffuse pediatric-type high-grade glioma (pHGG), RTK1 subtype, subclass C in an adult confirmed by genomic DNA methylation analysis. The tumor demonstrated PDGFRA, MYCN and MDM4 amplification, and ATRX and KIT pathogenic mutations. The tumor also harbored a SYN2::PPARG gene fusion not previously reported in glioma. The case illustrates the importance of integrating advanced molecular techniques into the diagnostic process for older patients with atypical presentations of high-grade glioma. The potential biological significance and possible future therapeutic implications of the SYN2::PPARG gene fusion are discussed.
