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.
This case report characterizes the molecular pathology of two synchronous IDH mutant gliomas in a 28-year-old female patient. The patient exhibited symptoms of dizziness, retro-orbital pain, headache, and numbness with paresthesia in her right arm. MRI imaging revealed two distinct non-enhancing T2/FLAIR hyperintense lesions in the left frontal and parietal lobes. Histopathologic and molecular analyses, including whole exome sequencing, were performed on the resected specimens from each location. The left parietal tumor was diagnosed as a grade 4 astrocytoma with an IDH1 R132H mutation, while the left frontal tumor was classified as a grade 2 oligodendroglioma with an IDH1 R132S mutation. Given the distinct molecular profiles of both synchronous tumors, treatment consideration was given to each individual primary tumor.
Aims We aimed to investigate a potential association between hypofractionated radiotherapy (HFRT) vs. conventional radiotherapy (CRT) and development of pseudoprogression in patients over the age of 65 treated for glioblastoma (GBM).Materials & methods Seventy-nine patients with glioblastoma (29 who received HFRT and 50 who received CRT) were included in this retrospective cohort study from a single institution. Demographic, clinical, and radiation information, including development of pseudoprogression and standard prognostic factors like Karnofsky Performance Status (KPS) and extent of surgical resection, were collected.Results Radiation regimen alone was not associated with development of pseudoprogression. Patients who had lower KPS at the time of diagnosis and received HFRT had lower rates of pseudoprogression. There was no association between radiation regimen, pseudoprogression, and any other clinical factors.Conclusion Older patients with glioblastoma who receive HFRT are not more likely to develop pseudoprogression than those who receive CRT. Patients with lower functional status receiving HFRT may be less likely to mount an inflammatory response leading to pseudoprogression. Prospective investigation is warranted to validate these results and evaluate other factors leading to treatment complications in older patients with glioblastoma in order to optimize outcomes and minimize toxicity.
Whether to surgically resect a margin of grossly normal appearing brain around anatomically amenable diffuse gliomas (i.e., perform a supratotal, supramarginal, or supramaximal resection) has been controversial. Over the past 5-10 years, however, evidence published by multiple independent groups has established a substantial survival benefit to this approach, moving the field towards a consensus that supramarginal resections should be offered when possible. However, many practitioners remain hesitant to offer supratotal resections due to concerns for variable neuropsychological outcomes and a mindset of “first, do no harm.” Unfortunately, and perhaps counterintuitively, available data also suggest that opting for more conservative surgical approaches when more aggressive resections are possible may result in both suboptimal long-term functional and survival outcomes. To explore this complex and actively evolving issue, here I review evidence surrounding the multidimensional clinical impacts of supramarginal resections across all diffuse glioma subtypes. I then evaluate what is known about anatomical-functional relationships subserving cognition, behavior, and mood regulation, and I examine ethical considerations that arise when counseling patients at the difficult time of diagnosis. I then conclude with a set of case examples that demonstrate how the principles explored in this review can be applied in real-world situations to optimize, individualize, and humanize oncological and functional outcomes.
A 7-year-old female with recurrent midline pilocytic astrocytoma harboring a rare STRN3::NTRK2 fusion achieved sustained near-complete radiographic and clinical response to larotrectinib, a selective TRK inhibitor. Initial subtotal resection of the midbrain/thalamic tumor was followed by progression, prompting molecular profiling that identified the STRN3::NTRK2 fusion. Larotrectinib therapy initiated at recurrence resulted in a rapid reduction by 3 months, resolution of pontine extension by 6 months, and near-complete resolution by 15 months. This case highlights the potential of molecular diagnostics in pediatric neuro-oncology, particularly for BRAF-negative midline gliomas where NTRK fusions are rare but actionable. The durable response supports prioritizing larotrectinib over conventional chemotherapy in unresectable/progressive NTRK-driven gliomas. Routine fusion screening in BRAF-negative cases should be considered to identify candidates for targeted therapy. This report expands the known spectrum of NTRK2 partners in pilocytic astrocytoma and reinforces the use of TRK inhibitors as a treatment for molecularly defined subsets of pediatric glioma.
Cerebral lesions are rare in hairy cell leukemia (HCL), and its incidence remains to be determined. Identifying the cause can be challenging. In this report, we present a case of brain lesions occurring several years after diagnosis. A 76-year-old male patient presented to the Emergency Department with confusion. He had been diagnosed with HCL in 1999 and had received five lines of treatment. Cerebral imaging revealed multiple nodular lesions, with edema and a hemorrhagic appearance. Cerebrospinal fluid tests were negative. The tumor origin was retained due to concomitant relapse (blood, lymph nodes). Despite the partial efficacy of rituximab-cladribine treatment, the patient died of Candida pneumonia. A review of the literature (PubMed, CrossRef, Google Scholar) identified seventeen cases between 1966 and 2024, with a median age of 59 years (33-80). Cladribine, with or without rituximab, was the most widely prescribed treatment regimen with a complete response rate of 57%. Four (23.5%) patients died (two from infection, one from gastrointestinal bleeding and one from an unknown cause). These atypical presentations suggest that brain imaging and advanced biological investigations should be performed to guide management.
Glioblastoma (GBM) is the most common malignant primary brain tumor, characterized by a high recurrence rate despite aggressive therapy. We present a case of a 32-year-old male with a recurrent WHO Grade IV IDH1-mutant astrocytoma after undergoing standard Stupp protocol chemoradiation and tumor-treating field therapy. Repeat surgery was performed where in vitro analysis of recurrent GBM cells revealed atypical behavior, rapid adhesion within minutes of plating, and the formation of radial glial-like cells (RGCs) with 3D aggregated cells, phenotypes absent in the primary tumor. These brain lipid-binding protein positive RGCs exhibited elongated processes that facilitated cancer cell migration, potentially contributing to tumor invasiveness. Extensive treatment between the primary and recurrent tumors may have induced this phenotypic shift, highlighting therapy-induced plasticity as a key factor in recurrence. The emergence of RGCs in recurrent GBM underscores the need for targeted therapies addressing tumor adaptability to improve treatment outcomes.
Epidermoid cysts are uncommon accounting for less than 1% of all intracranial tumors. Among them, giant intradiploic epidermoid cysts of the posterior fossa i.e. those exceeding 5 cm are an even rarer entity. Here we report on the complete resection of a 7 cm posterior fossa epidermoid cyst involving the occipital bone in a 32-year-old female presenting with an acute on chronic exacerbation of headaches and vertigo. Complete resection including the cyst wall is crucial in preventing recurrence and malignant transformation. We add to limited existing data by reporting on the first systematic review to date assessing 25 cases of giant epidermoid cysts of the posterior fossa to discuss presentation, clinical and radiographic features and definitive management strategies.
Aim: A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy.Methods: Pre- and post-contrast T1-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans. Univariate and multivariate Cox regression analyses were used to test the influence of contrast-enhancing tumor volume, total cellularity, mean Cyt and mean ECF at baseline, immediately post-treatment and the pre- and post-treatment rate of change in volume and cellularity on overall survival (OS).Results: Smaller Cyt and larger ECF after treatment were significant predictors of OS, independent of tumor volume and other clinical prognostic factors (HR = 3.23 × 10-6, p < 0.001 and HR = 2.39 × 105, p < 0.001, respectively). Both post-treatment volumetric growth rate and the rate of change in cellularity were significantly correlated with OS (HR = 1.17, p = 0.003 and HR = 1.14, p = 0.01, respectively).Conclusion: Changes in histological characteristics estimated from a radio-pathomic ML model are a promising tool for evaluating treatment response and predicting outcome in rGBM.
Glioblastoma is associated with a dismal prognosis with the standard of care involving surgery, radiation therapy and temozolomide chemotherapy. This review investigates the features that make glioblastoma difficult to treat and the results of glioblastoma immunotherapy clinical trials so far. There have been over a hundred clinical trials involving immunotherapy in glioblastoma. We report the survival-related outcomes of every Phase III glioblastoma immunotherapy trial with online published results we could find at the time of writing. To date, the DCVax-L vaccine is the only immunotherapy shown to have statistically significant increased median survival compared with standard-of-care in a Phase III trial: 19.3 months versus 16.5 months. However, this trial used an external control group to compare with the intervention which limits its quality of evidence. In conclusion, glioblastoma immunotherapy requires further investigation to determine its significance in improving disease survival.
Aim: Brain metastases (BM) are a common site of disease progression and treatment failure in non-small-cell lung cancer (NSCLC) and can be identified in up to 30-50% of patients. Although they are common, there is no standardized screening protocol for development of BM in NSCLC. Multiple clinical variables predict increased BM occurrence, and, when present, should be used to initiate screening MRI.Materials & methods: We performed a single center retrospective review of NSCLC patients, examining BM development and overall survival. Available clinical, radiographic and molecular data were reviewed for association with BM and overall survival. A predictive model for BM development was created for multivariate analysis.Results: Risk factors for new BM development in NSCLC included younger age, larger primary lung tumor, Karnofsky performance score (KPS) <70, pre-existing liver or bone metastases, large cell histology and family history of cancer. Factors associated with decreased OS were larger primary lung tumor, extracranial metastases at time of diagnosis, large cell histology and poorly-differentiated carcinoma histology.Conclusion: There are multiple high risk features for developing BM in NSCLC. Each of these factors should routinely be investigated, and presence should prompt brain MRI to allow earlier diagnosis and treatment of BM.
Aim: Neurofilament light chain (NfL) is a nonspecific sensitive biomarker of axonal damage.Methods: This case series identified cancer patients with neurological complications who had serum NfL measurements and paired these results to outcomes.Results: NfL serum levels were available in 15 patients with hematological malignancies or solid tumors. The neurological complications studied were immune effector cell-associated neurotoxicity syndrome, immune checkpoint inhibitor-related encephalopathy, anoxic brain injury, Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis, transverse myelitis, paraneoplastic syndrome, central nervous system demyelinating disorder and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. All patients but one with serum NfL >900 pg/ml died during hospitalization.Conclusion: Serum NfL levels consistently corresponded to death, disease severity or recovery in this series.
Aim: Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive primary CNS neoplasm, predominantly observed in children. The use of autologous stem cell transplantation (ASCT) in pediatric ATRT has shown promise; however, its utility in adult ATRT remains unclear. Patients & methods: This study presents the case of an adult patient with ATRT who is in remission after ASCT and reviews the literature on ASCT in adults with ATRT. Four cases of ATRT in adults who underwent ASCT were identified, with pertinent data summarized. Results: All five patients survived longer than the historical average survival rate, four of whom had no clinical or radiographic evidence of disease at the final follow-up. Conclusion: Based on limited data, there may be a role for ASCT in the treatment of adults with ATRT.
Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate the principal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.
Aim: To evaluate the neuro-oncology providers' experience with patient online access to electronic records. Methods: Cross-sectional survey for physicians and advanced care providers within the field of neuro-oncology in the USA. Results: 65 providers completed the survey, from all major regions of the USA. 58% reported that at least once per month, patients contacted them outside of an office visit about provider notes or a laboratory or imaging finding accessed online. 54% of providers did not think that all laboratory results should be released automatically, and only 25% of providers thought that all radiology reads should be released immediately. 97% thought that some patients suffered substantial distress viewing test results prior to appointments. Qualitative responses aligned with the quantitative results. Conclusion: Most neuro-oncology providers are concerned about the immediate release of laboratory and imaging findings to patients without guidance.
Glioblastoma is the most common malignant primary brain tumor. Despite its infiltrative nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of TP53 mutation, TERT mutation, PTEN mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations in predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.
Primary effusion lymphoma (PEL) is an uncommon B-cell lymphoma associated with human herpesvirus 8 and comprises 3–4% of all HIV-related lymphomas. It traditionally presents as a pleural, pericardial, and/or peritoneal effusion, though it can occasionally manifest as an extracavitary or solid mass in the absence of an effusion. The extracavitary or solid variant of primary effusion lymphoma has been reported in the skin, gastrointestinal tract, lung, and lymph nodes. However, very few cases have been reported in the central nervous system. We describe a case of extracavitary or solid variant of primary effusion lymphoma presenting as a brain mass in an HIV-positive man, highlighting the clinicopathologic and immunophenotypic findings of a rare entity.
