All cancers, including brain tumors, arise from driver genomic and epigenomic alterations and evolve through the sequential acquisition of additional abnormalities. The emergence of next-generation sequencing technologies in the early 2000s enabled rapid and large-scale genomic and epigenomic analyses, leading to substantial advances in our understanding of the molecular pathogenesis of brain tumors. Consequently, driver alterations with potential therapeutic relevance have been progressively identified. Furthermore, continued technological innovations in sequencing technologies have consistently expanded our insights into brain tumor biology. In this review, we summarize recent findings from omics studies on brain tumors and discuss their biological and clinical implications.
Understanding cerebral hemodynamics and metabolism is essential for the diagnosis and treatment of ischemic cerebrovascular disease. Advances in imaging modalities and techniques have enabled the quantitative assessment of hemodynamic compromise and facilitated tailored treatment. In acute ischemic stroke, computed tomography/magnetic resonance perfusion imaging supports the identification of salvageable tissue (the penumbra) and contributes to the selection of endovascular thrombectomy (EVT), particularly within the delayed time window. In chronic intracranial atherosclerotic disease (ICAD), quantitative assessments of cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and oxygen extraction fraction (OEF) are useful for evaluating the risk of recurrence. The results of clinical trials for extracranial-intracranial bypass surgery vary due to differences in selection criteria and perioperative risks; therefore, patient selection based on rigorous hemodynamic evaluation is crucial. Repeated hemodynamic assessments are helpful in determining treatment strategies in moyamoya disease, for instance, which is progressive, even in asymptomatic cases. Postoperative cerebral hemodynamics may present with a mixture of hyperperfusion and hypoperfusion. To reduce the risk of postoperative complications, it is key to accurately understand the hemodynamic status. Collectively, the measurement of cerebral hemodynamics and metabolism is crucial for individualized and evidence-based management of ischemic cerebrovascular disease.
Primary central nervous system lymphoma (PCNSL) is a form of aggressive extranodal lymphoma confined to the central nervous system. Outcomes have substantially improved thanks to the introduction of high-dose methotrexate-based induction chemotherapy and consolidation strategies (including autologous stem cell transplantation); however, therapeutic challenges remain, particularly in elderly patients and those with relapsed or refractory disease. Recent genomic studies have indicates that PCNSL is characterized by frequent MYD88 and CD79B mutations, resulting in constitutive activation of the B-cell receptor and NF-κB signaling pathways, concurrent with an immunosuppressive tumor microenvironment. These insights provide a rationale for the development of targeted therapies and immunotherapies. Bruton's tyrosine kinase inhibitors and immunomodulatory drugs have shown promising activity in both relapsed and frontline settings, and are currently being evaluated in combination with maintenance strategies. CD19-directed chimeric antigen receptor T-cell therapy and CD20×CD3 bispecific antibodies have also emerged as potential therapeutic options for relapsed/refractory PCNSL, with encouraging efficacy and manageable toxicity profiles. This review summarizes the molecular pathogenesis of PCNSL, current standard treatments, and recent advances in targeted therapies and immunotherapeutic strategies that could improve treatment outcomes.
Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterized by the development of neoplasms in multiple organs. Hemangioblastoma is one of the most common tumors associated with VHL disease. In 2024, the "Clinical Practice Guidelines for VHL Disease" were established in Japan to provide guidance for the diagnosis, treatment, and management of VHL disease. Furthermore, in 2025, the HIF-2αinhibitor belzutifan was approved for insurance coverage in Japan for VHL-associated tumors, including hemangioblastomas. In this article, we first provide an overview of VHL disease and the "Clinical Practice Guidelines for VHL Disease," and then discuss the diagnosis and treatment of hemangioblastomas, including surgery, endovascular therapy, and radiotherapy. Finally, we review the role of the HIF-2αinhibitor belzutifan. In the future, management of VHL disease and hemangioblastomas will likely require not only individual treatment modalities, but also optimal multimodal strategies combining surgery, radiotherapy, and systemic drug therapy.
Craniopharyngiomas are benign sellar and parasellar tumors that present significant clinical challenge because of their close proximity to the optic apparatus, hypothalamus, and pituitary gland. Recent molecular studies have identified distinct driver mutations, namely, CTNNB1 in adamantinomatous craniopharyngiomas and BRAF V600E in papillary craniopharyngiomas, leading to a deeper understanding of tumor biology and treatment strategies. Advances in endoscopic endonasal transsphenoidal surgery have improved surgical safety and expanded the indications for minimally invasive resection, whereas radiotherapy remains an effective option for residual or recurrent disease. Molecular targeted therapy with BRAF and MEK inhibitors has resulted in remarkable tumor shrinkage in papillary craniopharyngiomas harboring the BRAF V600E mutation, and recent clinical studies have established this approach as a promising treatment option. These agents have emerged not only as effective treatment options for recurrent or refractory disease but also as promising options for neoadjuvant treatment and function-preserving management. Future treatment strategies are likely to incorporate molecular subtypes, patient age, and functional outcomes to achieve individualized care. In addition, the development of reliable preoperative molecular diagnostic techniques, including liquid biopsy, may further facilitate the integration of targeted therapies into routine clinical practice.
Artificial intelligence (AI) is rapidly reshaping the diagnosis and treatment of malignant brain tumors. Within the molecularly defined 2021 World Health Organization (WHO) framework, deep learning now supports several tasks: noninvasive, rapid prediction of molecular alterations from MRI and intraoperative optical imaging (radiogenomics); integrated interpretation of histology and genomics for prognosis; and accelerated treatment development through pathology foundation models, drug discovery, and large language model-based clinical trial matching and decision support. Across these advances, one recurring obstacle remains: distribution shift, or domain shift. Models whose performance depends on the provenance of their training data often perform less well at external institutions, and high discriminatory performance, as measured by the receiver operating characteristic area under the curve (ROC AUC), does not guarantee clinical reliability. We illustrate this issue through our study of IDH mutation prediction, which compared convolutional and transformer models with physicians using an international dataset and a Japanese cohort. External discrimination remained moderate, yet probability calibration deteriorated, whereas experienced clinicians maintained better calibration. We argue that the next frontier is not higher point-estimate accuracy but trustworthy AI: models that express well-calibrated uncertainty, abstain or defer in ambiguous cases, and request additional data within a human-in-the-loop workflow. Brain tumor care must move from prediction to trust.
Translational research on malignant brain tumors provide a bidirectional framework that links basic science with clinical practice to advance precision medicine. Despite progress in surgery, radiotherapy, chemotherapy, and molecular classification, outcomes remain poor, particularly for diffuse high-grade gliomas, because of treatment resistance, intratumoral heterogeneity, and the limited clinical implementation of molecular insights. Recent advances have highlighted the value of integrating intraoperative molecular diagnostics, molecular imaging, and patient-derived models into a unified translational platform. Rapid intraoperative assessment of key molecular alterations can support real-time surgical and therapeutic decision-making. Molecular imaging, including amino acid and hypoxia PET, enables the noninvasive evaluation of tumor biology and spatial heterogeneity. Patient-derived xenograft models and primary cultured cells retain tumor-specific molecular and phenotypic characteristics, enabling functional analyses of drug sensitivity, resistance mechanisms, and potential therapeutic strategies. Together, these approaches establish a multidimensional precision-medicine framework that integrates temporal, spatial, and functional information. Continued progress will require progress close collaboration across medicine, basic science, and data science, supported by systems that efficiently translate research findings back into clinical care. This integrated strategy is poised to accelerate the development of more effective personalized therapies for malignant brain tumors.
The World Health Organization (WHO) classification of brain tumors, which is based on the histogenetic concept, underwent a major transformation in the revised fourth edition published in 2016. Molecular genetic information was incorporated into the classification system, enabling the distinction of tumors based on the presence or absence of IDH mutations and 1p/19q co-deletion. This represents a significant paradigm shift in glioma diagnosis. In the fifth edition (WHO CNS5), the classification evolved by clearly separating adult- and paediatric-type gliomas and integrating genetic information directly into tumor grading. Molecular alterations are essential components of diagnosis. Consequently, the diagnostic criteria were refined to better reflect biological behavior and clinical outcomes. The forthcoming sixth edition may further advance this molecularly driven approach. Simultaneously, efforts are underway to establish a more coherent framework for using newly identified tumor entities and emerging molecular terminology. Thus, the WHO classification continues to evolve toward a more biologically meaningful and clinically relevant system for glioma diagnosis.
Medulloblastoma is a prevalent malignant pediatric central nervous system tumor. While medulloblastoma was historically risk-stratified by clinical factors, the WHO 2021 classification integrated molecular profiling, fundamentally transforming its diagnosis and management. The tumor is categorized into four primary molecular subgroups using techniques such as DNA methylation profiling: WNT-activated, SHH-activated, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated tumors generally exhibit the most favorable prognosis. SHH-activated tumors present varying outcomes depending on patient age and genetic alterations, such as TP53 mutations. Group 3 tumors, especially those with MYC amplification, frequently metastasize and have poor outcomes, whereas Group 4 tumors show a more prolonged clinical course. Standard treatment involves maximal safe resection, craniospinal irradiation (CSI), and chemotherapy. However, to mitigate severe late complications, molecular subtyping now enables precision and risk-adapted therapies. This includes exploring CSI dose reduction for the favorable WNT subgroup and utilizing novel molecular biomarkers for Groups 3 and 4. For infants, treatment primarily relies on chemotherapy to avoid CSI. Furthermore, recurrence patterns strongly correlate with these molecular subtypes. Re-biopsy and molecular re-evaluation are crucial upon relapse to distinguish genuine recurrences from radiation-induced secondary tumors.
Meningiomas have traditionally been classified and treated according to histopathological grade and extent of resection. However, recent advances in molecular biology have revealed that histology alone does not fully explain the clinical behavior of these tumors. The 2021 World Health Organization classification introduced molecular criteria for meningioma grading, including CDKN2A/B homozygous deletion and TERT promoter mutation as defining features of grade 3 disease. In parallel, large-scale multi-omics studies integrating genomic, epigenomic, and transcriptomic data have established biologically and clinically meaningful molecular subgroups. These findings indicate that copy number alterations, including 22q loss, 1p loss, and 1q gain, may provide practical markers for risk stratification in daily practice. Molecular profiling is also beginning to refine therapeutic decision-making, including the role of surgery, radiotherapy, and systemic treatment. Emerging approaches such as molecular targeted therapy, radioligand therapy, immune checkpoint inhibition, and CDK pathway inhibition suggest a transition from conventional grade-based management toward precision medicine. This review summarizes recent progress in the molecular classification and personalized treatment of meningiomas.
Glioblastoma is the most common and aggressive primary brain tumor. Despite advances in multimodal treatment, including surgery, radiotherapy, and temozolomide-based chemotherapy, the prognosis remains poor. Surgical resection plays a central role in glioblastoma management, with the primary objective of achieving maximal safe resection by maximizing tumor removal while preserving neurological function. Recent advances in surgical support technologies have substantially improved the safety and efficacy of glioblastoma surgery. Neuronavigation, tractography, intraoperative neurophysiological monitoring, awake mapping, and 5-aminolevulinic acid fluorescence-guided surgery enable surgeons to accurately visualize tumor boundaries and critical functional structures. Furthermore, emerging technologies, including augmented reality, image enhancement systems, and rapid intraoperative molecular diagnostics, provide additional anatomical and biological information that may facilitate precise surgical decision-making. This review summarizes the principles of glioblastoma surgery and discusses the recent innovations in surgical support technologies. The integration of anatomical, functional, vascular, and molecular information is transforming glioblastoma surgery into a more sophisticated form of information-guided surgery, with the goal of improving both oncological and functional outcomes.
Central nervous system (CNS) germ cell tumors (GCTs) are rare neoplasms that predominantly affect adolescents and young adults and occur at a notably higher incidence in East Asian populations. They are classified into two major categories: germinomas and non-germinomatous GCTs (NGGCTs). Germinomas are highly radiosensitive and chemosensitive, with long-term survival rates exceeding 90% following combined chemoradiotherapy. Current therapeutic focus on reducing radiation exposure, particularly whole-ventricular irradiation, while maintaining excellent tumor control, as exemplified by the ongoing CNSGCT2021 trial in Japan. In contrast, NGGCTs require intensified multimodal treatment incorporating alkylating-agent-based chemotherapy and craniospinal irradiation, and second-look surgery for residual disease. Despite these advances, outcomes for relapsed NGGCTs remain poor, underscoring the urgent need for novel therapeutic approaches. Recent genomic studies have identified recurrent activating mutations in the KIT/RAS/MAPK and PI3K/AKT/mTOR pathways, particularly in germinomas, providing potential targets for precision oncology approaches. The germinoma tumor microenvironment is characterized by abundant immune infiltration and PD-L1 expression, which has generated interest in immune checkpoint inhibitors. Additionally, liquid biopsy biomarkers, including circulating tumor DNA and microRNAs, show promise for less invasive diagnosis and disease monitoring. Long-term follow-up remains essential, given the risk of late relapse beyond 10 years and accumulation of treatment-related complications over decades.
Pediatric gliomas constitute the largest group of pediatric brain tumors and are biologically distinct from adult gliomas. The 2021 fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) introduced a molecularly integrated classification system and recognized pediatric-type gliomas as distinct entities. In pediatric low-grade gliomas, activation of the MAPK pathway is a common molecular hallmark, with BRAF V600E mutations, BRAF fusions, FGFR1 alterations, and NF1-associated abnormalities representing major driver events. These discoveries have supported the development of targeted therapies, including dabrafenib plus trametinib, tovorafenib, and MEK inhibitors. In pediatric high-grade gliomas, diffuse midline glioma, H3 K27-altered, remains one of the most devastating tumors, although recent advances have led to the approval of dordaviprone in the United States. In addition, infant-type hemispheric gliomas frequently harbor NTRK, ROS1, or ALK fusions and may respond markedly to corresponding targeted therapies. Comprehensive molecular diagnostics have therefore become essential for accurate classification and treatment selection. This review summarizes the current WHO CNS5 classification of pediatric gliomas and highlights recent advances in molecularly guided therapeutic strategies.
Various driver gene mutations have been identified, and agents targeting these molecular abnormalities have been developed and are being used in treatment. Some of these driver gene abnormalities are also associated with a high frequency of brain metastases. In patients with non-small cell lung cancer (NSCLC), more than 80% of brain metastases had a molecular target. Tyrosine kinase inhibitors are highly effective against brain metastases in patients with epidermal growth factor receptor-mutated or anaplastic lymphoma kinase fusion-positive NSCLC. Recently, the efficacy of the antibody-drug conjugate, T-DXd, against HER2+ breast cancer has also been confirmed. Many other molecularly targeted therapies are also effective against brain metastases; thus, many patients with brain metastases may benefit from these treatments. Although molecularly targeted therapy has become an important treatment modality for brain metastases, its limitations, such as not being curative and having a limited duration of effect, are also becoming clear. In the era of precision medicine, it is important to coordinate conventional local treatment with individually tailored molecularly targeted therapy. For that purpose, it is essential to understand the efficacy and limitations of targeted therapy for brain metastasis for each molecular target.
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a poor prognosis despite advances in multimodal treatment. Current standard of care includes maximal safe resection and radiotherapy with concomitant and adjuvant temozolomide, which is called the Stupp regimen. Tumor-treating fields are incorporated into standard therapies and have demonstrated survival benefits in newly diagnosed GBM. Bevacizumab improves progression-free survival; however, its effect on overall survival remains limited. Recent advances in comprehensive molecular analyses have accelerated the development of novel therapies for GBM. Oncolytic virotherapy has emerged as a promising strategy for inducing direct tumor lysis and antitumor immunity. Immune checkpoint inhibitors, dendritic cell vaccines, CAR-T cell therapy, and gene therapy have been actively investigated. Precision oncology approaches based on genomic profiling, including basket and umbrella trials, are expanding the therapeutic possibilities for selected patients with actionable alterations.
Recent advances in molecular profiling have revealed that ependymomas are biologically distinct entities with unique molecular alterations and clinical behaviors. These findings have been incorporated into the 2021 WHO Classification of Tumors of the Central Nervous System, integrating anatomical location and molecular features into the diagnostic framework. This review summarizes the current molecular classification of ependymomas, role of DNA methylation profiling in diagnosis, and biological and clinical characteristics of the major molecular subgroups. Additionally, we discuss current treatment strategies, molecular risk stratification, and future directions in the management of ependymomas.
Cancer genomic medicine is an integral component of neuro-oncology, enabling personalized treatments based on tumor-specific genomic alterations. In Japan, comprehensive genomic profiling (CGP) is performed using several tissue- and plasma-based platforms to detect genomic mutations, copy number alterations, gene fusions, tumor mutational burden, and other molecular biomarkers. Tissue-based assays are preferred for brain tumors because of the limited sensitivity of plasma testing. CGP results were interpreted by expert molecular tumor boards supported by the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), integrating genomic and clinical data and providing information on potential targeted therapies and clinical trials. Real-world studies have demonstrated that actionable alterations can be identified in most patients, although only a few patients ultimately receive genomically matched treatments. However, the selected patients may achieve meaningful clinical benefits. Currently, approved molecularly targeted therapies in neuro-oncology include vorasidenib, dabrafenib plus trametinib, entrectinib or larotrectinib, and pembrolizumab for IDH1/2-mutant gliomas, BRAF V600E-mutant gliomas, NTRK fusion-positive tumors, and TMB-high tumors, respectively. Future challenges include improving patient access to genomic medicine, optimizing the timing of testing, expanding genomic analyses, and facilitating the development of novel targeted therapies for rare brain tumors.
Lower-grade gliomas comprise a biologically heterogeneous group of adult diffuse gliomas, primarily defined by their molecular alterations. In current practice, management should integrate maximal safe resection, individualized use of radiotherapy, and rational systemic therapy based on the tumor subtype, growth pattern, and anticipated long-term functional outcomes. Surgery remains the cornerstone of treatment because the extent of resection influences tumor control, seizure burden, functional outcomes, and timing of adjuvant therapy. Although radiotherapy is effective, its timing, dose, and field design should be optimized to preserve neurocognitive function and quality of life in patients with prolonged life expectancy. Combined chemoradiotherapy remains essential for select high-risk tumors, whereas temozolomide alone cannot be considered a universal substitute for radiotherapy-based strategies. The emergence of IDH inhibitors, particularly vorasidenib, has expanded therapeutic options for select patients with residual or recurrent non-enhancing grade 2 IDH-mutant gliomas following surgery by prolonging progression-free survival and delaying the need for subsequent intervention, without apparent deterioration in health-related quality of life or neurocognition. This review summarizes current evidence and proposes a practical framework for integrating surgery, radiotherapy, conventional chemotherapy, and IDH inhibition into routine clinical decision-making.
The 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS5) marks a major shift toward molecularly integrated diagnostics, distinguishing circumscribed astrocytic gliomas and glioneuronal tumors from diffuse gliomas based on characteristic genomic and epigenetic signatures. These tumors are predominantly driven by MAPK pathway alterations, including BRAF fusions and BRAF V600E mutation, whereas others harbor mTOR pathway activation or distinct drivers, such as PRKCA and MN1. Advances in precision oncology have transformed clinical management, and targeted therapies, such as dabrafenib/trametinib and everolimus, have been established; selumetinib received expanded adult approval in Japan in 2025. Moreover, next-generation type II RAF inhibitors, exemplified by tovorafenib, and emerging combinatorial approaches targeting pathway crosstalk offer promising strategies to overcome therapeutic resistance. This review synthesizes current molecular definitions and evolving personalized treatment paradigms for circumscribed gliomas. Integrating these molecular insights into routine practice is essential for optimizing tumor control and preserving neurological function in the CNS5 era.
Pediatric patients are not simply small adults; pediatric neurosurgical care requires specific considerations based on developmental anatomy, physiology, and psychosocial contexts. This review summarizes the practical points frequently encountered by early career neurosurgeons, focusing on clinical assessment, imaging, and perioperative management. Clinical presentation varies markedly with age: infants often exhibit nonspecific signs, such as poor feeding, irritability, or progressive head enlargement, whereas school-aged children may report headaches, nausea, gait disturbance, or behavioral changes. Imaging should prioritize low invasiveness and radiation exposure. MRI is preferred when feasible; however, sedation is often required in infants and young children, and safe practice should follow the established recommendations regarding fasting, airway risk assessment, and monitoring. Perioperative management includes weight-based fluid and medication dosing, judicious prophylactic antibiotics, and meticulous intraoperative care. Particular attention is required to prevent hypothermia, airway complications during positioning, pressure injuries, adhesive-related skin damage, and head-fixation-related complications in patients with thin cranial bones. Finally, building trust with caregivers is essential. Clinicians should recognize the profound burden of discussions about diagnosis and surgery and continuously refine their communication skills to deliver bad news.
