Neurological Surgery最新文献

Pediatric brain tumors differ from their adult counterparts in terms of tumor biology, anatomical constraints, and surgical challenges. Endoscopic transnasal skull base surgery (ETS) has been widely adopted in adults, and is also increasingly being applied in children as a minimally invasive approach to sellar and parasellar lesions. In pediatric cases, ETS provides a direct ventral corridor; however, it is associated with unique limitations. These include underdeveloped paranasal sinuses restricting surgical space, adherence to postoperative rest is difficult, and the skull base or midfacial growth plates, particularly the sphenooccipital synchondrosis, may be affected. Furthermore, agitation and crying may cause abrupt intracranial pressure elevation, thereby jeopardizing skull base reconstruction. Despite these challenges, advances in endoscopic equipment, navigation, and multilayer reconstruction have enabled outcomes comparable to those in adults. Pediatric ETS is applied to a wide spectrum of tumors, including craniopharyngiomas, pituitary neuroendocrine tumors, chordomas, Rathke's cleft cysts, germ cell tumors, and optic pathway gliomas. In the era of targeted therapy, minimally invasive biopsy for molecular diagnosis has gained new clinical value for ETS. Perioperative management must address pediatric-specific risks, such as limited blood volume, higher cerebrospinal fluid leak rates, and long-term craniofacial development. Ultimately, pediatric ETS requires a multidisciplinary approach involving neurosurgeons, endocrinologists, otolaryngologists, anesthesiologists, oncologists, nurses, and other allied specialists, to achieve comprehensive care.

With improved cure rates for pediatric brain tumors, attention has increasingly turned to enhancing quality of life after treatment. Children with brain tumors commonly develop cognitive impairment due to the combined effects of the tumor itself, radiation therapy, chemotherapy, surgical treatment, hydrocephalus, neurological complications, and predisposing factors. Patients undergoing pediatric brain tumor treatment are prone to localized cognitive deficits and generalized brain dysfunction, such as intellectual decline and fatigue. Difficulties arising from cognitive impairment often emerge during the late phase of treatment, thereby necessitating ongoing assessment. It is important to promote patient independence while recognizing developmental stages and prevent secondary impairments through appropriate assessment and support.

Tumor-treating fields (TTF) are alternating electric fields applied to the brain through scalp arrays. Although TTF therapy has shown efficacy in adults with supratentorial high-grade glioma, its safety and efficacy in children remain unproven. Pediatric and adult high-grade gliomas differ genetically, but share clinical features that support trials in children. Recently, a pediatric case series using TTF has been reported, and a few prospective studies are underway. Because pediatric high-grade gliomas are rare and genetically diverse, these studies were designed as feasibility trials for various malignant brain tumors. Their primary goal is to confirm safety and feasibility; however, assessing the efficacy in each pediatric tumor subtype, including high-grade gliomas, is challenging. To address this issue, our clinical research team planned an investigator-initiated trial, specifically for pediatric supratentorial high-grade gliomas. The aim of this study was to expand the regulatory approval of TTF therapy in children by establishing safety and exploratory efficacy data supplemented by accumulated evidence in adults.

Clinicians commonly encounter cases of childhood brain tumors that are difficult to diagnose pathologically in a clinical setting. In such situations, molecular genetic analysis is essential for the diagnosis and clinical management of pediatric brain tumors. This analysis supports pathological diagnosis, identifies potential targets for molecular therapy, and predicts patient prognosis. According to the updated World Health Organization classification of central nervous system (CNS) tumors, molecular genetic analysis is essential for diagnosing several brain tumors, including High-Grade Astrocytoma with Piloid Features (HGAP) and diffuse glioneuronal tumors with oligodendroglioma-like features and nuclear clusters (DGONC). Comprehensive Genomic Profiling (CGP) was first made available for molecular analysis in our country in 2019. Herein, we describe the clinical importance of detecting molecular alterations in pediatric brain tumors. This article also provides a comprehensive review of molecular classification using DNA methylation analysis, which has recently emerged as a diagnostic tool for CNS tumors.

Advances in the treatment of pediatric brain tumors have markedly improved survival rates; however, long-term survivors still commonly experience delayed effects, particularly endocrine disorders. Growth hormone deficiency, central hypothyroidism, gonadal dysfunction, including pubertal abnormalities, and central diabetes insipidus are the most common such complications. Their onset is influenced by tumor type, surgical intervention, and cranial irradiation. Survivors of craniopharyngioma commonly develop panhypopituitarism and hypothalamic obesity, whereas survivors of germ cell tumors frequently present with diabetes insipidus and pubertal disturbances. Patients with medulloblastoma, particularly those receiving craniospinal irradiation, are at high risk of growth hormone deficiency and multiple hormonal deficits. These endocrine complications may be progressive and asymptomatic in the early stages, thus underscoring the necessity for systematic follow-up. Lifelong surveillance is recommended, with evaluations conducted at 1, 5, 10, and 20 years after treatment, focusing on growth, puberty, thyroid and adrenal functions, and metabolic status. The transition from pediatric to adult care, fertility preservation, and the management of lifestyle-related diseases represent additional challenges. Comprehensive multidisciplinary follow-up is essential to ensure an optimal quality of life in pediatric brain tumor survivors.

Medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (ATRT) are highly aggressive pediatric brain tumors that necessitate multimodal therapy. Historically, treatment strategies in Japan have varied across institutions due to the absence of standardized protocols. The establishment of the Japan Children's Cancer Group (JCCG) enabled nationwide clinical trials based on central pathological and molecular diagnoses. In MB, intensification of chemotherapy has enabled a reduction in the craniospinal irradiation (CSI) dose while maintaining survival outcomes. The ongoing JCCG MB19 trial has incorporated molecular subgrouping into risk stratification and employed high-dose chemotherapy (HDC) to balance survival and neurocognitive preservation. However, early reports on radiation necrosis, particularly after proton therapy, highlighted new safety concerns that require careful evaluation. The treatment outcomes for ATRT have gradually improved with multimodal regimens; however, the prognosis remains poor, especially in metastatic cases. The JCCG AT20 trial attempted to standardize treatment approaches by combining platinum, sarcoma-based agents, and frequent intrathecal methotrexate, followed by HDC and local radiotherapy. CSI was administered only to older patients with metastases. Despite these advances, the absence of new therapeutic agents has limited further progress. In the case of medulloblastoma, it is crucial to further investigate dose modulation in local radiotherapy to find a balance between efficacy and toxicity. Additionally, in the case of ATRT; there is an urgent need for novel treatments, such as targeted therapies and immunotherapies.

Fertility preservation treatment is becoming increasingly popular in Japan, but very few pediatric brain tumor patients have undergone this treatment even though such tumors are relatively common and affected patients are important candidates for fertility preservation. Fertility preservation treatments for girls include oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC). However, OC requires transvaginal procedures and daily controlled ovarian stimulation, which can be difficult to implement, and OTC is still a new option, and there have been very few live births till now. For boys, sperm cryopreservation, including after testicular sperm extraction (TESE), is the only fertility preservation option. Among pediatric patients with brain tumors, boys are at higher risk of fertility loss (gonadal failure), especially those with germ cell tumors. Furthermore, more than half of the treatment protocols for atypical teratoid rhabdoid tumor or ependymoma have been shown to result in gonadal failure in both boys and girls. Currently, the reproductive outcomes of fertility preservation in pediatric brain tumor patients are unclear, and more cases need to be investigated.

Recent advances in molecular profiling have transformed pediatric brain tumors management. The use of targeted agents is guided by actionable alterations including the BRAF V600E mutation, NTRK fusions, NF1 pathway activation, and H3 K27M mutation. Dabrafenib plus trametinib has shown superiority over chemotherapy in pediatric low-grade gliomas and activity against high-grade diseases. Larotrectinib and entrectinib provide tumor-agnostic options for NTRK-fusion-positive tumors with central nervous system penetration. Selumetinib offers clinical benefits in NF1-associated plexiform neurofibromas and shows promise for treating NF1-related low-grade gliomas. Tovorafenib, a type II RAF inhibitor active in BRAF-altered tumors (including BRAFKIAA1549 fusion), achieved robust responses, thereby leading to FDA approval. ONC201 (dordaviprone) has received accelerated approval for the treatment of H3 K27M-mutant diffuse midline gliomas, with Japanese trials and patient-initiated programs expanding access. Abemaciclib, a CDK4/6 inhibitor, is under phase II evaluation for pediatric high-grade glioma and diffuse midline glioma, including sites in Japan. Neurosurgeons play a pivotal role in securing high-quality biopsies, thus enabling comprehensive molecular diagnostics and facilitating enrollment in international trials. This review summarizes current targeted therapies and ongoing studies and outlines practical considerations for integrating precision oncology into pediatric neuro-oncology in Japan.

Diffuse intrinsic pontine glioma (DIPG) remains one of the most devastating pediatric central nervous system tumors, with a median survival of approximately 11 months despite decades of research. The identification of histone H3 K27M mutations marked a pivotal moment, leading to major advancements in understanding the molecular and epigenetic characteristics of these tumors. This discovery enabled molecular classification and provided a basis for the development of novel therapeutic strategies. In recent years, clinical trials have investigated molecular targeted agents and epigenetic modulators. Immunotherapeutic approaches, such as CAR-T cell therapy, have shown promising early results, whereas innovative drug delivery techniques, including convection-enhanced delivery and focused ultrasound, aim to overcome the challenges of the blood-brain barrier. Two major international registries, the International DIPG/DMG Registry (IDIPGR) and the European Society for Paediatric Oncology (SIOPE) DIPG/DMG Registry, play crucial roles in collecting comprehensive clinical data across multiple countries. The DIPG-2023 registry study was launched in Japan to collect prospective clinical, radiological, and molecular data systematically and to provide a high-quality external control cohort for future intervention trials. These collaborative efforts highlight a new era of DIPG/DMG research, offering cautious optimism for therapeutic progress in this historically refractory disease.

Deep brain stimulation (DBS) targets the anterior nucleus of the thalamus (ANT), and has emerged as a promising treatment for drug-resistant epilepsy. ANT-DBS is thought to exert its antiepileptic effect by activating inhibitory interneurons in the cingulate gyrus, thereby modulating epileptic activity through the Papez circuit and default mode network, both major components of the limbic system. Among the ANT subnuclei, the anteroventral nucleus (AV) is considered the most promising stimulation site because of its extensive connectivity with the limbic system. However, direct visualization of the AV nucleus using MRI is challenging. In contrast, the ANT-mammillothalamic tract (MTT) junction is clearly identifiable on imaging, and serves as a practical landmark for targeting. There are two major surgical approaches for ANT-DBS: transventricular and extraventricular. Thus, the transventricular approach may offer superior electrode placement accuracy. As increasing evidence indicates that seizure outcomes are more closely related to the precise stimulation site than to stimulation parameters, image-guided targeting based on the ANT-MTT junction is considered critically important for optimizing clinical outcomes.