Published papers

Abstract Leptomeningeal dissemination (LMD), known as carcinomatous meningitis, occurs in approximately 5% of all cancer patients. LMD presents an extremely poor prognosis, with an average life expectancy of 4-6 weeks. While treatments such as whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, their effects are limited, which urgently necessitates new therapeutic strategies for LMD. We evaluated the efficacy of a stem cell (SC)-based therapeutic strategy for LMD in various solid cancers based on two primary advantages: (1) LMD is a condition where cancer cells spread within a single closed space without separation, and SCs with cancer tropism and chemotaxis can easily reach these cells; (2) Repeated intrathecal injections of drugs are invasive and risky, but SCs can continuously secrete therapeutic agents into the cerebrospinal cavity after a few injections, increasing local concentrations of these substances. Our findings suggest that treatment using engineered SCs may be an effective option against LMD from breast, lung, and malignant melanoma, which are types of cancer that tend to metastasize to the central nervous system. Specifically, we found that engineered allogeneic SCs simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) have efficacy for LMD of triple negative breast cancer and non-small cell lung cancer. In addition, twin SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against programmed death receptor-1 (PD-1) show encouraging results in managing LMD in cases of malignant melanoma. We believe that SC therapy has the potential to become a new therapeutic option for LMD in the future.

Background/Aim: Many glioma patients struggle to return to work after surgery because of higher brain dysfunction. Although the right frontal lobe has historically been considered functionally silent, reports of performing awake surgery to evaluate higher brain functions in patients with tumors in this area have increased. We present two cases of patients who underwent awake surgery for malignant glioma in the right frontal lobe to preserve emotional recognition and facilitate an early return to work. Case Report: Case 1 was a 48-year-old right-handed woman employed as a nursery school teacher and case 2 was a 21-year-old right-handed man employed in sales. Both had contrast-enhancing right frontal lobe tumors exhibiting high signal intensity on fluid attenuated inversion recovery imaging and underwent awake surgery. During the operation, cortical mapping was performed using the Reading the Mind in the Eyes, calculation, and motor tasks. Resection of sites involved in motor and emotional recognition functions was avoided. In case 1, all regions of high signal intensity were completely resected; in case 2, all regions exhibiting enhancement were resected. Both patients were discharged home without neurological deficits and returned to work within 21 days after surgery. Conclusion: It may be important to focus not only on overall survival and progression-free survival in glioma patients, but also on factors associated with life satisfaction, such as time to return to work after surgery and time until work becomes difficult. Awake surgery aimed at preserving higher brain functions is useful and may also improve life satisfaction.

Background – The retrosigmoid approach is widely used for vestibular schwannoma resection. If the tumor is large, significant cerebellar retraction may be required, which can cause cerebellar edema. The presigmoid retrolabyrinthine route preserves the labyrinth and reduces cerebellar retraction and manipulation but provides only a narrow surgical corridor. We report the use of a combined approach to safely resect a large vestibular schwannoma with brainstem compression while avoiding complete postoperative deafness. Methods – A 24-year-old man presented with a large right vestibular schwannoma causing considerable brainstem compression. A combined temporal–suboccipital craniotomy with near-total mastoidectomy was performed to expose the sigmoid sinus while preserving the labyrinth. Microsurgical dissection was performed via the retrosigmoid corridor, while a rigid endoscope inserted through the presigmoid route provided direct visualization of the brainstem side. Results – This dual-corridor, dual-visualization technique enabled safe subperineural tumor removal and identification of the facial nerve. Gross total resection was achieved, and the postoperative course was uneventful. At approximately 6 months postoperatively, facial nerve function remained normal (House–Brackmann grade I). Formal postoperative pure-tone audiometry demonstrated residual hearing on the operated side, predominantly in the low-frequency range. Although serviceable hearing was not preserved, complete postoperative deafness was avoided. Conclusion – In large vestibular schwannomas with vertical brainstem extension, retrosigmoid resection alone may require excessive cerebellar retraction. Adding a presigmoid retrolabyrinthine corridor improves brainstem access, minimizes cerebellar retraction and manipulation, and facilitates safe tumor removal. This combined approach is a practical strategy for patients with significant brainstem compression.

BACKGROUND AND OBJECTIVES: – Facial nerve preservation is critical in skull base surgery. Transcranial facial motor-evoked potential (tfMEP) monitoring can be limited by interindividual primary motor cortex (M1) facial cortex variability and intraoperative perturbations. We evaluated a functional MRI (fMRI)–guided, neuronavigation-assisted montage to personalize stimulating electrode placement and reduce thresholds during cerebellopontine angle tumor surgery.METHODS: – In a prospective cohort (n = 20), tfMEPs were recorded simultaneously using 2 montages: (1) fMRI-guided electrode directly over the patient-specific M1 facial hotspot identified by preoperative task fMRI and (2) conventional C3/C4. Train-of-five stimulation elicited compound muscle action potentials from orbicularis oculi/oris. The primary end point was stimulation threshold (mA) to elicit >50 µV, measured at predefined stages (precraniotomy through closure). Secondary analyses assessed threshold changes after durotomy/cerebrospinal fluid (CSF) drainage and postoperative House–Brackmann (HB) grades.RESULTS: – fMRI-guided placement yielded lower baseline thresholds than conventional within patients (mean 65.5 vs 73.5 mA; Δ = −8.9 mA; P < .0001). The advantage persisted at closure (85.3 vs 96.3 mA; P < .0001). After durotomy/CSF drainage, thresholds increased modestly with both montages (+3.3 vs +4.0 mA; between-group P = .65). Monitoring feasibility was 100%, providing continuous data early in the case when direct nerve stimulation was not yet possible. At the latest follow-up, 17/20 (85%) had HB I and 3/20 (15%) HB II; no patient had permanent moderate/severe palsy.CONCLUSION: – Neuronavigation-assisted, fMRI-guided tfMEP reliably targets the individual M1 facial area and significantly lowers stimulation thresholds vs conventional C3/C4, without increasing susceptibility to threshold drift after CSF loss. This simple, adoptable workflow may enhance intraoperative decision making for facial nerve preservation. Larger multicenter studies are warranted to validate outcome prediction and refine threshold-based alarm criteria.

The SH3PXD2A-HTRA1 fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic NF2 status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; P = 0.012), trigeminal nerve origin (OR, 2.88; P = 0.042), and intratumoral hemorrhage (OR, 18.61; P = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (P = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; P = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (P = 0.046). Only 33% of fusion gene-positive tumors indicated somatic NF2 alteration. The SH3PXD2A-HTRA1 fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of NF2. Our findings provide a basis for future clinical investigations.

Background: Awake surgery with intraoperative language mapping has become increasingly refined, allowing assessment not only of motor but also higher brain functions. Language remains the most critical function to evaluate and preserve. However, reports of multilingual patients undergoing such procedures are still limited, particularly those involving Japanese, a linguistically and structurally unique language. Case description: We present the case of a 32-year-old right-handed multilingual male (Japanese L1, English L2, French L3), a film director and actor, who underwent awake craniotomy for a recurrent low-grade glioma involving the left temporal lobe. Preoperative functional MRI confirmed left hemispheric language dominance across all three languages, although French and English showed broader activation than Japanese during semantic fluency tasks. During surgery, cortical mapping with object naming and reading tasks was performed in Japanese, English, and French. Naming errors were observed in the posterior superior temporal gyrus across all three languages, whereas semantic paraphasia in the posterior middle temporal gyrus and reading impairment in the posterior inferior temporal gyrus were specific to Japanese. Postoperative MRI revealed subtotal resection with preservation of language function. Histopathology confirmed astrocytoma, IDH-mutant, WHO grade 3. Conclusion: This case represents the first report of intraoperative language mapping in a Japanese–English–French trilingual patient, demonstrating both overlapping and language-specific cortical regions. The findings underscore the importance of individualized and multimodal language mapping in multilingual patients, particularly when typologically distant languages such as Japanese are involved.

PURPOSEThe humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184).MATERIALS AND METHODSVEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response.RESULTSSixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas.CONCLUSIONThis study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.

Objective: Trigeminal schwannomas are rare benign tumors originating from the Schwann cells of the trigeminal nerve. Despite the common occurrence of trigeminal neuropathy in trigeminal schwannomas, a detailed analysis has not yet been performed because of the rarity of this disease. This study aimed to analyze trigeminal neuropathy in trigeminal schwannoma resection and identify the risk factors for postoperative worsening of trigeminal neuropathy. Methods: A retrospective analysis of 86 surgical cases was performed at our institution between 1975 and 2018. Obtained parameters included age, sex, diagnosis, reoperation, tumor size, tumor location, presence or absence of cysts, surgical approach, degree of tumor removal, and pre/postoperative trigeminal neuropathy. Uni- and multivariate analyses were performed to identify the risk factors for worsening postoperative sensory disturbances. Results: Of 83 patients, 58.1% had preoperative trigeminal neuropathy. Postoperative sensory disturbance occurred in 27.9%, with worsening in two cases and de novo symptoms in 22 cases. Regarding risk factors for worsening postoperative sensory disturbances, older age, smaller tumor size, middle and posterior (MP) type, gross total removal (GTR), and anterior transpetrosal approach were identified in the univariate analysis, while MP type and GTR were identified in the multivariate analysis. Conclusions: This study analyzed trigeminal neuropathy in trigeminal schwannomas in detail and identified tumor location and removal rate as risk factors for worsening postoperative sensory disturbances. Treatment strategies to reduce the risk of trigeminal neuropathy should be considered.

Introduction: Glioblastomas can manifest as multiple, simultaneous, noncontiguous lesions. We genetically analyzed multiple glioblastomas and discuss their etiological origins in this report. Case Presentation: We present the case of a 47-year-old woman who presented with memory impairment and left partial paralysis. Radiographic imaging revealed three apparently noncontiguous lesions in the right temporal and parietal lobes extending into the corpus callosum, leading to diagnosis of multicentric glioblastomas. All three lesions were excised. Genetic analysis of the lesions revealed a TERT promoter C228T mutation, a roughly equivalent amplification of EGFR, and homozygous deletion of CDKN2A/B exclusively in the two contrastenhanced lesions. Additionally, the contrast-enhanced lesions exhibited the same two-base pair mutations of PTEN, whereas the non-enhanced lesion showed a partially distinct 13-base pair mutation. The other genetic characteristics were consistent. Rather than each having arisen de novo, we believe that they had developed by infiltration and are therefore best classified as multifocal glioblastomas. Conclusion: Our findings underscore anew the possibility of infiltration by glioblastomas, even within regions devoid of signal alterations on T2-weighted images or fluid-attenuated inversion recovery images. Genetic analysis can play a crucial role in differentiating whether multiple glioblastomas are multifocal or multicentric.

Cerebrospinal fluid (CSF) leakage is a common complication associated with endoscopic endonasal skull-base surgery (EESBS). Postoperative mobilization-associated postural changes are considered to cause CSF leakage. However, no study has demonstrated a robust relationship between postural changes and CSF leakage. We used upright computed tomography (CT) to clarify the effects of postural changes on the reconstructed skull base (RSB) after EESBS. Thirty patients who underwent EESBS at our institution were prospectively included, and their upright and supine CTs were compared to measure morphological changes in the RSB. Patient clinical data were also collected from medical charts and surgical videos, and their relationships with morphological changes were assessed. In upright CTs, the RSB shifted intracranially by 0.94 (0.0–2.9) mm on average. This shift was larger in cases with lesions extending to the sphenoid sinus, dural defects, intraoperative pulsation of the RSB, and large bone windows. The direction of the change was opposite to intuitive movement driven by gravity because of reduced intracranial pressure in the sitting position. Thus, these shifts can be directly associated with postoperative CSF leakage caused by reconstruction material displacement. Skull-base reconstruction and postoperative postural management accounting for these morphological changes may be necessary for preventing CSF leakage.

Purpose: Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly. Methods: Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed. Results: In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171). Conclusion: The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients.

Purpose: This study aimed to examine the venous anatomy of the horizontal fissure (HF) of the cerebellum by using contrast-enhanced magnetic resonance imaging (MRI) and computed tomography venography (CTV). We also studied the venous anatomy and cerebellar structures surrounding the HF relevant to the suboccipital trans-HF (SOTHF) approach in cadaver studies. Methods: We conducted an imaging analysis of 200 cerebellar hemispheres from 100 patients who underwent surgical treatment for intracranial supratentorial lesions between March 2021 and March 2023 at our institution. All patients underwent preoperative contrast-enhanced MRI and CTV. A cadaver study was conducted to assess the feasibility of the medial, intermediate, and lateral surgical corridors of the SOTHF approach while preserving the veins. We also present a clinical case. Results: Veins traversing the HF longitudinally, which act as a potential barrier when splitting the HF, were observed in 82% of the hemispheres, with an average of 1.28 per hemisphere. Distinctive veins running horizontally along the HF, observed in 24% of hemispheres, also act as potential barriers during wide HF opening. Cadaver studies demonstrated essential anatomical structures around the HF and that the medial, intermediate, and lateral corridors of the SOTHF approach could be achieved while preserving surrounding venous structures. Conclusion: The SOTHF approach is feasible for accessing deep cerebellar lesions, the medial aspect of cerebellopontine angle, and the upper fourth ventricle. Preoperative analysis and prediction of the venous architecture around the HF can enhance the safety and efficiency of the surgery.

Objective: Endoscopic endonasal surgery (EES) for deep intracranial lesions has gained popularity following recent developments in endoscopic technology. The operability of invasive pituitary neuroendocrine tumors (PitNETs) depends on the anatomy of the nasal cavity and paranasal sinus. This study aimed to establish a simple volume reconstruction algorithm of the nasal cavity and paranasal sinus. Additionally, this is the first study to demonstrate the relationship between the segmentation method and the clinical significance in patients with PitNET. Methods: Pre-and postoperative tumor volumes were analyzed in 106 patients with primary (new-onset) PitNETs (80 nonfunctioning and 26 functioning) who underwent EES. The efficiency and accuracy of the semiautomatic segmentation with manual adjustments (SSMA) method was compared with other established segmentation methods for volumetric analysis in the nasal cavity and paranasal sinuses. Correlations between the measured nasal cavity and paranasal sinus volumes and the extent of tumor removal were evaluated. Results: The SSMA method yielded accurate and time-saving results following the volumetric analyses of nasal cavity and paranasal sinuses with complex structures. Alternatively, the manual and semiautomatic segmentation methods proved time-consuming and inaccurate, respectively. The sphenoid sinus volume measured by SSMA was significantly correlated with the extent of tumor removal in patients with nonfunctioning Knosp grade 3 and 4 PitNET (r = 0.318; p = 0.015). Conclusion: The volume of sphenoid sinus potentially could predict the extent of resection due to better visualization of the tumor for PitNETs with CS invasion.

Background: A combined transpetrosal approach (CTP) is often used for large lesions in the posterior cranial fossa (PCF). Although CTP provides a wide surgical corridor, it has complex and time-consuming bony work of mastoidectomy and cosmetic issues. Here, we describe a simple combined surgical technique to approach the supratentorial region, anterolateral surface of the brainstem, petroclival region, and foramen magnum by drilling only the petrous apex with a combination of retrosigmoid approach (RA). Clinical presentation: A 27-year-old female was referred with extra-axial left cerebellopontine angle space-occupying epidermoid cyst extending to the prepontine cistern, anterior to the basilar artery, superior to the chiasma, and caudally to the foramen magnum. A one-stage surgical procedure using the anterior transpetrosal approach (ATP) and RA was performed after one-piece temporal-suboccipital craniotomy. These two approaches complemented each other well. Near-total removal was achieved. Conclusion: A one-stage surgical procedure using ATP and RA provides the wider viewing and better visualization of the PCF with minimal technical difficulty.

The original version of this Article omitted from the author list the 10th author Tetsuro Hikichi, who is from OncoTherapy Science, Inc., 3-2-1, Sakado, Takatsu-ku, Kawasaki City, Kanagawa, 213-0012, Japan. This author has been added to the article. Consequently, the 5th sentence in the Authors Contributions has been modified to read “RT, MF, YM, KO, KK, YO, MS, NO, HF, TH, and SN collected the data”. Additionally, the following was added to the Competing Interests: TH is an employee of OncoTherapy Science, Inc. This has been corrected in both the PDF and HTML versions of the Article.

© Shibao et al. Object: Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. Methods: Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T-lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. Results: This treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. Conclusion: These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.

AbstractAlthough endoscopic skull-base reconstruction protocols to reduce cerebrospinal fluid (CSF) leakage are reported, the most effective management strategies have not been determined. We describe the successful repair of a spontaneous CSF leak using a vascularized middle turbinate flap (MTF) via an endonasal endoscopic approach and also discuss the effective reconstruction with other available pedicled flaps. An 11-year-old girl had a 5-month history of intermittent CSF rhinorrhea. Endoscopic endonasal skull base reconstruction was performed using the pedicled MTF technique, which sufficiently covered the unilateral cribriform plate and ethmoidal fovea including suspicious leakage site. Middle turbinate flaps may be good for repairing spontaneous CSF leaks, which commonly have small, low-flow CSF fistulas around a cribriform plate. As spontaneous CSF leaks are known to have a higher recurrence rate, MTF may be advantageous because more of the normal structures are retained.

Objective: We sought to elucidate the long-term surgical outcomes and incidence of recurrence and reoperation of endoscopic endonasal cyst fenestration for Rathke cleft cyst (RCC). Methods: A retrospective review of the chart and operation record of RCC surgical cases between January 2008 and August 2021 at our institution was conducted. Patient characteristics, intraoperative findings, and postoperative follow-up outcomes were evaluated. Results: A total of 27 patients were analyzed, with a median postoperative follow-up period of 52 months (range, 1–150 months). Preoperative symptoms were visual dysfunction (59%), headache (41%), and pituitary dysfunction (22%). Endoscopic cyst fenestration was performed in all patients. Ten (37%) patients had intraoperative cerebrospinal fluid leakage. Among them, the only patient in whom sellar floor reconstruction was not performed experienced a repair operation due to postoperative cerebrospinal fluid leakage. No patients experienced postoperative hypopituitarism. Preoperative headache, visual dysfunction, and pituitary hormone disorder improved in 73%, 75%, and 67% of patients, respectively. Although postoperative cyst regrowth was observed in 8 patients (30%), no patient experienced worsening or novel symptoms and none required reoperation. Conclusions: Patients with a symptomatic RCC can be effectively treated with endoscopic endonasal cyst fenestration. Reversal of the presenting symptoms resulted, including headache, visual dysfunction, and pituitary hormone dysfunction, in the majority of patients. In our series, appropriate reconstruction of the sellar floor reduced the risk of postoperative cerebrospinal fluid leakage without impacting cyst regrowth. This simple technique appears to effectively disrupt cyst progression in most cases, even after a relatively long-term follow-up period.