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To evaluate the pathomechanism of the recurrence of intracranial germinoma after complete response and to confirm the association of the initial magnetic resonance imaging and therapeutic factors with recurrence.This study included patients who were followed up for ≥5 years and who were treated in our hospital from 1980 to 2021. Those with germinoma and germinoma with syncytiotrophoblastic giant cells were diagnosed pathologically. Data were categorizedbased on "gender," "single region," "intraventricular dissemination at the initial diagnosis," "hydrocephalus," "types of radiation therapy (RT)," and "chemotherapy." Fisher's exact probability test was used to assess differences between the no recurrence and recurrence groups.Among 43 patients, 34 had no recurrence, 5 had delayed recurrence (≥60 months), and 4 had early recurrence (60 months). Follow-up periods were 143.5 (60-380), 198 (88-222), and 132.5 (75-291) months for the no recurrence, delayed recurrence, and early recurrence groups, respectively. Five patients with delayed recurrence showed 3 intracranial lesions and 2 spinal lesions. Four patients with early recurrence showed 3 intracranial lesions and 1 spinal lesion. Differences in delayed recurrences (focal RT vs. RT including whole-ventricle system; P = 0.0491) were significant in Fisher's exact test.RT including the whole-ventricle system reduces delayed craniospinal relapses including dissemination, local, and distant recurrences even ≥5 years after complete response in patients with primary central nervous system germinoma.

Objective To investigate differences in uptake regions between methyl-11C-L-methionine positron emission tomography (11C-MET PET) and gadolinium (Gd)-enhanced MRI, and to examine the effects on dose distribution of changing the threshold value for definition of tumor boundaries.Methods Twenty consecutive patients with grade 3 or 4 glioma who had recurrence after postoperative RT between April 2016 and October 2017 were examined in the study. This study is simulation study assuming all patients received RT. Clinical target volume (CTV) was contoured using the Gd-enhanced region (CTV-Gd), T2-high region (CTV-T2), tumor/normal tissue (T/N) ratios of 11C-MET PET of 1.3 and 2.0 (CTV (T/N 1.3), CTV (T/N 2.0)), and the PET-edge method (CTV(P-E)) for stereotactic radiotherapy planning for recurrent malignant glioma after radiotherapy. Differences among CTVs were evaluated and the dose distribution for the normal brain was simulated for each CTV.Results The Jaccard index (JI) for concordance of CTV (Gd) with CTVs using 11C-MET PET was highest for CTV (T/N 2.0), with a value of 0.7. In a comparison of pixel values of MRI and PET, the correlation coefficient for cases with higher JI was significantly greater than that for lower JI cases (0.37 vs. 0.20, P = 0.007). D50% and D33% of the brain in radiotherapy planning using each CTV differed significantly (P = 0.03, P = 0.02) and those using CTV (T/N 1.3) were higher than with use of CTV (Gd). V90% and V95% for each CTV differed in a simulation study for actual treatment using CTV (Gd) (P = 1.0×10− 7, P = 3.0×10− 9) and those using CTV (T/N 1.3) and CTV (P-E) were lower than with CTV (Gd). Comparing with CTV (T2), the JI showed no significant difference with any CTV using PET. D50% and D33% of the brain were significantly higher than any CTV using PET.Conclusions The region of 11C-MET accumulation is not necessarily similar to the Gd-enhanced or T2 high region. A change of the tumor boundary using 11C-MET PET can cause significant changes in doses to the brain and the CTV.

Objective To evaluate the gustatory function before and after vestibular schwannoma (VS) surgery. Methods In this retrospective study, we evaluated the gustatory function of 12 patients who underwent VS surgery at Tsukuba University Hospital between 2012 and 2018. Gustatory function was examined using electrogustometry before VS surgery and 3 months, 6 months and 1 year after surgery. Electrogustometry was tested at the area mapped to the chorda tympani nerve, glossopharyngeal nerve and greater superficial petrosal nerve (GSPN). Intergroup mean comparisons of the threshold were performed using a one-way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test. Results The gustatory function mapped to the chorda tympani nerve was significantly disturbed 6 months after the surgery as compared with the preoperative function (p = 0.033) and that the dysfunction recovered at 1 year. However, gustatory function mapped to the glossopharyngeal nerve and greater superficial petrosal nerve (GSPN) was not impaired. Conclusion The gustatory function mapped to the chorda tympani nerve is impaired after surgery for VS. The dysfunction peaked at 6 months after surgery, and recovered within 1 year.

Non-vestibular schwannomas (NVSs) of the skull base occur in several sites, and few previous studies have evaluated the usefulness of the endoscopic endonasal transmaxillary-pterygoid approach (EETMPA) to resect these lesions. We aimed to evaluate the characteristics and clinical outcomes of patients who underwent EETMPA for skull-base NVSs and to investigate the efficacy, safety, and indications for the procedure. We retrospectively reviewed the clinical data of 10 consecutive patients (mean age, 45 ± 17) who underwent EETMPA for skull-base NVSs at the University of Tsukuba hospital between 2013 and 2020. We also calculated the total tumor volume and the size of the corridor to the tumor for EEA (SCEEA) in nine patients who underwent EEA for NVSs adjacent to the Meckel’s cave or cavernous sinus. Nine patients (9/10), including five women (5/10), underwent primary surgery. Gross total resection and subtotal resection were achieved in five patients each (5/10). Postoperatively, one patient showed a new and mild cranial nerve V sensory deficit and one patient showed slight worsening of abducens nerve palsy. The greater palatine nerve was amputated in two patients; however, permanent perception loss in the soft palate was observed in one patient. The Vidian nerve was sacrificed in four patients, and new dry eye occurred in one patient. None of the patients experienced postoperative tumor recurrence or regrowth during the follow-up period of 40 ± 28 months. EETMPA is safe and effective for excising skull-base NVSs which are not eligible for radiosurgery leading to a high rate of successful resection and a high rate of but mild neurological sequela. The EEA is appropriate when the tumor extends to the paranasal sinus with sufficient SCEEA.

INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

Background Expansion of preoperative edema (PE) is an independent poor prognostic factor in high-grade gliomas. Evaluation of PE provides important information that can be readily obtained from magnetic resonance imaging (MRI), but there are few reports on factors associated with PE. The goal of this study was to identify factors contributing to PE in Grade 3 (G3) and Grade 4 (G4) gliomas. Methodology PE was measured in 141 pathologically proven G3 and G4 gliomas, and factors with a potential relationship with PE were examined in univariate and multivariate analyses. The following eight explanatory variables were used: age, sex, Karnofsky performance status (KPS), location of the glioma, tumor diameter, pathological grade, isocitrate dehydrogenase (IDH)-1-R132H status, and Ki-67 index. Overall survival (OS) and progression-free survival (PFS) were calculated in groups divided by PE (1 vs. ≥1 cm) and by factors with a significant correlation with PE in multivariate analysis. Results In univariate analysis, age (p = 0.013), KPS (p = 0.012), pathology grade (p = 0.004), and IDH1-R132H status (p = 0.0003) were significantly correlated with PE. In multivariate analysis, only IDH1-R132H status showed a significant correlation (p = 0.036), with a regression coefficient of -0.42. The median follow-up period in survivors was 38.9 months (range: 1.2-131.7 months). The one-, two-, and three-year OS rates for PE1 vs. ≥1 cm were 77% vs. 68%, 67% vs. 44%, and 63% vs. 24% (p = 0.0001), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 67%, 85% vs. 40%, and 81% vs. 21% (p0.0001), respectively. The one-, two-, and three-year PFS rates for PE1 vs. ≥1 cm were 77% vs. 49%, 64% vs. 24%, and 50% vs. 18% (p = 0.0002), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 48%, 77% vs. 23%, and 73% vs. 14% (p0.0001), respectively. Conclusions IDH1-R132H status was found to be a significant contributor to PE. Cases with PE1 cm and those with the IDH1-R132H mutation clearly had a better prognosis.

Background: Recent studies have revealed that bevacizumab (BEV) can improve the survival of patients with newly diagnosed unresectable glioblastoma (GBM) with poor performance status. For patients who develop early clinical deterioration, early initiation of BEV would be beneficial. However, the safety and feasibility of early initiation of BEV remain to be determined because of the lack of studies addressing adverse events associated with BEV initiation Methods: Thirty-one consecutive patients with newly diagnosed GBM who underwent biopsy followed by BEV administration were investigated. The relationships between the timing of BEV administration and treatment response, survival outcome, and adverse events were analyzed. Results: Response rates based on the RANO criteria and overall survival times were similar between the early and standard BEV groups. No wound dehiscence was observed in the early BEV group, and only one case was observed in the standard BEV group. Patients in the early BEV group were more likely to have undergone biopsy with a smaller skin incision than those in the standard BEV group. Equivalent treatment effects of BEV were achieved in patients who developed early clinical deterioration and those without clinical deterioration. Conclusion: Early BEV administration is effective in controlling early clinical deterioration and does not increase the risk of wound-healing complications. Further studies with larger numbers of patients are needed to validate our results.

BackgroundGlioblastoma peritumoral edema (PE) extent is associated with survival and progression pattern after tumor resection and radiotherapy (RT). To increase tumor control, proton beam was adopted to give high-dose boost (> 90 Gy). However, the correlation between PE extent and prognosis of glioblastoma after postoperative high-dose proton boost (HDPB) therapy stays unknown. We intend to utilize the PE status to classify the survival and progression patterns.MethodsPatients receiving HDPB (96.6 GyE) were retrospectively evaluated. Limited peritumoral edema (LPE) was defined as PE extent 1 cm from the tumor bed edge.ResultsAfter long-term follow-up (median 88.7, range 63.6–113.8 months) for surviving patients with (n = 13) and without (n = 32) LPE, the median overall survival (OS) and progression-free survival (PFS) were 77.2 vs. 16.7 months (p = 0.004) and 13.6 vs. 8.6 months (p = 0.02), respectively. In multivariate analyses combined with factors of performance, age, tumor maximum diameter, and tumor resection extent, LPE remained a significant factor for favorable OS and PFS. The rates of 5-year complete response, EPD, and distant metastasis with and without LPE were 38.5% vs. 3.2% (p = 0.005), 7.7% vs. 40.6% (p = 0.04), and 0% vs. 34.4% (p = 0.02), respectively.ConclusionsThe LPE status effectively identified patients with relative long-term control and specific progression patterns after postoperative HDPB for glioblastoma.

Background Patients with neurohypophyseal germ cell tumors (GCTs) typically present with visual problems. Hence, this study aimed to assess optic pathway involvement based on clinical and radiological findings and to validate the outcome of visual function. Methods A total of 16 patients with newly diagnosed neurohypophyseal GCTs who were treated at the University of Tsukuba Hospital between 2000 and 2020 were included in this study. Results The median interval from symptom onset to diagnosis was 173.5 days (range, 33-1588 days). Patients with visual disturbance at diagnosis had a longer time to diagnosis compared with those without. Ophthalmologic abnormalities were frequently observed, with an incidence rate of 69%. Fifty percent of patients exhibited optic pathway involvement detected via magnetic resonance imaging (MRI). Visual impairment was more severe in the patients with optic pathway involvement (p = 0.002). Post-treatment visual impairment was improved but was still significantly severe in patients with optic pathway involvement than in those without involvement (p = 0.010). Visual field deficit more likely remained with an improvement rate of 50%, whereas the improvement rate of visual acuity was 78%. Further, none developed late-onset visual deterioration during the follow-up period. Conclusions Visual disturbance and optic pathway involvement are common in neurohypophyseal GCTs. Visual impairment particularly in patients with optic pathway involvement on MRI is more likely to remain at follow-up, although the outcome of visual function is acceptable in most cases.

Background Brain tumor patients tend to develop postoperative epileptic seizures, which can lead to an unfavorable outcome. Although the incidence of postoperative epileptic seizures and adverse events are improved with the advent of levetiracetam (LEV), postoperative epilepsy occurs at a frequency of 4.6% or higher. In brain tumor patients, the addition of sodium channel blockers (SCBs) to LEV significantly reduces seizures, though confirmed in a non-postoperative study. Thus, the combination of SCBs with LEV might be promising. Objective In this prospective randomized controlled trial we investigated the safety, evaluated by adverse events during one and two weeks after surgery, and the efficacy, evaluated by the incidence of early epilepsy, including non-convulsive status epilepticus (NCSE), of using LEV alone or SCBs added to LEV in patients who underwent craniotomy or biopsy for brain tumors or brain mass lesions. Methods Patients with brain tumors or brain mass lesions undergoing surgical interventions, excluding endoscopic endonasal surgery (EES), with a diagnosis of epilepsy were eligible for this study. Patients are randomized into either Group A or B (B1 or B2) after the informed consents are taken; LEV alone in Group A patients, while LEV and SCBs in Group B patients (GroupB1, intravenous fosphenytoin plus oral lacosamide (LCM) and GroupB2, intravenous LCM plus oral LCM) were administered postoperatively. Fifty-three patients were enrolled during the first two and a half years of the study and four of them were excluded, resulting in the accumulation of 49 patients' data. Results Postoperative epileptic seizures occurred only in three out of 49 patients during the first week (6.1%) and in seven patients within two weeks after surgery (14.3%, including the three patients during the first week). In Group A, epileptic seizures occurred in two out of 26 patients during the first week (7.7%) and in five patients within two weeks (19.2%) after surgery. In Group B, epileptic seizures occurred in one out of 23 patients during the first week (4.3%) and in two patients during the first two weeks (8.7%). Low complication grade of epileptic seizures was observed in Group B rather than in Group A, however, without significant difference (p=0.256). There was no difference in the frequency of adverse effects in each group. Conclusion Although not statistically significant, the incidence of epileptic seizures within one week after surgery was lesser in LEV+SCBs groups than in LEV alone. No hepatic damage or renal function worsening occurred with the addition of LCM, suggesting the safety of LEV+SCBs therapy.

The programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) pathway is involved in preventing immune system‐mediated destruction of malignant tumors including glioblastoma. However, the therapeutic influence of PD‐1/PD‐L1 inhibition alone in glioblastoma is limited. To develop effective combination therapy involving PD‐1/PD‐L1 inhibition, we used a non‐replicating virus‐derived vector, hemagglutinating virus of Japan‐envelope (HVJ‐E), to inhibit tumor cell PD‐L1 expression by delivering siRNA targeting PD‐L1. HVJ‐E is a promising vector for efficient delivery of enclosed substances to the target cells. Moreover, HVJ‐E provokes robust antitumoral immunity by activating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and by suppressing regulatory T lymphocytes (Treg). We hypothesized that we could efficiently deliver PD‐L1‐inhibiting siRNAs to tumor cells using HVJ‐E, and that synergistic activation of antitumoral immunity would occur due to the immunostimulating effects of HVJ‐E and PD‐1/PD‐L1 inhibition. We used artificially induced murine glioma stem‐like cells, TS, to create mouse (C57BL/6N) glioblastoma models. Intratumoral injection of HVJ‐E containing siRNA targeting PD‐L1 (siPDL1/HVJ‐E) suppressed the expression of tumor cell PD‐L1 and significantly suppressed tumor growth in subcutaneous models and prolonged overall survival in brain tumor models. Flow cytometric analyses of brain tumor models showed that the proportions of brain‐infiltrating CTL and NK cells were significantly increased after giving siPDL1/HVJ‐E; in contrast, the rate of Treg/CD4+ cells was significantly decreased in HVJ‐E‐treated tumors. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ‐E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non‐replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma., HVJ‐E containing PD‐L1 siRNA significantly prolonged overall survival in mouse brain glioblastoma models. The therapeutic performance was mediated by antitumor immune responses via increased proportions of brain‐infiltrating CTL and a decreased rate of Treg among CD4+ T cells. This non‐replicating immunovirotherapy appears to show great promise as an attractive novel alternative to treat patients with glioblastoma.

Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.

Background Pediatric meningiomas account for less than 2% of pediatric brain tumors. Pediatric clear cell meningiomas (CCMs) occurring in the posterior fossa are particularly rare. Therapeutic strategies differ among the previous pediatric CCM case reports. Therefore, to clarify the clinical features of pediatric CCMs, we report a rare case of dumbbell-type pediatric CCM and a corresponding literature review. Case Description A 7-year-old boy with complaints of headache, left facial palsy, dysarthria, and left-sided ataxic gait was emergently admitted to our hospital. His consciousness level was slight stupor, with Glasgow Coma Scale score 3-5-6, and he showed left ptosis, dysarthria, and ataxias of the left trunk and extremities. Magnetic resonance imaging (MRI) scan showed acute obstructive hydrocephalus because of the tumor's compression of the brainstem. The dumbbell-shaped tumor extended from the lateral wall of the cavernous sinus, through the left Meckel's cave, to the cerebellopontine angle. Physical examination and perioperative MRI scan showed no evidence regarding neurofibromatosis type I or II. The tumor was removed in a 2-staged operation. Postoperative proton therapy was done to treat some residual tumors. One year after postoperative proton therapy, there is no recurrence, and apart from left corneal and facial hypesthesia, he is healthy. Conclusions We reported a rare case of pediatric skull base–type CCM with huge extension originating from the anteromedial wall of Meckel's cave firmly adhered to the cavernous sinus wall to the posterior fossa that was successfully treated with surgery and postoperative proton therapy. CCM has a high recurrence rate; therefore, careful prolonged follow-up is needed.

Although chemoimmunotherapy often lengthens glioblastoma (GBM) survival, early relapses remain problematic as immunosuppressive M2 macrophages (Mϕ) that function via inhibitory cytokine and PD-L1 production cause immunotherapy resistance. Here, we detail anti-PD-L1 antibody effects on the tumor microenvironment, including Mϕ infiltration, using a temozolomide (TMZ)-treated glioma model. In addition, we tested combinations of anti-PD-L1 antibody and the M2Mϕ inhibitor IPI-549 on tumor growth. We simulated late TMZ treatment or relapse stage, persistent GBM cells by generating TMZ-resistant TS (TMZRTS) cells. M2Mϕ-associated cytokine production and PD-L1 expression in these cells were investigated. TMZRTS cells were then subcutaneously implanted into C57BL/6 mice to determine the effectiveness of an anti-PD-L1 antibody and/or IPI-549 treatment on infiltration of CD163-positive Mϕ, usually considered as an M2Mϕ marker into tumor tissues. CD163 expression in samples from human GBM patients were also evaluated. CD163-positive Mϕ heavily infiltrated TMZRS tumor tissues after in vivo anti-PD-L1 antibody treatment. Tumor growth was strongly inhibited by anti-PD-L1 antibody and IPI-549 combination therapy. Anti-PD-L1 antibody treatment significantly reduced infiltration of CD163-positive Mϕ into tumors, while combined PD-L1 antibody and IPI-549 therapy remarkably inhibited tumor growth. These therapies may be useful for recurrent or chronic GBM after TMZ treatment, but clinical safety and effectiveness studies are needed.

The detailed epidemiology and mechanism of post-craniotomy headaches are not well understood. This study aimed to establish the actual clinical incidence and causes of post-craniotomy headaches. Suboccipital craniotomy surgeries performed in six institutions within the five-year study period were included. This study included 311 patients (138 males, 173 female; mean age, 59.3 years old). A total of 145 patients (49%) experienced post-craniotomy headaches. Microvascular decompression surgery, craniectomy and facial spasms were significant risk factors for post-craniotomy headaches. In most cases, the post-craniotomy headaches disappeared within one month; however, some patients suffered from long-term headaches. The craniotomy site and the methods of dura and skull closures should be individually determined for each patient. However, to prevent post-craniotomy headaches, craniotomy, instead of craniectomy, may be considered.

Background Germinoma preferentially occurs in pediatric and young adult age groups. Although they are responsive to treatment with chemotherapy and radiation, the treatment may cause long-term sequelae in their later lives. Here, we searched for clinical and histopathological features to predict the prognosis of germinoma and affect treatment response. Methods A total of 114 germinoma cases were included in the analysis. We investigated the association between clinical factors, tumor cell content, and progression-free survival (PFS). Results The tumor cell content was widely distributed from Conclusions We found that tumor cell content significantly affected the prognosis of germinomas. Although validation of these results using an independent and larger cohort is necessary, this potentially opens the possibility of leveraging this pathological factor in future clinical trials when stratifying the treatment intensity.

Background and objective Postoperative radiotherapy is usually indicated for both grade 3 glioma and grade 4 glioblastoma. However, the treatment results and tumor features of grade 3 glioma clearly differ from those of glioblastoma. There is limited information on outcomes and tumor progression for grade 3 glioma. In this study, we evaluate the result of postoperative radiotherapy for grade 3 glioma and focus on the correlation of MRI findings with prognosis. Methods In this study, 99 of 110 patients with grade 3 glioma who received postoperative radiotherapy and were followed up for more than one year were retrospectively analyzed. The total irradiation dose was 60.0 Gy in 30 fractions, and daily temozolomide or two cycles of nimustine (ACNU) was concurrently administered during radiotherapy. The median follow-up period was 46 months (range: 2-151 months). Results In multivariate analysis, pathology [anaplastic oligodendroglioma (AO) vs. anaplastic astrocytoma (AA)], the status of surgical resection (biopsy vs. partial resection or more), and contrast enhancement (enhanced by MRI image or not) were significant factors for overall survival (OS). The five-year OS for AO vs. AA cases were 76.8% vs. 46.1%, total to partial resection vs. biopsy cases were 72.7% vs. 21.0%, and non-enhanced vs. enhanced cases were 82.5% vs. 45.6%, respectively. In multivariate analysis, the status of surgical resection and longer extension of preoperative edema (PE) were significant factors for progression-free survival (PFS). The five-year PFS for the total to partial resection vs. biopsy cases were 52.9% vs. 10.7%, and non-extensive PE vs. extensive PE (EPE) cases were 62.2% vs. 19.1%, respectively. Conclusion Our results suggest that a contrast-enhanced tumor on MRI and a longer PE may also be significantly associated with OS and PFS among grade 3 glioma patients.

Aims Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. Methods We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. Results Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). Conclusions The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Background Schwannoma originating from the greater superficial petrosal nerve is an extremely rare type of facial nerve schwannoma located in the middle cranial fossa around the midportion of the petrous bone. Here, we provide the first report of greater superficial petrosal nerve schwannoma presenting with contralateral facial palsy and hemiparesis due to compression of the pyramidal tract by associated intradural peritumoral cyst. Case Description A 69-year-old woman presented with a 6-month history of gradually worsening gait unsteadiness. Magnetic resonance imaging demonstrated a well-defined tumor occupying the right middle cranial fossa and extending into the tympanic cavity. Notably, the tumor accompanied a large cyst in the intradural space, resulting in a leftward midline shift. Extradural exploration through thinned periosteal dura mater revealed the tumor within the interdural space. After debulking of most of the tumor in a pull-out, piecemeal fashion, intradural exploration revealed the peritumoral cyst located between the meningeal dura mater and brain parenchyma. Following the disappearance of the mass effect from the tumor, fenestration of the peritumoral cyst, which had been deeper-seated than the tumor, was easily achieved while avoiding excessive retraction of the temporal lobe. Postoperatively, mild left hemiparesis involving the face resolved completely and no new symptoms such as right facial palsy, hearing disturbance, or xerophthalmia developed as postoperative complications. Conclusion The combination of extradural and intradural approaches in the appropriate order is essential for fenestration of an intradural peritumoral cyst along with removal of an interdural tumor.

Background: Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification.Methods: A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated. Results: The tumor cell content was widely distributed from =50%) showed shorter PFS than those with a lower tumor cell content (

The authors describe a usual case of infiltrative low-grade glial neoplasm with a marked enhanced area which is difficult to diagnose. A 42-year-old man had the diffuse mass lesion partially with apparent enhancement in the right temporal lobe, the insular, and the basal ganglia regions. Final pathological diagnosis from the removed specimens was IDH-wildtype diffuse astrocytoma according to 2016 WHO classification, although it had unusual findings including gliomesenchymal reaction. The nodule-like enhancement was thought to be owing to the mesenchymal component. Several molecular analysis including pyrosequence analysis, Ion Torrent™ next-generation sequencing and multiplex ligation-dependent probe amplification analysis detected no genomic abnormality. IDH-wildtype diffuse astrocytoma is a heterogeneous category and has a minor subset with a silent genomic landscape like the present case.

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-021-02318-1.

Purpose. Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. This retrospective study analyzed the prognostic factors of initially diagnosed glioblastoma patients at our institution to analyze the effect of these methods on prognosis. Methods. Two hundred seventy-seven patients with initially diagnosed glioblastoma who were treated in our institution from 2009 to 2020. Various data, including extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. Results. The median OS of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases were 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative MRI use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and combination of immunotherapies including autologous formalin-fixed tumor vaccine were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS% values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. Conclusion. GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

Background: We report a case of a giant pituitary adenoma with marked extension into the third ventricle that was successfully removed using combined simultaneous endoscopic endonasal surgery (EES) and microscopic transventricular port surgery. Case Description: A 47-year-old woman, who complained of memory disturbance, had a giant pituitary adenoma with marked extension into the third ventricle that was causing obstructive hydrocephalus. She underwent combined EES and microscopic transventricular surgery using a port retractor system. Most of the tumor was resected from the EES side with assistance from the transcranial side with minimum cortical trajectory damage. The tumor was completely excised without any complications. Conclusion: For giant pituitary adenoma with marked extension into the third ventricle, combined simultaneous EES and transventricular surgery using a port retractor system is effective to maximize the extent of tumor resection while also preventing complications. Using port surgery on the transcranial side, microscopic secure dissection is possible with minimum additional cortical damage.

Background Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion? Methods Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI). Results A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI. Conclusion CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.

Background The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. Methods A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Results Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. Conclusion All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

Background: Neurovascular compression is an extremely rare etiology of isolated abducens nerve palsy. We describe a successfully treated case of isolated abducens nerve palsy due to sandwich-type compression by the vertebral artery (VA) and anterior inferior cerebellar artery (AICA). Case Description: A 30-year-old man presented with a 6-month history of horizontal diplopia without other symptoms. Magnetic resonance imaging (MRI) demonstrated pinching of the left abducens nerve between the elongated left VA and left AICA. MRI showed no abnormal findings in the brainstem, cavernous sinus, or orbit. Surgery was performed using a standard lateral suboccipital approach. The abducens nerve was found to be severely compressed from both sides by the VA and AICA, with marked indentation. First, the VA was transposed and fixed to the dura mater of the petrous bone using a Teflon sling with the dripping of fibrin glue. Next, because of limited mobilization due to penetration of the AICA into the nerve, the AICA transfixing the nerve was attached to the pons with Teflon felt and fibrin glue to move the AICA away from the main trunk of the abducens nerve. The abducens nerve palsy gradually improved and eventually resolved by 4 months after the operation. Conclusion: When an elongated vertebrobasilar artery is identified as the offending vessel on high-resolution MRI, microvascular decompression can be carefully considered as a treatment option for patients with isolated abducens nerve palsy.

Lateral skull base meningiomas, particularly sphenoorbital meningiomas, sometimes extend extremely widely into adjacent structures including the paranasal sinuses. For endonasal skull base reconstruction using a vascularized nasoseptal flap for prevention of postoperative cerebrospinal fluid (CSF) leak, the simultaneous combined transcranial and endoscopic endonasal approach was applied for resection of these extensive tumors. We performed a retrospective review of four patients treated with the simultaneous combined transcranial and endoscopic endonasal approach for resection of lateral skull base meningiomas. Preoperative characteristics, tumor extent, extent of resection, complications, and postoperative outcomes were analyzed. The tumor extended into the paranasal sinus, infratemporal fossa, and pterygopalatine fossa in all patients. Extracranial extension into the cavernous sinus or superior orbital fissure was detected in two and three patients, respectively. In one patient without extension into the cavernous sinus and superior orbital fissure, gross total resection was achieved, whereas in the other three patients, subtotal resection was performed, and small residual masses of the tumor remained in the cavernous sinus or superior orbital fissure to minimize the risk of postoperative ocular nerve damage. No patients experienced postoperative CSF leak. The simultaneous combined transcranial and endoscopic endonasal approach is useful for a subgroup of patients with lateral skull base meningiomas for prevention of postoperative CSF leak. Particularly in recurrent cases in which vascularized flaps from the transcranial side are likely unavailable due to prior tumor resection, this combined approach is worth considering depending on tumor extension into the paranasal sinus.

Despite cumulative evidence supporting the idea that gross total resection (GTR) contributes to prolonged survival of patients with glioblastoma (GBM), the survival outcome of such patients remains unsatisfactory. To develop more effective postoperative therapeutic strategies for patients who underwent GTR, identification of prognostic factors influencing survival is urgently needed. Here we retrospectively analyzed prognostic factors for patients who underwent GTR of newly diagnosed GBM, with a particular focus on the influence of the subventricular zone (SVZ) as the tumor location. Forty-eight consecutive patients with newly diagnosed GBM who underwent GTR during the initial operation were investigated. Tumor involvement of the SVZ was significantly associated with overall survival (OS). The SVZ-positive group had a significantly shorter median OS of 12.2 months, compared to 34.9 months for the SVZ-negative group. The occurrence of leptomeningeal dissemination was significantly influenced by tumor involvement of the SVZ, but was not significantly influenced by ventricular opening during surgery. We observed a statistically significant difference in OS according to radiation modality. The median OS was 36.9 months for patients treated with high-dose proton beam therapy, compared with 26.2 months for patients treated with conventional radiotherapy. We demonstrated that tumor involvement of the SVZ was associated with poor survival of patients who underwent GTR of newly diagnosed GBM, suggesting the potential need for therapeutic strategies that specifically target tumors in the SVZ. Further prospective studies to evaluate whether radiotherapy targeting the SVZ improves survival of patients with tumor involvement of the SVZ who had undergone GTR are warranted.

Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with 89Zr-Df-IAB2M (anti-PSMA minibody). Eighty-three tissue specimens including gliomas, metastatic brain tumors, primary central nervous system lymphomas (PCNSL), or radiation necroses were analyzed by immunohistochemical staining with PSMA antibody. 89Zr-Df-IAB2M PET scans were performed in three patients with recurrent high-grade gliomas or metastatic brain tumor. PSMA was highly expressed in the vascular endothelium of high-grade glioma and metastatic brain tumor, whereas PSMA was poorly expressed in the vascular endothelium of PCNSL and radiation necrosis. PSMA expression in high-grade gliomas and a metastatic brain tumor was clearly visualized by PET imaging with 89Zr-Df-IAB2M. Furthermore, a trend toward a positive correlation between the degree of 89Zr-Df-IAB2M uptake and PSMA expression levels in tumor specimens was observed. PET imaging of PSMA using 89Zr-Df-IAB2M may have potential value in the differential diagnosis of high-grade glioma from PCNSL or radiation necrosis as well as in the prediction of treatment efficacy and assessment of treatment response to bevacizumab therapy for high-grade glioma.

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an inflammatory central nervous system disorder that gives rise to brainstem symptoms such as diplopia and articulatory disorders. It shows characteristic "salt-and-pepper" enhancing brainstem lesions on magnetic resonance imaging (MRI) scans. We present an unusual case of CLIPPERS, in which a 29-year-old man initially presented with a seizure. Brain MRI revealed faint open-ring enhancements in the right frontal lobe, and a brain biopsy was performed to make a definitive diagnosis. Immunohistological tests showed perivascular infiltration by primarily CD3- and CD20-positive cells, albeit including a few CD68-positive cells, which confirmed a diagnosis of CLIPPERS. Both the symptoms and the MRI findings were markedly improved by 3 courses of steroid (methylprednisolone) pulse therapy, followed by oral steroid (prednisolone) administration. This case shows that CLIPPERS can present as a phenotype of cortical lesions and seizures as the first signs. A brain biopsy should therefore be actively carried out for differential diagnosis, especially when other, cortically based inflammatory disorders are suspected.