Search

Gliomas are characterized by immunosuppressive features. Programmed death-ligand 1 (PD-L1) is overexpressed and plays an important role in the immunosuppressive tumor microenvironments of gliomas. However, the radiographical and prognostic significance of PD-L1 expression remains unclear.Using tissue microarrays, we evaluated PD-L1 expression and the presence of tumor-infiltrating CD4+ and CD8+T cells and CD204+macrophages using immunohistochemical analysis. Contrast enhancement area and fluid-attenuated inversion recovery (FLAIR) hyperintensity area were evaluated by two-dimensional analysis. Kaplan-Meier analysis was performed to evaluate the overall survival time in 44 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma.We evaluated 71 patients with newly diagnosed high-grade gliomas who were treated between October 1998 and April 2012. PD-L1 expression was observed in 15 patients (21.1%). A significant association of PD-L1 expression with the CD4+ and CD8+ T cell densities, but not with CD204+ macrophage densities, was observed (p = 0.025, p = 0.0098, and p = 0.19, respectively). The FLAIR-to-enhancement ratio was significantly higher in PD-L1+ tumors than in PD-L1- tumors (p = 0.0037). PD-L1 expression did not show a significant association with the median survival time (PD-L1 + vs. PD-L1-: 19.2 vs 14.9 months; p = 0.39).PD-L1 expression was associated with CD4+ and CD8+ T cell infiltration, indicating a significant interplay between PD-L1 and immune cells. The positive correlation of PD-L1 expression with an increased FLAIR-to-enhancement ratio suggested that radiographical characteristics could reflect the immunological status. Our results did not support the prognostic impact of PD-L1 in patients with IDH-wildtype glioblastomas.

Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear.To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM.Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined.Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores 90 was 48.6% and 29.6% in the early and late diagnosis groups ( P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated).Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM.

The treatment of cancer-associated stroke is determined based on stroke etiology; however, the optimal treatment and therapeutic benefits remain unclear. We aimed to evaluate the clinical and functional outcomes of patients with cancer and acute ischemic stroke, especially focusing on patients with cryptogenic stroke. We retrospectively reviewed consecutive cancer patients diagnosed with acute ischemic stroke at our institution between January 2018 and December 2019. Stroke subtype, cancer treatment after stroke, modified Rankin Scale (mRS) scores before and at ischemic stroke, 3 months after ischemic stroke or last follow-up, and discharge destination were evaluated. We analyzed 48 cancer patients with acute ischemic stroke, including 24 with cryptogenic stroke and 24 with known stroke mechanisms. The median survival time of the patients was 62 days. Thirty-one patients (64.6%) discontinued cancer treatment after stroke. Forty patients (83.3%) and 37 (77.1%) were in poor functional states (defined as mRS score ≥ 3) at stroke onset and 3 months after stroke or last follow-up. Twenty-two patients (91.7%) with cryptogenic stroke discontinued cancer treatment after stroke, whereas 15 patients (62.5%) with known stroke mechanisms continued cancer treatment (p = 0.0004). Home or rehabilitation hospital discharge destinations were less frequently seen in patients with cryptogenic stroke (n = 7, 29.2%) than those with known stroke mechanisms (n = 15, 62.5%, p = 0.021). Stroke has a significant negative impact on patients’ functional states and cancer treatment strategy, leading to short survival times, especially in patients with cryptogenic stroke.

Purpose Although the usefulness of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI. Methods This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74–89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status. Results The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% Conclusion Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors.

Introduction: Basal cell carcinoma (BCC) is the most common malignant skin neoplasm with an increasing incidence worldwide. Its local destructive behavior can cause invasion to the deeper construction and reach the brain parenchyma. Case Report: A 62-year-old male presented with myiasis of the occipital part of the skull with a large skin defect. Brain images showed a mass lesion in the cerebellum. The histological diagnosis, by biopsy of the skin lesion, was BCC. Conclusion: Our case was an intradural infiltration of BCC, which was difficult to diagnose on initial presentation because the lesion was covered by myiasis. It is notable that neurosurgeons and oncologists should be aware of the natural history of BCC, since it could infiltrate into the brain, mimicking a case of intracranial tumor.

Purpose: The neurological status of glioblastoma (GBM) patients rapidly deteriorates. We recently demonstrated that early diagnosis and surgery within three weeks from the initial symptoms are associated with improved survival. While GBM is a semi-urgent disease, the prehospital behaviors and clinical outcomes of GBM patients are poorly understood. We aimed to disclose how prehospital patient behavior influences the clinical outcomes of GBM patients. Methods: IDH-wildtype GBM patients treated at our institution between January 2010 and December 2019 were reviewed. Patients were divided into two groups: neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Patient demographics and prognoses were examined. Results: Of 170 patients, 109 and 61 were classified into the neurosurgeon and non-neurosurgeon groups, respectively. The median age of neurosurgeon group was significantly younger than the non-neurosurgeon group (61 vs. 69 years old, P = 0.019) and in better performance status (preoperative KPS scores ≥ 80: 72.5% vs. 55.7%, P = 0.027). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P < 0.0001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P = 0.038). Conclusion: Seeking an initial evaluation by a neurosurgeon was associated with prolonged survival in GBM patients. A short duration from the first hospital visit to the first surgery is essential in enhancing GBM patient prognosis.

Purpose Gliomas are characterized by immunosuppressive features. Programmed death-ligand 1 (PD-L1) is overexpressed and plays an important role in the immunosuppressive tumor microenvironments of gliomas. However, the radiographical and prognostic significance of PD-L1 expression remain unclear. Methods Using tissue microarrays, we evaluated PD-L1 expression and the presence of tumor-infiltrating CD4 + and CD8 + T cells and CD204 + macrophages using immunohistochemical analysis. Contrast enhancement area and fluid-attenuated inversion recovery (FLAIR) hyperintensity area were evaluated by two-dimensional analysis. Kaplan–Meier analysis was performed to evaluate the overall survival time in 44 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma. Results We evaluated 71 patients with newly diagnosed high-grade gliomas who were treated between October 1998 and April 2012. PD-L1 expression was observed in 15 patients (21.1%). A significant association of PD-L1 expression with the CD4 + and CD8 + T cell densities, but not with CD204 + macrophage density, was observed (p = 0.025, p = 0.0098, and p = 0.19, respectively). The FLAIR-to-enhancement ratio was significantly higher in PD-L1 + tumors than in PD-L1- tumors (p = 0.0037). PD-L1 expression did not show a significant association with the median survival time (PD-L1 + vs. PD-L1-: 19.2 vs. 14.9 months; p = 0.39). Conclusion PD-L1 expression was associated with CD4 + and CD8 + T cell infiltration, indicating a significant interplay between PD-L1 and immune cells. The positive correlation of PD-L1 expression with an increased FLAIR-to-enhancement ratio suggested that radiographical characteristics could reflect the immunological status. Our results did not support the prognostic impact of PD-L1 in patients with IDH-wildtype glioblastomas.

Background/purpose Recent advances in cancer treatment provide surgical indication chances of metastatic brain tumors, and awake craniotomy for them is increasing. However, a small number of hospitals can perform awake craniotomy by limitation of hospital capacity. Here we show a single center retrospective analysis of awake craniotomy for metastatic brain tumor. Materials and Methods we analyzed consecutive 35 cases from January 2016 to January 2022 in our hospital. Rehabilitation staff evaluated them before surgery and after within a week. Result Patients characteristic were as follows. Mean and median age 57.0 (16-81) and median 62 respectively. Left side tumor were 31(88.6%). Frontal lobe was 26(74.3%), temporal lobe 5(14.3%), parietal lobe 3(8.6%), occipital lobe 1. Origin of cancer was lung 17(48.6%), gastrointestinal lesion 5(14.3%), breast 4(11.4%), soft tissues 3(8.6%), radiation necrosis 4(11.4%), uterus and malignant melanoma 1 respectively. KPS was 100-90 18(51.4%), KPS 80 6(8.6%) and KPS70 11(31.4%). Gross total removal was 30, partial removal was 5. MMSE of before and after surgery was mean 27.1 and median 29. Trail Making Test (TMT) of 24 cases test showed improvement in 11 (45.8%) cases. Median OS was 18.8 months (95%CI: 11.2-526). Discussion/conclusion We selected most awake craniotomy on left frontal lobe and each evaluating scales showed no deterioration. Awake craniotomy for metastatic brain tumor is effective procedure for saving function.

Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH-wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value.

PurposeWe aimed to explore the clinical impact of long-term maintenance temozolomide (TMZ) on glioblastoma (GBM) patient outcomes. MethodsWe included 41 patients with isocitrate dehydrogenase (IDH) 1/2-wildtype GBM, who completed 12 cycles of TMZ between June 2006 and December 2019. Associations between the Karnofsky performance status at 12 cycles (KPS at 12 cycles), residual tumor at 12 cycles, MGMT promoter methylation status, maintenance therapy regimen, or maintenance TMZ beyond 12 cycles and outcomes were assessed.ResultsThe median progression-free survival and median survival time were 25.0 and 45.1 months. Multivariate analysis based on KPS at 12 cycles, residual tumor at 12 cycles, maintenance therapy regimen, maintenance TMZ beyond 12 cycles, and the MGMT promoter methylation status revealed that KPS at 12 cycles ≥ 80 was significantly associated with increased survival after completing 12 cycles (p = 0.0007). The median survival time for 26 patients with KPS at 12 cycles ≥ 80 was significantly longer than that for 15 those with KPS at 12 cycles < 80 (89.3 months vs. 30.7 months: p < 0.0001). The 5-year survival rate for patients with KPS at 12 cycles ≥ 80 was 57.0%. The median survival after first progression was 11.9 months in 29 patients who had tumor progression.ConclusionsPatients who completed 12 cycles of TMZ with KPS at 12 cycles ≥ 80 had an extremely favorable OS, suggesting these patients could receive maximum benefits from prolonged TMZ. Long-term maintenance TMZ does not appear to negatively affect survival after tumor progression.

Athyrium yokoscense shows strong tolerance to cadmium exposure, even at levels that are many times greater than the toxic levels in ordinary plants. To determine the mechanism of Cd tolerance in A. yokoscense, we grew these plants under high Cd conditions and observed the tissue-specific accumulation of Cd and generation of reactive oxygen species, which is one of the major physiological responses to Cd stress. Fuchsin staining indicated the existence of a casparian strip in A. yokoscense roots, which may participate in Cd hypertolerance in A. yokoscense. Moreover, we performed RNA-seq of RNA samples from A. yokoscense plants treated with or without Cd exposure and obtained comprehensive RNA sequences as well as the Cd-responsive expression patterns of individual genes. Through de novo transcriptome assembly and gene expression analysis, we found that A. yokoscense showed normal features with no significant change in the expression levels of any transporter genes, even under high Cd exposure conditions. Our results demonstrate that A. yokoscense has an unusual mechanism that allows the invading Cd to partition into the distal roots, thus avoiding translocation of Cd into the xylem.

Intracranial growing teratoma syndrome (iGTS) is rare phenomenon which is observed in non-germinomatous germ cell tumor (NGGCT) after chemotherapy. The clinical features of iGTS are rapidly increasing in size compared with relapse, no elevation of tumor marker in spite of tumor regrowth, multiple cystic lesions in cranial imaging, and histopathologically diagnosed as mature teratoma. Here we present a 14-year-old man with iGTS which was revealed at 44 months after initial chemotherapy. He was diagnosed as pineal immature teratoma by histopathological specimen, and we performed chemotherapy and radiation therapy. After this treatment, we found growing cystic lesion in tumor removal cavity at 26 months after surgery. The histopathological findings showed dermoid cyst in first salvage surgery. Following this result, we observed him without adjuvant chemotherapy. However he had continuous headache, abnormal eye movement at 44 months after initial treatment. Cranial MRI showed regrowing cyst. In second salvage surgery, mature teratoma was demonstrated on histopathological specimen, and we diagnosed as iGTS. Although most reported iGTSs show rapid increasing after initial chemotherapy, few reported cases show regrowth at chronic phase as our case. In long-term follow-up of germ cell tumor, iGTS is important as differential diagnosis.

Background We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). Methods We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. Results The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9–30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. Conclusions RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.

Background Brain tumors are diagnosed based on pathological and genetic features defined by WHO classification. Although targeted gene panels are clinically available, most of them do not cover all the necessary genes for the diagnosis of brain tumors. Moreover, broad copy number analysis, which the current WHO classification requires, usually lacks in the gene panel. Another problem is that those panels demand a high burden of time and cost, which disturbs rapid diagnosis and broad application. To overcome those problems, we developed a rapid and cost-effective workflow of molecular diagnosis for brain tumors. Methods Our panel contains 109 genes of which 68 are necessary for fundamental molecular diagnosis and 41 are other common driver genes. To detect copy number changes and structural variants, which generate a fused gene, additional probes are placed on common SNPs and introns containing common breakpoints. MGMT methylation status is examined at the same time using bisulfite-converted DNA amplification. Sequencing data is analyzed using a supercomputer. Results The analysis time is within 4 days: 2 days for library preparation, 1 day for sequencing, and 12 hours for analysis. Detected driver alterations were validated by whole genome sequencing data. MGMT methylation status was correlated between the results of our workflow and pyrosequencing. Conclusions We have developed a rapid comprehensive molecular analysis workflow that detects genetic alterations and MGMT methylation. Our method allows a cost-effective molecular diagnosis with high accuracy, which would improve molecular diagnosis for brain tumors.

Background Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Here, we report the result of phase I part and the current status of phase II part. Patients and Methods Patients between 20 and 74 years of age with supratentorial GBM histologically diagnosed according to the World Health Organization 2016 classification were eligible. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. Results Between February 2021 and January 2022, the first three patients were treated with 1,500 mg/day MF and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. The median age of the patients was 41 years. Three tumors (42.9 %) were IDH1/2 mutants and 4 (57.1 %) were IDH1/2 wild-types. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2. Only one grade 3 seizure was reported, which was likely related to the tumor. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up. Conclusion MF dose of up to 2,250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to phase II study with 2,250 mg/day MF.

Introduction Glioma is a rare type of tumor, and the research on fatigue and QOL in glioma patients is limited. Research from other countries has reported patients with intense fatigue in the preoperative stage, but no similar studies could be found in Japan. In the present study, we report a retrospective investigation of fatigue assessment performed during preoperative rehabilitation evaluation. Participants and Methods Participants were 90 patients admitted to the hospital for glioma surgery between January 2016 and December 2020 who underwent five specific preoperative evaluations: KPS, MMSE, Motor-Functional Independence Measure (Motor FIM), Cancer Fatigue Scale (CFS), and grip strength. Participants were divided into a CFS-High(CFS-H) group (CFS>19 points) and a CFS-Low (CFS-L) group (CFS Results Participants were 90 patients with high-grade glioma. Fifty-seven were men, and the median age was 45 (15-81). Thirty-three participants (37%) had intense fatigue before surgery (CFS-H group: 33 participants, CFS-L group: 57 participants). In the CFS-H group and CFS-L group respectively, age was 46.5/44 (p=0.36), MMSE was 24 points/29 points (p=0.00255), Motor FIM was 89 points/91 points (p=0.0383), and grip strength was 22.2kg/25.5kg (p=0.194). Discussion The present study suggests that some Japanese high-grade glioma patients also experience intense fatigue before surgery. Compared to patients with low fatigue, those with high fatigue were suggested to have significant declines in cognitive function and ADL.

Background and Purpose In Japan, cancer-gene profiling (CGP) tests, such as the OncoGuide NCC Oncopanel System, FoundationOne CDx Cancer Genome Profile (F-one), and FoundationOne Liquid CDx Cancer Genome Profile, are covered by insurance and clinically applied to promote cancer genomic medicine. Information from CGP tests is managed at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and shared with clinicians after discussions at the Expert Panel (EP). We provide an overview of the registered pediatric CNS tumors. Methods We extracted and analyzed CNS/brain data from the C-CAT registry from June 2019 to June 2022 for ages 0–19 years. Variables such as age, gender, histopathological diagnosis, CGP test type, ECOG Performance Status (PS), registration status, genetic abnormalities, and treatments were analyzed. Results Among 1133 patients of all ages with CNS tumors, 361 (31.9%) were aged 0–19 years; Of the 918 patients aged 0-19 years with any type of cancer, those with CNS tumors accounted for 34.2%; 188 patients were aged under 10 years, 173 patients were teenagers, 174 patients were males, 187 patients were females; PS was 0 in 47.9% of patients. The most common histopathological diagnoses were medulloblastoma, diffuse midline glioma and glioblastoma. Genetic abnormalities included TP53 mutations in 85 cases, H3F3A mutations in 38 cases, STK11 mutations in 36 cases, BRAF mutations in 33 cases, BRAF-KIAA1549 fusions in 24 cases, and TMB high in 16 cases. Seventy-six patients (21.1%) were offered treatment options in the EP, and 26 patients (7.2%) received the recommended treatment, including two in physician-initiated trials, four in company trials, eleven in treatments within insurance coverage, and eleven in others. Discussion This is the first report of genetic analysis of pediatric CNS tumors on a nationwide scale. Pediatric CNS tumors have a large number of registered cases; thus, drug development for them is urgently needed.

Background Brain metastases (BM) to the cerebellum account for approximately 20% of all of BM. From the results of JCOG0504 clinical trial, observation with salvage SRS (stereotactic radiosurgery) has been established as a standard therapy for a patient after complete resection of BM. However, we often experience early local recurrence after resection of cerebellar BM, therefore, we retrospectively analyzed them to consider the appropriate timing of SRS. Methods We extracted surgical cases with cerebellar BM from January 2015 to March 2022 and analyzed the patient characteristics, treatment content, postoperative intracranial progression-free survival (IC-PFS) and postoperative overall survival (OS). Results A total of 57 cases were enrolled (male: female = 43.9%: 56.1%) in this study. The median age was 61.9 years (51.9-68.2). The common primary lesions were NSCLC (31.6%), colorectal cancer (19.3%), and breast cancer (17.5%). The IC-PFS was 4.5 months (2.6-5.7) and the OS was 11.6 months (9.1-21.8), but the local recurrent rate within 3 months was 43.4%. The rate of patients with leptomeningeal metastases (LMM) at the first recurrence was 26.3%, significantly higher than 7.7% in JCOG0504 (p=0.000224). In the postoperative observation group (no SRS within a month), the OS was 25.3 months (11.6-NA), which was longer than the 15.6 months (11.4-20.8) of JCOG0504. RT was performed in 18 patients at the recurrence (SRS: 15, WBRT (whole-brain radiotherapy): 9). SRS was the only factor that prolonged the OS (25.2 vs. 6.1 months (p=0.0212)). Furthermore, in the patients who underwent radiotherapy within 1 month after surgery, postoperative SRS (10.2 vs. 3.1 months, p=0.00437), and postoperative SRS to the resection cavity (11.0 vs. 3.7mo, p=0.0012) significantly prolonged the OS. Conclusion Since cerebellar BM has high recurrence and frequent LMM, early SRS for a resected cavity after surgery might lead to more favorable outcomes in cerebellar BM patients.

High-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) for the patient with primary central nervous system lymphoma (PCNSL) has been used as treatment at relapse or as consolidation therapy. We report on the efficacy, safety, and future issues of HDC-ASCT. Twelve patients with PCNSL (10 males and 2 females) underwent HDC-ASCT, ranging in age from 45 to 66 years (median 58 years) and KPS from 70 to 100 (median 90) at the time of HDC-ASCT. HDC-ASCT was performed at the time of consolidation therapy (without radiation) in 7 patients, at first recurrence in 4 (including 1 without radiation), and at second recurrence in 1. Department of Neurosurgery and Neuro-Oncology (NSNO) was in charge from diagnosis to just before transplantation, Department of Hematopoietic Stem Cell Transplantation (HSCT) was in charge of HDC-ASCT, and Department of NSNO was in charge after discharge again. The conditioning regimen consisted of busulfan 3.2mg/kg/day for 4 days and thiotepa 5mg/kg/day for the 2 following days, followed by ASCT. The observation period after HDC-ASCT ranged from 2.8 to 43 months (median 16.1 months), and the hospitalization period for HDC-ASCT ranged from 26 to 38 days (median 33 days), with no serious complications. All patients have returned to society and there have been no deaths to date, but two patients (after 4.7 months and 10.9 months) had relapses, of which two were treated with tirabrutinib, and one was subsequently treated palliatively. HDC-ASCT in PCNSL is an important option to improve outcomes. Since the main focus of this treatment is Department of HSCT, it is important to have sufficient cooperation and communication among the departments from the time of tumor diagnosis until after the patient is discharged from transplantation, and it is essential to be fully aware of each role.

Purpose: We aimed to elucidate the clinical characteristics, treatment outcomes, and genetic alterations in patients with radiation-induced glioma (RIG).Methods: Patients with high-grade glioma who satisfied the Cahan’s criteria for RIG in our database during 2001–2021 were included. Isocitrate dehydrogenase (IDH) 1 and 2, telomerase reverse transcriptase (TERT) promoter, B-Raf (BRAF), and histone H3.3 (H3F3A) and methylation status of the O-6-methylguanine DNA methyltransferase (MGMT) promoter were analyzed. Methods: We identified 11 patients with RIG, including 7 glioblastoma (GBM), IDH1/2-wildtype; 2 GBM, not otherwise specified (NOS); 1 anaplastic astrocytoma (AA), IDH1/2-wildtype; and 1 AA, NOS. The median latency period was 17 years (range: 9–30 years). The median progression-free survival (PFS) and median survival time (MST) were 11.3 months and 28.3 months, respectively. The median PFS in patients treated with initial reirradiation (N = 5) tended to be longer than that in patients without initial reirradiation (N = 6) (17.0 vs 8.1 months; p = 0.51), but not MST (29.6 vs 27.4 months; p = 0.28). There were no alterations in IDH1/2, TERT promoter, BRAF and H3F3A mutations. Two tumors had a hypermethylated MGMT promoter. In one case, different IDH2 mutation status between primary and secondary tumor was useful to diagnose the secondary tumor as RIG. Conclusions: RIG may occur more than 20 years after the treatment for primary disease; therefore, long-term follow-up is needed. Reirradiation could be a therapeutic option for RIG. Identifying IDH1/2 mutation status has a diagnostic impact on establishing RIG in cases of recurrent glioma.

Objective With an increase in the number of imaging examinations and the development of imaging technology, a small number of glioblastomas (GBMs) are identified by incidental radiological images. These incidentally discovered glioblastomas (iGBMs) are rare, and their clinical features are not well understood. Here, we investigated the clinical characteristics and outcomes of iGBM. Methods Data of newly diagnosed iGBM patients who were treated at our institution between August 2005 and October 2019 were reviewed. An iGBM was defined as a GBM without a focal sign, discovered on radiological images obtained for reasons unrelated to the tumor. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS). Results Of 234 patients with newly diagnosed GBM, four (1.7%) were classified as having iGBM. Health screening was the most common reason for tumor discovery (75.0%). The preoperative Karnofsky performance status score was 100 in three patients. Tumors were found on the right side in three cases. The mean volume of preoperative enhanced tumor lesion was 16.8 cm3. The median duration from confirmation of an enhanced lesion to surgery was 13.5 days. In all cases, either total (100%) or subtotal (95–99%) resections were achieved. The median PFS and OS were 11.5 and 20.0 months, respectively. Conclusions The iGBMs were often small and in the right non-eloquent area, and the patients had good performance status. We found that timely therapeutic intervention provided iGBM patients with favorable outcomes. This report suggests that early detection of GBM may lead to a better prognosis.

Background: Several studies have reported that gross total resection contributes to improved prognosis in patients with butterfly glioblastoma (bGBM). However, it sometimes damages the corpus callosum and cingulate gyrus, leading to severe neurological complications. Case Description: We report two cases of bGBM that was safely and maximally resected using brief and exact awake mapping after general anesthesia. Two patients had butterfly tumors in both the frontal lobes and the genu of the corpus callosum. Tumor resection was first performed on the nondominant side under general anesthesia to shorten the resection time and maintain patient concentration during awake surgery. After that, awake surgery was performed for the lesions in the dominant frontal lobe and genu of the corpus callosum. Tumor resection was performed through minimal cortical incisions in both frontal lobes. Postoperative magnetic resonance imaging showed gross total resection, and the patients had no chronic neurological sequelae, such as akinetic mutism and abulia. Conclusion: bGBM could be safely and maximally resected by a combination of asleep and brief awake resection, which enabled patients to maintain their attention to the task without fatigue, somnolence, or decreased attention. The bilateral approach from a small corticotomy can avoid extensive damage to the cingulate gyrus.

Purpose of the report This study aimed to determine the most effective metabolic index of FDG-PET and MET-PET to differentiate high- and low-grade gliomas, and then to characterize tumor metabolism according to the 2016 WHO classification. We also developed a new calculation method of potential infiltrative tumor volume to overcome the current limitations of tumor evaluation according to metabolic index, which focuses solely on tumor core area. Materials and methods Patients who underwent both FDG-PET and MET-PET, as well as surgical treatment, were retrospectively identified. All tumors were diagnosed histologically and included 44 high-grade and 19 low-grade gliomas. Metabolic indices of tumor-to-normal (T/N) ratio and maximum value within the tumor itself were compared between high- and low-grade tumors. A calculation method for potential infiltrative tumor volume was developed and compared between these 2 grades. Results T/N, calculated as tumor value divided by normal cortex value, was the most effective (area under the curve, 0.800 for FDG-PET; area under the curve, 0.773 for MET-PET) for differentiating high- and low-grade gliomas. Potential infiltrative volume effectively distinguished between high- and low-grade glioma (43.8 ± 30.2 mL vs 14.0 ± 12.6 mL; P = 0.005 [t test]). A combination of T/N, with a cutoff value of 0.9 or higher on FDG-PET and/or 3.0 or higher on MET-PET, and potential infiltrative volume, with a cutoff value of 20.0 mL or higher, provided a diagnostic accuracy of 89% in distinguishing high- from low-grade gliomas. Conclusions Evaluation of potential infiltrative volume surrounding the tumor core area, in addition to the T/N ratio of the tumor core, may help distinguish between high- and low-grade gliomas.

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

BACKGROUNDMalignant pleural mesothelioma (MPM) is a rare cancer, and in 80% of cases the cause is asbestos exposure. In 1972, the World Health Organization (WHO) declared asbestos is a carcinogenic substance. Since then, every developed country has restricted and banned the product. Because of its high heat resistance, asbestos had been widely used as building material for decades. The WHO estimated that approximately 125 million people are exposed to asbestos, and more than 107,000 die from asbestos-related diseases annually. Because of its long incubation period, the number of patients is estimated to keep increasing in the near future.OBSERVATIONSThe authors report a case of long-surviving MPM with a rushed clinical course after brain metastasis. A 69-year-old woman diagnosed with MPM (epithelial type) 6 years earlier presented with a brain metastasis. The pathological result of the brain metastasis was the sarcomatoid type. This case showed the possibility of subtype transition after long survival.LESSONSThis article aids in understanding the long-term natural history of MPM and the possibility of epithelial-mesenchymal transition. Neurosurgeons have to be aware of its the natural history and the possibility of brain metastasis.

Athyrium yokoscense shows strong tolerance to cadmium exposure, even at levels that are many times greater than the toxic levels in ordinary plants. To determine the mechanism of Cd tolerance in A. yokoscense, we grew these plants under high Cd conditions and observed the tissue-specific accumulation of Cd and generation of reactive oxygen species, which is one of the major physiological responses to Cd stress. Fuchsin staining indicated the existence of a casparian strip in A. yokoscense roots, which may participate in Cd hypertolerance in A. yokoscense. Moreover, we performed RNA-seq of RNA samples from A. yokoscense plants treated with or without Cd exposure and obtained comprehensive RNA sequences as well as the Cd-responsive expression patterns of individual genes. Through de novo transcriptome assembly and gene expression analysis, we found that A. yokoscense showed normal features with no significant change in the expression levels of any transporter genes, even under high Cd exposure conditions. Our results demonstrate that A. yokoscense has an unusual mechanism that allows the invading Cd to partition into the distal roots, thus avoiding translocation of Cd into the xylem.

background: IDH mutant astrocytoma has good prognosis compared with IDH wildtype one. In IDH mutant astrocytoma, However, patients with CDKN2A/B homozygous deletion (HD) are worse prognosis than non CDKN2A/B HD. Here we analyzed the prognosis of glioma patients identified with CDKN2A/B HD in our hospital. method: There were 62 cases, and female was 26. Mean age of all cases was 41.2 and median age was 38. In IDH gene status, R132H was 59 cases (95.2%), R172K 2 (3.2%) and R132S 1 (1.6%). All 62 cases were TERT wildtype. CDKN2A/B HD were 12 cases (19.4%). In log-rank test, the group of CDKN2A/B HD was poor prognosis than non HD. In astrocytoma grade 3, CDKN2A/B HD had significantly poor prognosis (p=0.002). In Cox proportional hazard model analysis, CDKN2A/B HD was effective predictive prognostic factor as well as age and grading (p=0.03). discussion/conclusion: We showed that CDKN2A/B HD was good predictive prognostic factor in IDH mutant astrocytoma.

Primary spinal germ cell tumors are rare, and spinal nongerminomatous germ cell tumors represent an even rarer subset for which no standard therapy has been established. The authors report the case of a 24-year-old woman with multifocal primary spinal germ cell tumors scattered from T-12 to L-5 that consisted of yolk sac tumor and mature teratoma. After diagnostic partial resection, the patient was treated with 30 Gy of craniospinal irradiation and 30 Gy of local spinal irradiation, followed by 8 courses of chemotherapy based on ifosfamide, cisplatin, and etoposide (ICE). Salvage surgery was also performed for residual mature teratoma components after the third course of ICE chemotherapy. Chemotherapy was continued after the operation, but ifosfamide was entirely eliminated from the ICE regimen because severe myelosuppression was observed after previous courses. The patient remains recurrence free as of more than 5 years after the completion of chemotherapy. This case suggests that this treatment strategy is an effective option for primary spinal yolk sac tumor.

The effectiveness of thrombectomy for acute ischemic stroke has been established, and earlier treatment produces better outcomes. If possible to identify large-vessel occlusion (LVO) at the prehospital phase, eligible patients can be shipped directly to a hospital that can perform thrombectomy. The purpose of this study was to determine factors that are specific to LVO and can be known before hospital arrival.The subjects were stroke patients during the period between July 2014 and June 2016, who had a National Institutes of Health Stroke Scale (NIHSS) score of 8 or higher and came to our hospital within 6 hours of onset. These patients were divided into an LVO group and a non-LVO group, and background factors, mode of onset, individual NIHSS item scores, and blood pressure at the time of the visit were retrospectively investigated. The selected factors were compared with LVO prediction scales reported in the past.There were 196 stroke patients who had NIHSS scores of 8 or higher and arrived at the hospital within 6 hours. Of these 196 patients, 56 had LVO. This LVO group included a significantly higher number of patients with the 2 items of atrial fibrillation (odds ratio [OR], 11.5: 95% confidence interval [CI], 4.04-32.9; P .0001) and systolic blood pressure of 170 mm Hg or lower (OR, 2.99: 95% CI, 1.33-6.71, P = .008). These 2 items predicted LVO equally to existing LVO prediction scales.The 2 items of atrial fibrillation and systolic blood pressure of 170 mm Hg or lower were significantly correlated with LVO.

Background Although inactivation of the von Hippel-Lindau gene (VHL), located on chromosome 3p25, is considered to be a major cause of hemangioblastomas (HBs), the incidence of biallelic inactivation of VHL is reportedly low. The aim of this study was to determine the prevalence of VHL alterations in HBs, as well as to identify additional molecular aberrations. Methods Genetic and epigenetic alterations were comprehensively and comparatively analyzed in 11 VHL-related and 21 sporadic HBs. Results VHL alterations detected by sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were more frequent in VHL-related HBs than in sporadic HBs (100% vs 62%; P = 0.029). VHL alterations were found only in 4 sporadic HBs by direct sequencing; however, targeted deep sequencing detected 9 additional alterations. Loss of heterozygosity (LOH) on chromosome 3 was found in 64% and 57% of VHL-related and sporadic HBs, respectively, by single nucleotide polymorphism (SNP) array analysis. Among 19 tumors with chromosome 3 LOH, 5 were classified as copy-neutral LOH. VHL promoter hypermethylation was detected only in sporadic HBs (33%), indicating that epigenetic suppression of VHL is a common mechanism in sporadic HBs. The rate of biallelic VHL inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. LOH on either chromosome 6 or 10 was detected only in sporadic HBs (43%). Conclusion Although biallelic inactivation of VHL is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB.

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0422-z) contains supplementary material, which is available to authorized users.