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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 current World Health Organization classification of diffuse astrocytic and oligodendroglial tumors requires the examination of isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Conventional analysis tools, including Sanger DNA sequencing or pyrosequencing, fail in detecting these variants of low frequency owing to their limited sensitivity. Digital polymerase chain reaction (dPCR) is a recently developed, highly sensitive, and precise quantitative rare variant assay. This study aimed to establish a robust limit of quantitation of the dPCR assay to detect a small fraction of IDH1 R132H mutation. The dPCR assays with serially diluted IDH1 R132H constructs detected 0.05% or more of mutant IDH1 R132H in samples containing mutant DNA. The measured target/total value of the experiments was proportional to the dilution factors and was almost equal to the actual frequencies of the mutant alleles. Based on the average target/total values, together with a twofold standard deviation of the normal DNA, a limit of quantitation of 0.25% was set to secure a safe margin to judge the mutation status of the IDH1 R132H dPCR assay. In clinical settings, detecting IDH1 R132H using dPCR assays can validate ambiguous immunohistochemistry results even when conventional DNA sequencing cannot detect the mutation and assure diagnostic quality.

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.

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.

Background Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. Methods A serum miRNA profile (miRNomes)–based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. Results Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type–specific serum miRNomes. Conclusions This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.

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.

Objective: Leptomeningeal dissemination (LMD) is a severe complication of glioblastoma (GBM) and has become a more common and indispensable clinical proposition with improved patient prognosis. Although infratentorial leptomeningeal dissemination (ITD) of GBM is rare, it is clinically significant as it may largely influence patient prognosis. Here, we investigated the clinical characteristics and prognosis of patients with ITD.Methods: Data of patients with newly diagnosed isocitrate dehydrogenase (IDH)-wildtype GBM treated at our institution between October 2008 and December 2018 were reviewed. ITD was defined as the dissemination of GBM, which first emerged as a supratentorial tumor, and later disseminated in the infratentorial region as the first recurrent site.Results: Of 160 patients with newly diagnosed IDH-wildtype GBM, seven (4.4%) were classified as having ITD. ITD lesions were in the fourth ventricle in two patients, extra-cerebellum or extra-brainstem in two, and intra-cerebellum in three. The primary symptoms of ITD were gait disturbance (85.7%, n=6), nausea and vomiting (28.6%, n=2), cerebellar mutism (14.3%, n=1), and none (14.3%, n=1). In four cases (57.1%), symptoms were confirmed before ITD discovery.The median progression-free survival (PFS) and overall survival of the patients were 12.2 and 19.7 months, respectively. Radiotherapy was performed in five patients, and all the patients received chemotherapy. The PFS and overall survival rates from ITD diagnosis were 2.9 and 7.1 months, respectively. Patients with favorable prognoses were younger and had higher Karnofsky performance status (KPS) scores.Conclusions: Radiotherapy or molecular-targeted therapy may be effective in some cases of ITD and may contribute to extending survival. Carefully checking the infratentorial region of patients with GBM during follow-up and rapidly treating ITD before their KPS score starts declining are crucial.

CIC-rearranged sarcoma is a high-grade sarcoma, most often harboring CIC::DUX4 fusion, and is characterized by a distinct round cell histology, co-expression of ETV4 and WT1, and a specific DNA methylation class. Herein, we report a brain tumor with ATXN1::DUX4 that had an indistinguishable phenotype and DNA methylation profile from CIC-rearranged sarcoma. A 40-year-old man presented with a 5 cm hemorrhagic mass in the right frontal lobe of the cerebrum. The tumor was resected and histologically showed a dense proliferation of relatively monomorphic round cells with multifocal myxoid changes. Immunohistochemically, the tumor was diffusely positive for ETV4, WT1, and DUX4. Through classic histomorphology and immunoprofile, the tumor was provisionally diagnosed as CIC-rearranged sarcoma. However, no CIC fusions or mutations were identified using CIC break-apart fluorescence in situ hybridization (FISH) or FoundationOne CDx. Despite multiple surgeries and adjuvant chemoradiation therapy, the patient succumbed 16 months after presentation. RNA exome sequencing detected an in-frame intraexonic ATXN1 (exon 9)::DUX4 (exon 1) fusion, which was validated by reverse transcription-polymerase chain reaction and ATXN1 FISH assay. Upon DNA methylation analysis, the tumor matched with CIC-rearranged sarcoma both by the Deutsche Krebsforschungszentrum classifier and t-distributed stochastic neighbor embedding. Along with a recent report of a similar pediatric brain tumor, the present case suggests that ATXN1::DUX4 is a recurrent alternative molecular event in the sarcoma type that is presently defined by CIC rearrangement, which prompts an expansion of the tumor concept.

Background There is no standard treatment for patients with recurrent high-grade gliomas who progress after bevacizumab treatment. We evaluated the outcomes of re-irradiation combined with bevacizumab for patients refractory to bevacizumab. Methods Between January 2015 and September 2019, patients with progression after bevacizumab treatment were treated with re-irradiation combined with bevacizumab (25 Gy in five fractions). Results Fourteen patients [glioblastoma, isocitrate dehydrogenase (IDH) wild type (N = 6), glioblastoma, IDH mutant (N = 4), anaplastic astrocytoma, IDH wild type (N = 1), anaplastic astrocytoma, IDH mutant (N = 1), glioblastoma, not otherwise specified (N = 1) and radiologically diagnosed brainstem glioma (N = 1)] were included in this study. The median survival and progression-free survival times after re-irradiation combined with bevacizumab were 6.1 and 3.8 months, respectively. The 6-month survival and progression-free survival rates were 54.5 and 15.7%, respectively. Patients with a Karnofsky performance status of ≥70 tended to have longer median survival time (9.3 vs. 5.4 months, respectively; P = 0.058) and had a significantly longer median progression-free survival time (4.2 vs. 3.7 months, respectively; P = 0.046) than those with a Karnofsky performance status of Conclusions Re-irradiation combined with bevacizumab for patients with recurrent high-grade gliomas who progress after bevacizumab treatment was feasible. Re-irradiation combined with bevacizumab is a potential treatment option, especially for patients with a Karnofsky performance status of ≥70.

Homozygous deletion (HD) of CDKN2A is one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/B HD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2A HD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2A HD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2A HD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2A HD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P

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.

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.

Human coenurosis is caused by the larval stages of Taenia species, mainly Taenia multiceps and Taenia serialis. T. multiceps has been reported to cause human central nervous system (CNS) infections, but no CNS case caused by T. serialis has been reported. The authors report the first case of human neurocoenurosis caused by T. serialis, which was confirmed by mitochondrial DNA analysis. A 38-year-old man presented with visual disturbance and headache, and subsequent magnetic resonance imaging (MRI) revealed a ring-enhancing cystic lesion in the left occipital lobe. Biopsy was performed, and the resultant histopathological diagnosis was that of low-grade B-cell lymphoma. Chemotherapy was initiated, but a subsequent MRI showed increased ring enhancement. Due to the unexpected clinical course, a surgical resection of the lesion was performed. The lesion was completely removed. Pathological examination showed multiple scolices with hooklets, suckers, and numerous calcareous corpuscles. Therefore, the diagnosis of neurocysticercosis was made. However, mitochondrial DNA analysis showed that the disease was definitively coenurosis caused by T. serialis. Albendazole was administered, with no evidence of recurrence at 12 months following the operation. In this study, we demonstrate that T. serialis can cause CNS infection and that genetic analysis is recommended to establish a definitive 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.

Objective We retrospectively reviewed the post-irradiation course of cases treated with radiotherapy for the gliomas involving thalamus or brainstem. Methods Thirty-seven gliomas involving thalamus or brainstem treated with radiotherapy from 2007 to 2021 in our hospital were included. Median age was 47 (19-79) years, and KPS at the start of irradiation was 80% or less in 26 cases. Tumor localization was thalamus only/brainstem only/both thalamus and brainstem for 20/9/8 cases. Two cases did not undergo biopsy, and the others underwent surgery before irradiation. Two cases underwent partial excision of the lesion near the thalamus, 6 cases underwent partial excision from other than the thalamus-brainstem, and 27 cases underwent biopsy only. The pathological diagnosis based on the WHO classification at the time of surgery was glioblastoma (GBM) in 8 cases, high-grade glioma other than glioblastoma (HGG) in 23 cases (including 9 cases of diffuse midline glioma K27M), and low-grade glioma (LGG) in 6 cases. Results Median observation period was 16(2-66) months. Median PFS/median OS/5-year OS rate were 13 months/25 months/20% in all 37 cases. Median PFS was 66/18/7 months for LGG/ HGG/ GBM, and 5-year OS was 75/16/15%. Symptomatic cerebral edema associated with tumor growth was observed in one GBM 9 months after irradiation. In HGG, 7/23 cases underwent the VP shunting before irradiation, and one case who underwent ventriculostomy before irradiation had a VP shunting created for worsening hydrocephalus 3 months after irradiation. In one case of GBM, a VP shunt was created immediately after surgery. Conclusions Compared to the past reports of gliomas, it was suggested that the localization in thalamic brainstem was a factor for a worse prognosis in HGG.

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.

“Stroke mimics” mean diseases presenting with acute neurological impairments that are taken for stroke. Discriminating them is crucial to avoid improper treatment or delayed correct treatment. We describe a 48‐year‐old woman presenting with a sudden onset of scintillating scotoma and left‐lower quadrantanopsia. Hyperacute cerebral infarction was suspected. However, brain magnetic resonance imaging (MRI) revealed a mass at the cortico‐medullary junction in the right occipital lobe. We diagnosed her as metastatic melanoma. We suspected that neurological deficits can be attributed to seizure, and therefore introduced levetiracetam. She showed neurological improvement immediately. Our case demonstrated the importance of considering brain tumor as a differential diagnosis in patients presenting with acute‐onset neurological deficits. In addition to appropriate treatment of tumor, the use of newer antiepileptic drugs resulted in good neurological prognosis in metastatic brain tumors., Brain MRI and CT showed a mass lesion 2 cm in diameter at the cortico‐medullary junction in right occipital lobe. The findings were typical characteristics of metastatic melanoma.

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.

Background and ObjectivesMutant isocitrate dehydrogenase (IDH) 1/2 gene products gain a new ability to produce D-2-hydroxyglutarate (D2HG). IDH1/2 mutations are thought to be associated with seizures owing to the structural similarity between D2HG and glutamate. However, the effects of D2HG on seizures in clinical settings are not fully understood. We sought to investigate the relationship between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures using clinical samples.MethodsWe included 104 consecutive patients with diffuse glioma who underwent surgery from August 2008 to May 2016 and whose clinical presentation and IDH1/2 status were identified. The presence of preoperative seizures, tumor location, histopathologic diagnosis, IDH1/2 status, and 1p/19q codeletion were assessed from the patient charts. Tissue 2HG concentration was measured using liquid chromatography–tandem mass spectrometry. To evaluate 2HG distribution without artefactual tissue disruption, we applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) in 12 patients' surgically resected samples. We assessed the correlation of preoperative seizures with tissue 2HG concentration, IDH1/2 status, WHO grade, and 1p/19q codeletion.ResultsTissue 2HG concentration was higher in IDH1/2 mutant tumors (IDH-Mut, n = 42) than in IDH1/2 wild-type tumors (IDH-WT, n = 62) (median 4,860 ng/mg vs 75 ng/mg) (p < 0.0001). MALDI-MSI could detect 2HG signals in IDH-Mut, but not in IDH-WT. Preoperative seizures were observed in 64.3% of patients with IDH-Mut and 21.0% patients with IDH-WT (p < 0.0001). The optimal cutoff value of tissue 2HG concentration for predicting preoperative seizures was 1,190 ng/mg, as calculated by the receiver operating characteristic curve. Increased preoperative seizure risk was only observed in tumors with 2HG concentration above the cutoff value among IDH-Mut (IDH-Mut with above the cutoff value: 71.4% vs IDH-Mut with below the cutoff value: 28.6%; p = 0.031). Multivariate analysis, including IDH1/2 mutation status, tissue 2HG concentration, WHO grade, and 1p/19q codeletion, revealed that only increased tissue 2HG concentration was associated with preoperative seizures (odds ratio 5.86, 95% confidence interval 1.02–48.5; p = 0.048).DiscussionWe showed that high tissue 2HG concentration was associated with preoperative seizures, suggesting that excess 2HG increases risk of preoperative seizures in IDH1/2 mutant tumors.

Background: This study evaluated the outcomes of reirradiation combined with bevacizumab (Bev) for patients with recurrent high-grade gliomas that progressed after treatment with Bev.Methods: Between January 2015 and September 2019, 14 patients who experienced progression after Bev treatment were treated with reirradiation consisting of 25 Gy in five fractions combined with Bev (ReRT/Bev). The isocitrate dehydrogenase (IDH) 1/2 mutation status was analysed by pyrosequencing. Results: The diagnoses of 14 patients at the time of reirradiation included six cases of glioblastoma (GBM) with IDH-wildtype, four cases of GBM with IDH-mutant, one case of anaplastic astrocytoma (AA) with IDH-wildtype, one case of AA with IDH-mutant, and one case of GBM not otherwise specified (NOS), and one case of radiologically diagnosed brainstem glioma. The median overall survival (OS) and progression-free survival (PFS) times with ReRT/Bev were 6.1 months and 3.8 months, respectively. The 6-month OS and PFS rates were 54.5% and 15.7%, respectively. The median OS and PFS did not differ significantly between patients with IDH-wildtype (N=7) and IDH-mutant (N=5) (OS: 7.3 [wildtype] vs 6.0 [mutant] months, p = 0.64; PFS: 3.8 [wildtype] vs 3.7 [mutant] months, p = 0.56). The median OS and PFS did not differ significantly between patients with a diagnosis of GBM (N=6) and those with a diagnosis of non-GBM (N=7) (OS: 9.3 [GBM] vs 6.0 [non-GBM] months, p = 0.19; PFS: 4.0 [GBM] vs 3.8 [non-GBM] months, p = 0.31). Four patients (28.6%) achieved a complete or partial radiological response and three patients (21.4%) experienced improvement after ReRT/Bev. Tumor recurrences were observed in 12 patients, including 3 (21.4%) in-field recurrence; 5 (35.7%) marginal recurrence, 3 (21.4%) out-field recurrence, and 1 (7.1%) had in-field and out-field recurrence. Grade 3/4 toxicities included leukopenia in four patients (28.6%), hypertension in three (21.4%), proteinuria in one (7.1%), and gastrointestinal haemorrhage in one (7.1%) with ReRT/Bev. Conclusions: ReRT/Bev for patients with high-grade glioma who experienced progression after Bev was effective and involved acceptable toxicities.

Introduction: Germ cell tumors (GCTs) are uncommon neoplasms predominantly arising in midline tissues. The prognostic significance of histopathology in predicting metastatic GCT behavior is poorly understood. Methods: Multicenter international cohort study including 29 patients with GCTs metastatic to brain were retrospectively investigated (18 patients from Mayo Clinic and 11 patients from the intracranial germ cell tumor genome analysis consortium in Japan). Clinical characteristics were analyzed using the Chi-square test (two-tailed) for categorical variables and using the log-rank test for survival data. Results: Median age at treatment was 31years (range 14–58). Primary disease sites were testis (71%), mediastinum (18%), and female reproductive organs (11%). Median metastatic interval was 223days (range, 6–6124). Median follow-up was 346days (range, 1–5356), with 16 deaths (57%) occurring after the median overall survival of 455days. Actuarial one-year survival was 51%; 12-of-16 deaths (75%) were attributed to intracranial disease. Appearance of the same GCT subtype at the metastatic site as the primary was high for non-seminomatous GCT (NSGCT, 64–100%), but low for seminoma/dysgerminoma and mature teratoma (MT, 14, 17%, respectively). Gain of a new component was seen in 4 (20%)—3 of which included embryonal carcinoma (EC) at the primary site (75%). Incidence of cases without seminoma/dysgerminoma increased significantly after metastasis (p = 0.02). Metastatic interval was shorter in cases with histological change (199 vs 454days, p = 0.009). Overall survival was associated with MT primary histopathology (p = 0.02). Conclusion: Histological differentiation at the primary GCT site influences metastatic prognosis. Aggressive behavior is associated with NSGCT, while EC frequently demonstrates multi-directional histological differentiation after brain metastasis, and such histological dynamism is associated with shorter metastatic interval. Most metastases occurred within one year of diagnosis, emphasizing the need for close surveillance in newly diagnosed extra-cranial GCT.

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90–100%) were associated with favorable prognosis (p TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.