Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

MGMT protein expression is a reliable predictive biomarker for temozolomide-containing chemotherapy in osteosarcoma.

The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.

Performance status improvement and advances in systemic treatment after brain metastases resection: a retrospective single-center cohort study of non-small cell lung cancer patients.

BACKGROUND: Brain metastasis (BrM) is prevalent among patients with NSCLC, and surgical resection of BrM constitutes a promising treatment strategy for local management and histopathological diagnosis, although it is offered for a select group of patients. Limited information exists concerning the improvement in performance status (PS) following BrM resection or the outcomes stratified by subsequent systemic therapy. METHODS: We conducted a retrospective single-center cohort study including NSCLC patients with surgically resected BrM and focused on the improvement in PS and subsequent therapy after BrM resection. RESULTS: 71 patients were included, and the median overall survival was 18.3 months (95% confidence interval [95% CI]: 8.7, not reached). Patients with NSCLC who underwent surgical resection of BrM showed significant improvement in PS (18% and 39% showed ECOG PS of 0-1, before and after BrM resection, respectively [p = 0.006]), and patients with PS improvement were younger than those with PS unimprovement (median, 62 years versus 66 years; p = 0.041). Regarding subsequent systemic therapy after BrM resection, 21 patients (30%) received cytotoxic chemotherapy, 14 patients (20%) received tyrosine kinase inhibitors (TKIs), 3 patients (4%) received immune checkpoint inhibitors (ICIs), and 21 patients (30%) received no subsequent therapy. The survival outcomes of patients stratified by subsequent systemic treatments suggested the tendency that those who received TKI or ICI showed better survival outcomes, although a small number of patients hindered statistical comparisons. CONCLUSIONS: We describe the outcomes of patients with NSCLC who underwent surgical resection of BrM, revealing that younger patients were more likely to anticipate improvement in PS, and patients who received TKI or ICI after BrM resection tended to exhibit a more preferable prognosis.

Specific consistency score for rational selection of epilepsy resection surgery candidates.

OBJECTIVE: Degree of indication for epilepsy surgery is determined by taking multiple factors into account. This study aimed to investigate the usefulness of the Specific Consistency Score (SCS), a proposed score for focal epilepsy to rate the indication for epilepsy focal resection. METHODS: This retrospective cohort study included patients considered for resective epilepsy surgery in Kyoto University Hospital from 2011 to 2022. Plausible epileptic focus was tentatively defined. Cardinal findings were scored based on specificity and consistency with the estimated laterality and lobe. The total points represented SCS. The association between SCS and the following clinical parameters was assessed by univariate and multivariate analysis: (1) probability of undergoing resective epilepsy surgery, (2) good postoperative seizure outcome (Engel I and II or Engel I only), and (3) lobar concordance between the noninvasively estimated focus and intracranial electroencephalographic (EEG) recordings. RESULTS: A total of 131 patients were evaluated. Univariate analysis revealed higher SCS in the (1) epilepsy surgery group (8.4 [95% confidence interval (CI) = 7.8-8.9] vs. 4.9 [95% CI = 4.3-5.5] points; p < .001), (2) good postoperative seizure outcome group (Engel I and II; 8.7 [95% CI = 8.2-9.3] vs. 6.4 [95% CI = 4.5-8.3] points; p = .008), and (3) patients whose focus defined by intracranial EEG matched the noninvasively estimated focus (8.3 [95% CI = 7.3-9.2] vs. 5.4 [95% CI = 3.5-7.3] points; p = .004). Multivariate analysis revealed areas under the curve of .843, .825, and .881 for Parameters 1, 2, and 3, respectively. SIGNIFICANCE: SCS provides a reliable index of good indication for resective epilepsy surgery and can be easily available in many institutions not necessarily specializing in epilepsy.

Clinical and imaging characteristics of supratentorial glioma with IDH2 mutation.

PURPOSE: The rarity of IDH2 mutations in supratentorial gliomas has led to gaps in understanding their radiological characteristics, potentially resulting in misdiagnosis based solely on negative IDH1 immunohistochemical staining. We aimed to investigate the clinical and imaging characteristics of IDH2-mutant gliomas. METHODS: We analyzed imaging data from adult patients with pathologically confirmed diffuse lower-grade gliomas and known IDH1/2 alteration and 1p/19q codeletion statuses obtained from the records of our institute (January 2011 to August 2022, Cohort 1) and The Cancer Imaging Archive (TCIA, Cohort 2). Two radiologists evaluated clinical information and radiological findings using standardized methods. Furthermore, we compared the data for IDH2-mutant and IDH-wildtype gliomas. Multivariate logistic regression was used to identify the predictors of IDH2 mutation status, and receiver operating characteristic curve analysis was employed to assess the predictive performance of the model. RESULTS: Of the 20 IDH2-mutant supratentorial gliomas, 95% were in the frontal lobes, with 75% classified as oligodendrogliomas. Age and the T2-FLAIR discordance were independent predictors of IDH2 mutations. Receiver operating characteristic curve analysis for the model using age and T2-FLAIR discordance demonstrated a strong potential for discriminating between IDH2-mutant and IDH-wildtype gliomas, with an area under the curve of 0.96 (95% CI, 0.91-0.98, P = .02). CONCLUSION: A high frequency of oligodendrogliomas with 1p/19q codeletion was observed in IDH2-mutated gliomas. Younger age and the presence of the T2-FLAIR discordance were associated with IDH2 mutations and these findings may help with precise diagnoses and treatment decisions in clinical practice.

Protocol digest of a phase III randomized trial of gross total resection versus possible resection of fluid-attenuated inversion recovery-hyperintense lesion on MRI for newly diagnosed supratentorial glioblastoma: JCOG2209 (FLAMINGO).

The goal of surgery for patients with newly diagnosed glioblastoma (GBM) is maximum safe resection of the contrast-enhancing (CE) lesion on magnetic resonance imaging. However, there is no consensus on the efficacy of FLAIRectomy, which is defined as the possible resection of fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions surrounding the CE lesion. Although retrospective analyses suggested the potential benefits of FLAIRectomy, such outcomes have not been confirmed by prospective studies. Therefore, we planned a multicenter, open-label, randomized controlled phase III trial to evaluate the efficacy of FLAIRectomy compared with gross total resection of CE lesions in patients with newly diagnosed GBM. The primary endpoint is overall survival. In total, 130 patients will be enrolled from 47 institutions over 5 years. This trial has been registered at the Japan Registry of Clinical Trials (study number jRCT1031230245).

Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort.

BACKGROUND AND PURPOSE: Atherosclerotic burden increases the risk of both extracranial internal carotid artery stenosis (ICS) and intracranial large artery disease (ICAD). However, the differences in risk profiles have not been thoroughly investigated. METHODS: Participants were recruited from the Nagahama study cohort in Japan. Individuals over 60 years old who underwent 1.5-T head and neck magnetic resonance angiography (MRA) between July 2013 and February 2017 were included. ICAD was defined as WASID ≥ 50 %, and ICS was defined as NSCET ≥ 30 %. The prevalence and association of risk factors, including proatherogenic and proinflammatory factors, and the p.R4810K variant in the RNF213 gene, were investigated. Multivariable logistic regression analyses were performed. RESULTS: A total of 3089 individuals participated in the study, with a mean age of 68.1 ± 5.3 years, and 36.0 % were males. Among them, 52 (1.7 %) had ICS, 119 (3.8 %) had ICAD, and 15 (0.49 %) had both conditions. Alopecia areata was an independent predictor for both ICS (Odds ratio [OR] 3.5; 95 % CI 1.3-8.3) and ICAD (OR 2.1; 95 % CI 1.0-3.9). Diabetes (OR 3.7; 95 % CI 2.0-7.0) and older age (OR 2.4; 95 % CI 1.2-4.5) were associated only with ICS, while the RNF213 variant was associated with only ICAD (OR 5.7; 95 % CI 1.6-16.0). ICS and ICAD were also independently associated with each other. CONCLUSIONS: In this MRA-based large scale study, alopecia areata, known as a systemic inflammatory disease, was shown to be a common risk factor for ICS and ICAD. While conventional atherosclerotic factors were associated with ICS, non-atherosclerotic factors appear to contribute to ICAD in Japan.

Novel Manifestation of Retinal Hemangioblastomas Detected by OCT Angiography in von Hippel-Lindau Disease.

PURPOSE: To elucidate the clinical characteristics of atypical retinal vascular proliferation in patients with von Hippel-Lindau (VHL) disease using OCT angiography (OCTA). DESIGN: Prospective, observational study. PARTICIPANTS: Fifty-seven consecutive patients with a diagnosis of VHL disease who visited Kyoto University Hospital between January 2019 and March 2022. METHODS: Retinal hemangioblastomas (RHs) were assessed using multimodal imaging including OCTA. Retinal hemangioblastomas were classified into 2 phenotypes: nodular and flat. Nodular RHs were defined as typical RHs that were globular, well-circumscribed tumors, often accompanied with dilated feeder arterioles and draining venules. Flat RHs lacked a protruded red or colored mass, had variable and indistinct borders, and were not accompanied with feeder and draining vessels. MAIN OUTCOME MEASURES: The prevalence, distribution, and description of atypical flat RHs. RESULTS: Among 57 consecutive patients with VHL disease, 37 patients (64.9%) showed RHs in at least 1 eye. Bilateral RHs were seen in 23 patients (62.2%). Among 58 eyes of 37 patients with RHs, typical nodular RHs were detected in 54 eyes. Nodular RHs were seen mainly in the peripheral retina and occasionally in the peripapillary region, and they showed exudative changes in some cases. Flat RHs were detected in 7 eyes (12.1%). Four eyes showed only flat RHs, and 3 eyes showed both types in the same eye. Most flat RHs appeared as retinal hemorrhages or faint flat abnormal retinal vessels in the inner retina on the fundus examination, often within the macula area or peripapillary. In all eyes with flat RHs, OCTA showed abundant blood flow in the lesions. OCT revealed that flat RHs were seen mainly between the retinal nerve fiber layer and the ganglion cell layer, and occasionally within the inner nuclear layer. During a mean follow-up period of 20.4 ± 15.0 months, no flat RHs accompanied exudative change, tractional retinal detachment, or progression in size. CONCLUSIONS: Patients with VHL disease can demonstrate 2 distinct types of RHs: the classic nodular type and an atypical flat type. OCT angiography can be useful in improving the detection of atypical flat RHs, which can be difficult to detect clinically. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Seizure control by adding on other anti-seizure medication on seizure during levetiracetam administration in patients with glioma-related epilepsy.

BACKGROUND: Epilepsy is a major symptom in patients with glioma. Levetiracetam (LEV) is recognized as a first-line treatment for glioma-related epilepsy. Increasing the LEV dose is allowed into patients with seizure occurrence against its initial dose. However, the therapeutic efficacy of increasing the LEV dose in response to seizure occurrence remains unclear. METHODS: We retrospectively analyzed 236 glioma patients who were treated with antiseizure medications (ASMs) internally at our institute between September 2010 and December 2017. Of these, the analysis focused on 156 patients treated with LEV who had a clear history of administration. RESULTS: Seizure occurrences were observed in 21 of 75 patients (26.7%) who received LEV as first-line therapy and in 33 of 81 patients (40.7%) who received LEV as non-first-line treatment. The seizure control rate for seizure occurrence with LEV as first-line treatment was significantly higher in patients treated with addition of other ASMs (72.7%) than in those treated with increasing dose of LEV (20.0%) (p = 0.016). The seizure control rate for seizure occurrence with LEV as non-first-line treatment did not differ significantly between patients with addition of other ASMs (58.3%) and those treated with increasing dose of LEV (47.6%) (p = 0.554). CONCLUSIONS: Adding other ASMs was more effective than increasing the LEV dose for seizure control in patients treated with LEV as first-line treatment, but they demonstrated comparable efficacy in patients treated with LEV as non-first-line treatment.

Safety and efficacy of tumour-treating fields (TTFields) therapy for newly diagnosed glioblastoma in Japanese patients using the Novo-TTF System: a prospective post-approval study.

BACKGROUND: Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. METHODS: Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016-June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan-Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. RESULTS: Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6-88.3) and 53.6% (35.5-68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2-87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69-77%] and 43% [39-48%], respectively; 6-month progression-free survival rate: 56% (51-61%). CONCLUSION: This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.

"Transcallosal" periventricular anastomosis in moyamoya disease: the fourth periventricular anastomosis and a potential predictor of hemorrhage.

OBJECTIVES: Choroidal anastomosis is a risk factor for hemorrhage in moyamoya disease. One variant of choroidal anastomosis, "transcallosal anastomosis," originates from the medial posterior choroidal artery, and penetrates the corpus callosum to reconstruct the pericallosal artery. We aimed to investigate the prevalence and the bleeding rate of transcallosal anastomosis using sliding thin-slab maximum intensity projection reformatted from magnetic resonance angiography (MRA). MATERIALS AND METHODS: This study included 222 patients. We defined transcallosal anastomosis grades (0-2) and the stenosis of the anterior (ACA, 0-2), middle (MCA, 1-3), and posterior cerebral artery (PCA, 0-2) by MRA scores, independently by two coauthors. RESULTS: Grade-2 transcallosal anastomosis was detected in 21 patients (9.5 %). There were no correlations of the incidence of transcallosal anastomosis with previous bypass surgery (P = 0.23). Multivariate analysis revealed a significantly higher incidence in hemorrhagic onset and younger age (odds ratio [OR] 3.77, and 0.97). Transcallosal anastomosis had statistically significant correlation with ACA and PCA scores (P = 0.01 and 0.03), but not with MCA scores (P = 0.1). In multivariate analysis, ACA scores 1 and 2 were significantly higher (OR, 15.44 and 11.17), and PCA score 1 was also higher (OR, 3.07), but PCA score 2 was not. Interrater agreement for judgment of transcallosal anastomosis grade was strong (κ = 0.89). Two patients with Grade-2 transcallosal anastomosis had late hemorrhage in the corpus callosum (bleeding rate: 2.5 % per year). CONCLUSIONS: Transcallosal anastomosis may be associated with both advanced ACA and moderate PCA stenosis, and cause hemorrhage at the corpus callosum.

Chlorambucil-conjugated PI-polyamides (Chb-M'), a transcription inhibitor of RUNX family, has an anti-tumor activity against SHH-type medulloblastoma with p53 mutation.

Malignancy of medulloblastoma depends on its molecular classification. Sonic Hedgehog (SHH)-type medulloblastoma with p53 mutation was recognized as one of the most aggressive types of tumors. We developed a novel drug, chlorambucil-conjugated PI-polyamides (Chb-M'), which was designed to compete with the RUNX consensus DNA-binding site. Chb-M' specifically recognizes this consensus sequence and alkylates it to inhibit the RUNX transcriptional activity. In-silico analysis showed all the RUNX families were upregulated in the SHH-type medulloblastoma. Thus, we tested the anti-tumor effects of Chb-M' in vitro and in vivo using Daoy cell lines, which belong to SHH with p53 mutation. Chb-M' inhibited tumor growth of Daoy cells by inducing apoptosis. The same inhibitory effect was also observed by knocking down of RUNX1 or RUNX2, but not RUNX3. Apoptosis array analysis showed that Chb-M' treatment induced phosphorylation of p53 serine 15 residues. In a subcutaneous tumor model, intratumoral injection of Chb-M' induced tumor growth retardation. Chb-M' mediated inhibition of RUNX1 and RUNX2 can be a novel therapeutic strategy for SHH-type medulloblastoma with p53 mutation.

Evaluation of the efficacy and safety of TAS0313 in adults with recurrent glioblastoma.

BACKGROUND: TAS0313 is a multi-epitope long peptide vaccine targeting several cancer-associated antigens highly expressed in multiple cancer types, including glioblastoma (GBM). This cohort of a Phase 2 part evaluated the efficacy and safety of TAS0313 in patients with GBM. METHODS: TAS0313 (27 mg) was administered subcutaneously on Days 1, 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the disease control rate, progression-free survival (PFS) and 6- and 12-month progression-free survival rates (PFR) and safety. Immunological response was assessed as an exploratory endpoint. RESULTS: The best overall response was partial response in 1 patient, and the ORR (95% CI) was 11.1% (0.3-48.2%) in the per-protocol set (n = 9). A further 3 patients achieved stable disease, for a disease control rate (95% CI) of 44.4% (13.7-78.8%). Median (95% CI) PFS was 1.7 (1.3-NE) months and 6- and 12-month PFRs (95% CI) were 22.2% (3.4-51.3%) each. Common (≥ 20% incidence) treatment-related adverse events (AEs) were injection site reactions (n = 8, 80.0%), followed by pyrexia (n = 7, 70.0%), and malaise, injection site erythema and injection site pruritus (n = 2, 20.0% each). There were no grade 4 or 5 treatment-related AEs. No deaths occurred during the study. In some patients, TAS0313 treatment was confirmed to increase cytotoxic T lymphocyte and immunoglobulin G levels compared with baseline. CONCLUSION: TAS0313, a multi-epitope long peptide vaccine, demonstrated promising efficacy and acceptable safety in patients with recurrent GBM. CLINICAL TRIAL REGISTRATION: JapicCTI-183824 (Date of registration: Jan 11, 2018).

A novel SREBF1::NACC1 gene fusion in an unclassifiable intracranial tumour.

A 39-year-old man had an intracranial tumour without infiltration into the surrounding cerebral tissue. The tumour recurred seven times in 11 years but maintained a well-demarcated character. Histopathological examination of the 4th surgical specimens showed nests of tumour cells surrounding small blood vessels. The tumour cells harboured amphophilic cytoplasm and small round nuclei with fine chromatin, and perinuclear haloes and clear borders were frequently observed, which was unclassifiable histology. By the Deutsches Krebsforschungszentrum methylation classifier, the tumour was not classified into any of the methylation classes. mRNA sequencing identified a novel SREBF1::NACC1 gene fusion. This intracranial tumour could be a novel tumour entity with NACC1 rearrangement showing characteristic histological and diagnostic imaging findings.

Intra-cerebellar schwannoma with various degenerative changes: a case report and a systematic review.

BACKGROUND: Intra-cranial schwannomas account for less than 8% of brain tumors, among which more than 80% arise from the vestibular nerve. Intra-cerebellar schwannomas are extremely rare. Several cases have been previously reported but without remarkable degenerative changes on histology. CASE PRESENTATION: A 61-year-old man presented with worsening disorientation, and an imaging study revealed a cystic lesion (6.5 cm in the largest diameter) in the left hemisphere of the cerebellum accompanied by a mural nodule (2.5 cm) located just inside the skull with enhancement and focal calcification, in addition to hydrocephalus. The lesion was more than 5 mm from the left acoustic nerve. The patient underwent gross total resection. Pathological examination revealed remarkable degenerative changes with various morphological features. Tumor cells were pleomorphic with rich cytoplasm containing numerous eosinophilic granules. Blood vessels and extracellular matrix showed remarkable hyalinization. Immunohistochemical staining revealed that the tumor cells were positive for S-100 protein and negative for Olig2. The tumor was diagnosed as a schwannoma with marked degenerative changes. CONCLUSIONS: The present case is discussed with reference to a systematic review of previous reports of intra-cerebellar schwannoma. Intra-cerebellar schwannoma should be included in the differential diagnosis of cystic lesions with heterogeneous histopathological morphology in the cerebellum.

Optimal managements of elderly patients with glioblastoma.

Optimizing the management of elderly patients with glioblastoma is an ongoing task in neuro-oncology. The number of patients with this tumor type is gradually increasing with the aging of the population. Although available data and practice recommendations remain limited, the current strategy is maximal safe surgical resection followed by radiotherapy in combination with temozolomide. However, survival is significantly worse than that in the younger population. Surgical resection provides survival benefit in patients with good performance status. Hypofractionated radiotherapy decreases toxicities while maintaining therapeutic efficacy, thus improving treatment adherence and subsequently leading to better quality of life. The intensity of these treatments should be balanced with patient-specific factors and consideration of quality of life. This review discusses the current optimal management in terms of efficacy and safety, as well as future perspectives.

Infrequent RAS mutation is not associated with specific histological phenotype in gliomas.

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.

A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII).

BACKGROUND: The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved. METHODS: This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71-75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020. DISCUSSION: If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma. TRIAL REGISTRATION: Registry number: jRCTs031200099 . Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.

Short diameter may be a useful simple indicator of the tumor response in skull base meningiomas after conventionally fractionated stereotactic radiotherapy.

OBJECTIVES: The purpose of this study was to assess the radiological change patterns in skull base meningiomas after conventionally fractionated stereotactic radiotherapy (CFSRT) to determine a simple and valid method to assess the tumor response. MATERIALS AND METHODS: Forty-one patients with a benign skull base meningioma treated by CFSRT from March 2007 to August 2015 were retrospectively evaluated. We measured tumor volume (TV), long-axis diameter (LD), and short-axis diameter (SD) on both pre-treatment images and follow-up images of 1, 3, and 5 years after CFSRT, respectively. The paired t test was used to detect differences in the LD and SD change rates. Spearman's correlation coefficients were calculated to evaluate relationships between the TV and the diameters changes. RESULTS: The number of available follow-up MRIs that was performed at 1, 3, and 5 years after the CFSRT was 41 (100%), 34 (83%), and 23 (56%), respectively. The change rates of SD were significantly higher than those of LD at every time point and more strongly correlated with the change rates of tumor volume at 3 and 5 years after CFSRT. CONCLUSIONS: SD may be useful as a simple indicator of the tumor response for skull base meningioma after CFSRT. KEY POINTS: • The change rate in short-axis diameter is a useful and simple indicator of the response of skull base meningioma to conventionally fractionated stereotactic radiotherapy. • Conventionally fractionated stereotactic radiotherapy for skull base meningioma achieved excellent 5-year local control.