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Background: Isocitrate dehydrogenase-mutant astrocytoma without cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion typically follows a slow clinical course. However, some cases show early progression on magnetic resonance imaging, and these characteristics remain under-reported. This study aimed to elucidate the characteristics of isocitrate dehydrogenase-mutant astrocytoma showing early progression on magnetic resonance imaging., Methods: This retrospective study included 52 cases of primary astrocytoma, isocitrate dehydrogenase-mutant, Central Nervous System (CNS) 5 World Health Organization grade 2-3 according to the World Health Organization 2021 classification. Patients underwent surgery followed by radiation therapy and/or chemotherapy at our institution from 2006 to 2019. Progression-free survival and overall survival were analyzed., Results: There were 24 and 28 grade 2 and grade 3 astrocytomas, respectively. The median patient age was 38 years. Forty-three patients underwent radiotherapy. Progression was diagnosed by magnetic resonance imaging in 22 patients with initial radiotherapy. Thirteen of the 22 patients underwent surgery, and seven of the 13 patients received surgery within 24 months of the initial radiotherapy. Histopathologically, radiation necrosis was confirmed in four of these seven patients (57.1%). The true progression-free survival rate, excluding radiation necrosis, at 2 years after surgery was 91.3% for grade 2 astrocytoma and 88.5% for grade 3 astrocytoma. The 5-year overall survival rate was 85.7% for grade 2 tumours and 76.4% for grade 3 tumours., Conclusions: Radiation necrosis should be considered in cases showing early progression of isocitrate dehydrogenase-mutant astrocytoma, and a second surgery should be performed to confirm true recurrence or radiation necrosis. Astrocytomas with telomerase reverse-transcriptase promoter mutations may relapse relatively early and should be followed up with caution., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2A/B homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPA/CytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5., (© 2023. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

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., (© 2022. The Author(s).)

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 < 0.001 each), but neither were prognostically significant for oligodendroglioma or IDH-wildtype glioblastoma. IDH-mutant lower-grade astrocytoma with CDKN2A HD and deficient MTAP immunoreactivity exhibited overlapping unfavorable outcome with IDH-mutant glioblastoma. MTAP immunostaining was easily interpreted in 61% of the cases tested, but scoring required greater care in the remaining cases. An alternative MTAP antibody clone (2G4) produced identical scoring results in all but 1 case, and a slightly larger proportion (66%) of cases were considered easy to interpret compared to using EPR6893. In summary, loss of MTAP immunoreactivity could serve as a reasonable predictive surrogate for CDKN2A HD in IDH-mutant astrocytomas and IDH-wildtype glioblastomas and could provide significant prognostic value for IDH-mutant astrocytoma, comparable to CDKN2A HD.

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA)., Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108., Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events., Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Malignant astrocytomas are characterized by diffusely infiltrating nature, and the abnormality of p53 is a cytogenetic hallmark of astrocytic tumors. To elucidate the relationship between p53 abnormality and invasiveness of the tumors, we studied mutation and protein expression of p53 in 48 consecutive patients with malignant astrocytoma (14 anaplastic astrocytomas and 34 glioblastoma multiformes). The tumors were classified into three categories according to the features of magnetic resonance imaging, and 5, 7, and 36 tumors were classified into diffuse, multiple, and single type, respectively. We then examined how these tumor types correlate with MIB-1 staining index, TP53 gene mutation, and p53 protein expression. We found that p53 immunopositivity or TP53 mutation was frequently observed in diffuse and multiple types. These abnormalities of p53 were also associated with high MIB-1 staining index and strong expression of vascular endothelial growth factor. Furthermore, diffuse- and multiple-type tumors were significantly correlated with poor progression-free survival, whereas only multiple-type tumors were significantly correlated with poor overall survival. As diffuse and multiple features on imaging modalities represent invasive characteristics of the tumors, p53 abnormalities may affect the invasive and aggressive nature of malignant astrocytomas.

We present a case of a 12-year-old female with a germline TP53 mutation who presented with anaplastic astrocytoma and subsequent acute lymphoblastic leukemia (ALL) 13 months after starting treatment with temozolomide (TMZ). The patient had no family history of malignancy except her grand father and his siblings. Although alkylating agents such as TMZ are known to induce secondary hematologic malignancy, only several cases of treatment-related acute leukemia have been reported after TMZ-alone chemotherapy for malignant gliomas. We demonstrate a rare case of TMZ-related ALL in a child with glioma possibly associated with a germline TP53 mutation., (2010 Wiley-Liss, Inc.)