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Background: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001., Methods: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method., Results: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples., Conclusions: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

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 remains 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 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)., 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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022. 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).)

Background and Objectives: Mutant 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., Methods: We 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., Results: Tissue 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)., Discussion: We 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., (© 2021 American Academy of Neurology.)

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 <70. Four patients (28.6%) achieved a complete or partial radiological response, and three patients (21.4%) had an improved Karnofsky performance status after re-irradiation combined with bevacizumab. Grade 3/4 toxicities included leukopenia in four patients (28.6%), hypertension in three (21.4%), proteinuria in one (7.1%) and gastrointestinal hemorrhage in one (7.1%)., 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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

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 < 0.05). A multivariable Cox regression model revealed that 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.

Importance: A blood-based screening tool for detecting diffuse glioma is necessary to improve clinical outcomes., Objectives: To establish models using serum microRNAs to distinguish patients with diffuse glioma from control individuals without cancer (the Glioma Index) and to differentiate glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic brain tumors (the 3-Tumor Index)., Design, Setting, and Participants: This retrospective, case-control diagnostic study included 157 patients with diffuse glioma and 109 patients with central nervous system (CNS) diseases other than diffuse glioma diagnosed from August 1, 2008, through May 1, 2016, and 314 sex- and age-matched controls without cancer. Samples of patients with diffuse glioma and controls were randomly divided into training and validation set 1, and those of patients with CNS diseases other than diffuse glioma were allocated to an exploratory set. Samples of patients with GBM, PCNSL, and metastatic brain tumors were randomly divided into training and validation set 2. Data were analyzed from April 1, 2018, to March 31, 2019., Main Outcomes and Measures: The expression of 2565 microRNAs was assessed, and the diagnostic performance was evaluated by calculating the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, and accuracy., Results: A total of 580 patients were included in the analysis (309 [53.3%] male; median age, 57 years [range, 10-87 years]). In training set 1, 100 patients with diffuse glioma (median age, 56 years [range, 14-87 years]; 55 male [55.0%]) were compared with 200 control patients (median age, 56 years [range, 14-87 years]; 105 male [52.5%]), and the Glioma Index was constructed using 3 microRNAs (miR-4763-3p, miR-1915-3p, and miR-3679-5p). In validation set 1, the AUC was 0.99 (95% CI, 0.99-1.00); sensitivity, 0.95 (95% CI, 0.89-1.00); and specificity, 0.97 (95% CI, 0.93-1.00). The Glioma Index classified 39 of 42 PCNSL samples (92.9%) and 25 of 28 metastatic brain tumor samples (89.3%) as positive and 2 of 2 spinal tumors (100%) as negative in the exploratory set. In training set 2, 68 patients with GBM, 34 with PCNSL, and 23 with metastatic brain tumor were compared, and the 3-Tumor Index was constructed using 48 microRNAs. The 3-Tumor Index had an accuracy of 0.80, positively detecting 16 of 17 GBM samples (94.1%), 4 of 5 metastatic brain tumor samples (80.0%), and 4 of 8 PCNSL samples (50.0%) in validation set 2., Conclusions and Relevance: This study appears to have identified promising serum microRNA combinations for detecting diffuse glioma and for assessing histologic features of brain tumors.

Aims: Intraoperative consultation using frozen sections (FSs) is an integral component of clinical practice. As a quality control measure, FS diagnosis is subsequently compared with the findings on a FS control slide. These control slides can be used for immunohistochemistry, and the immunohistochemical performance in FS controls is known to be antibody-dependent. Isocitrate dehydrogenase (IDH) is mutated in >80% of lower-grade infiltrating gliomas in adults and in ~10% of glioblastomas, with IDH1 (R132H) being the most common mutation. IDH status is used as a major classifier of glioma. An IDH1 (R132H)-specific antibody (H09) has been accepted as a robust surrogate for genetic testing. In this study, we aimed to determine how previous freezing and thawing affects IDH1 immunohistochemistry., Methods and Results: Thirty cases of IDH1 (R132H)-mutant diffuse glioma, which were originally assessed on FSs, were retrieved. The positive IDH1 (R132H) status of each case was previously determined with pyrosequencing and H09 immunohistochemistry on permanent sections. The FS control tissue of each case was immunostained with H09 antibody. Among 30 gliomas, 25 showed negative reactivity on FS control slides, whereas, in the remaining five, the staining was uninterpretable, owing to a high diffuse background. Of the former 25 specimens, 20 showed at least focal areas with variably increased levels of background staining, whereas the remaining five specimens showed a relatively pristine background., Conclusions: We conclude that IDH1 (R132H)-specific (H09) immunohistochemistry often results in false-negative reactions on FS controls with focally increased background staining, and this application should be avoided in clinical practice., (© 2018 John Wiley & Sons Ltd.)

The radiological features of lower-grade gliomas (LGGs) classified according to isocitrate dehydrogenase (IDH) mutations and codeletion of chromosomal arms 1p and 19q (1p/19q codeletion) remain unclear. We aimed to systematically characterize the radiological features of molecularly classified LGGs using IDH and 1p/19q codeletion statuses. One hundred and one LGGs were re-classified into 36 tumors with IDH mutations (IDH-Mut), 35 tumors with IDH-Mut and 1p/19q codeletion (IDH-Mut/Codel), and 30 tumors with wildtype IDH (IDH-Wt). Calcification, heterogeneous signal intensity in T2-weighted images, and cortical invasion were significantly more frequent in IDH-Mut/Codel than in IDH-Mut and IDH-Wt tumors (calcification: 48.6 vs 5.6 and 6.7%, heterogeneity: 94.3 vs 33.3 and 50%, and cortical invasion: 94.3 vs 55.6 and 40.0%, respectively). A frontal location was significantly more frequent for IDH-Mut and IDH-Mut/Codel than for IDH-Wt tumors (52.8 and 71.4 vs 12.1%, respectively), and dense contrast-enhancement was significantly more frequent in IDH-Wt than in IDH-Mut and IDH-Mut/Codel tumors (50.0 vs 2.8 and 2.9%, respectively). In conclusion, IDH-Mut/Codel tumors were characterized by calcification, frontal location, heterogeneous signal intensity, and cortical invasion; IDH-Mut tumors differed from IDH-Wt tumors according to predominant frontal lobe location and less frequent dense enhancement patterns.

Objective: Although the number of long-term survivors of glioma has increased, there has been little research on the health-related quality of life of long-term survivors of Grade II glioma following treatment with surgery, radiotherapy and chemotherapy. In this study, we aimed to document the health-related quality of life of people diagnosed with Grade II glioma who had survived >10 years with no evidence of disease at the time of the health-related quality of life survey., Methods: To investigate the health-related quality of life of Grade II glioma survivors without evidence of disease, we surveyed 50 patients 0-20 years after their initial treatments. Each patient completed a multi-part health-related quality of life questionnaire. Based on these surveys, we examined the relationships between health-related quality of life scores and time since initial treatment, Karnofsky Performance Scale scores at the time of the survey, and history of recurrence, radiotherapy and chemotherapy., Results: Excepting bladder control, long-term survivors maintained their quality of life as determined by comparing patients surveyed < 5 and ≥ 10 years after their initial treatment (P < 0.05). Neither radiotherapy nor chemotherapy at the initial treatment was observed to affect health-related quality of life. However, a history of recurrence was significantly associated with deteriorations in many health-related quality of life functional and symptom scores. The Karnofsky Performance Scale scores of patients with a history of recurrence were significantly lower than those without it (P = 0.02). This deterioration was observed in both univariate and multivariate analyses., Conclusions: Our results indicate that declines in health-related quality of life among long-term survivors of Grade II glioma mainly result from impaired Karnofsky Performance Scale, which is a consequence of disease recurrence., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The association between p53 immunohistochemistry and TP53 mutation status has been controversial. The present study aims to re-evaluate the efficacy of p53 immunohistochemistry to predict the mutational status of TP53. A total of 157 diffuse gliomas (World Health Organization grades II-IV) were assessed by exon-by-exon DNA sequencing from exon 4 through 10 of TP53 using frozen tissue samples. Immunohistochemistry with a p53 antibody (DO-7) on paired formalin-fixed paraffin-embedded materials was assessed for the extent and intensity of reactivity in all cases. A total of 72 mutations were detected in 66 samples. They included 60 missense mutations, five nonsense mutations, four deletions and three alterations in the splicing sites. A receiver operating characteristic curve analysis revealed that strong p53 immunoreactivity in more than 10% of cells provided the most accurate prediction of mutation. Using this cutoff value, 52 of 55 immunopositive cases harbored a mutation, whereas only 14 of 102 immunonegative cases showed mutations, sensitivity and specificity being 78.8% and 96.7%. Tumors with frameshift mutations frequently showed negative immunostaining. Staining interpretation by an independent observer yielded comparable accuracy. We thus propose p53 immunohistochemistry as a moderately sensitive and highly specific marker to predict TP53 mutation., (© 2014 International Society of Neuropathology.)

Assessment of the mutational status of the isocitrate dehydrogenase 1/2 (IDH1/2) gene has become an integral part of the standard diagnostic procedure and, therefore, needs to be accurate. This may, however, be compromised by various factors including the method of analysis and a low tumor cell content. We have developed a rapid, sensitive and robust assay to detect all types of mutation in either IDH1 or IDH2 using pyrosequencing. The efficacy of detecting mutation was evaluated using a panel of control plasmids representing all the different types of IDH1/2 mutation and a set of 160 tumor specimens. The sensitivity of the assays was examined by a serial dilution analysis performed on samples containing various ratios of wild-type and mutant alleles. The pyrosequencing assay detected as little as 5 % of mutant alleles for most mutation types, while conventional Sanger sequencing required the presence of at least 20 % of mutant alleles for identifying mutations. The pyrosequencing assay detected IDH1/2 mutations in three samples which were missed by Sanger sequencing due to their low tumor cell contents. Our assay is particularly useful for the analysis of a large number of specimens as in a retrospective clinical study for example.

Background: The alkylating agent temozolomide (TMZ) is widely used for the treatment of gliomas. Although reports of treatment-related myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) associated with TMZ are accumulating, it remains unclear whether TMZ has the same leukemogenic potential as other alkylating agents., Methods: We performed a single-institution retrospective analysis using a database of 359 glioma patients given nimustine (ACNU)-based therapy, TMZ-based therapy, or combination therapy, who were followed up for a minimum of 2 months, between January 1990 and December 2009, at the National Cancer Center Hospital in Japan., Results: Of the 359 patients, 225 received ACNU alone or ACNU plus other chemotherapeutic drugs (ACNU-based group; median follow-up period, 31.4 mo), 63 patients received ACNU-based therapy followed by TMZ therapy (ACNU-TMZ group; median follow-up period, 19.1 mo), and 71 patients received TMZ alone or TMZ plus other chemotherapeutic drugs (TMZ-based group; median follow-up period, 16.9 mo). Three patients in the ACNU-based group developed MDS/AML (incidence rate: 2.9 cases per 1000 person-years), 2 patients in the ACNU-TMZ group developed MDS/AML (13.0 cases per 1000 person-years), and 1 patient in the TMZ-based group developed ALL (9.9 cases per 1000 person-years)., Conclusions: Despite the limitations of this study, published reports and our results suggest that TMZ induces secondary hematological malignancies, particularly ALL, and might shorten the latency period when used in combination with other chemotherapeutic agents.

Primitive polar spongioblastoma was first described by Russell and Cairns in 1947. However, the polar spongioblastoma pattern is often seen in many neuroepithelial tumors, and this category was deleted in the previous World Health Organization (WHO) classification. In 2010, Nagaishi et al. reported on a case involving a neuroepithelial tumor with the typical histological pattern of polar spongioblastoma and suggested that this tumor might not be suited to any of the neuroepithelial tumors in the current WHO classification. We report on an autopsy case involving an unclassified high-grade glioma with polar spongioblastoma pattern that was very similar to the case described by Nagaishi et al. A 44-year-old man who presented with a headache exhibited a tumor of the right frontal lobe on MRI. Histological diagnosis of the tumor obtained by gross total resection was high-grade glioma, which was composed of the parallel palisading of spindle tumor cells expressing GFAP, without microvascular proliferation (MVP) and necrosis. Conventional chemoradiotherapy was performed, but the case was complicated by cerebrospinal fluid (CSF) dissemination that resulted in multiple extraneural metastases through systemic diversionary CSF shunting. Finally, the patient died approximately 13 months after the initial treatment. Both the cerebral and Douglas pouch tumors that were obtained at autopsy were diagnosed as typical glioblastomas, and they were composed of the proliferation of atypical astrocytes with MVP and pseudopalisading necrosis without the formation of rhythmic palisading. Although the histological findings were different from that of the first operation, immunohistochemical and genetic profiles demonstrated almost the same results. This tumor was not classified as a typical glioblastoma by the initial findings, but it had the nature of a glioblastoma. These findings suggest that the tumor might be classified as a new subset of glioblastoma called glioblastoma with polar spongioblastoma pattern., (© 2012 Japanese Society of Neuropathology.)

The impact of isocitrate dehydrogenase (IDH1/2) mutations on the malignant progression of gliomas was investigated by comparing the histopathological features of 53 grade II and III gliomas after recurrence according to the IDH1/2 status. We identified IDH1/2 mutations in 44.4 % (16 of 36) of astrocytic tumors and 70.6 % (12 of 17) of oligodendroglial tumors. Histopathological malignant progression was observed in 68.8 % (11 in 16) and 55 % (11 in 20) of astrocytic tumors with and without IDH1/2 mutations, respectively. There were 8 secondary glioblastomas (GBM) that had progressed from 5 diffuse astrocytomas (DA) and 3 anaplastic astrocytomas (AA) with IDH1/2 mutations. Seven secondary GBMs were derived from 3 DAs and 4 AAs with wild-type IDH1/2. Malignant progression was observed in 47.1 % (8 of 17) of oligodendroglial tumors. All 12 oligodendroglial tumors with IDH1/2 mutations remained as such without progressing to GBM, whereas 3 of the 5 oligodendroglial tumors without IDH1/2 mutations progressed to GBM at recurrence. In conclusion, grade II and III gliomas developed to more malignant histological types, irrespective of the IDH1/2 mutation status, and the monitoring of the IDH1/2 status could be of value to predict the development of GBM in patients with oligodendroglial tumors.

Reliable prognostic biomarkers of grade II gliomas remain unclear. This study aimed to examine the role of mutations of isocitrate dehydrogenase (IDH1/2), 1p/19q co-deletion, and clinicopathological factors in patients with grade II glioma who were primarily treated with radiotherapy or chemoradiotherapy after surgery. Seventy-two consecutive patients, including 49 cases of diffuse astrocytomas (DA), 4 oligodendrogliomas (OL) and 19 oligoastrocytomas (OA), who underwent treatment from 1991 to 2010 at a single institution were examined. The overall survival (OS) of the DA patients (8.3 years) was significantly shorter than that of the OL and OA patients (11.7 years). IDH1/2 mutations were found in 46.9% of the DA patients and 82.6% of the OL and OA patients. The progression-free survival (PFS) and OS of the patients with IDH1/2 mutations (8.4 and 16.3 years) were significantly longer than those of the patients without IDH1/2 mutations (3.3 and 4.5 years). Among the patients with IDH1/2 mutations, those who were initially treated with chemoradiotherapy including nimustine hydrochloride (ACNU), had significantly longer PFS than those treated with radiotherapy alone, whereas no significant difference in PFS was observed between the chemoradiotherapy and radiotherapy groups in the patients without IDH1/2 mutations. Oligodendroglial tumors, age <40 years, initial Karnofsky performance status (KPS) ≥80, and IDH1/2 mutations were favorable prognostic factors regarding PFS and OS. IDH1/2 mutation was a predictive factor of response to chemoradiotherapy in grade II gliomas. Patients with IDH1/2 mutations may benefit more from chemoraiotherapy than those without IDH1/2 mutations.

Temozolomide (TMZ) is the standard chemotherapy treatment for glioblastoma. Lymphocytopenia is reported to be the most frequent and severe adverse effect of TMZ and leads to opportunistic infections. Few cases of TMZ-induced cytomegalovirus (CMV) reactivation have so far been reported, and there are no guidelines regarding the use of chemotherapy after recovery from CMV reactivation. We herein report the case of a 45-year-old man with glioblastoma who developed CMV hepatitis following surgery and chemoradiotherapy with concomitant TMZ and steroids. After successful treatment of the CMV infection with an antiviral agent and recovery from the lymphocytopenia were achieved, the patient resumed maintenance therapy with TMZ under careful monitoring of his lymphocyte count and CMV pp65 antigenemia level.

Objectives: Patients with malignant gliomas have an even worse prognosis than other cancer patients, and they sometimes undergo surgery and chemo-radiotherapy without having been informed of the nature of the disease and its prognosis in Japan. Often, patients with glioblastoma are only told that they have a brain tumor, although other family members are told of the real diagnosis and prognosis. Since patients with glioblastoma, often experience a rapid deterioration in their condition, they usually do not have enough time to seek a second opinion regarding their disease. We surveyed neurosurgeons in Japan with regard to their policies and attitudes concerning the disclosure of a diagnosis of glioma and their thoughts on the end-of-life care of glioma patients., Methods: A survey was performed in November, 2007. A questionnaire was sent by e-mail to 259 participants who planned to attend the 25th Brain Tumor Conference in Japan., Results: One hundred and thirty-two participants (51%) returned the questionnaire. Almost all the respondents were neurosurgeons specializing in malignant brain tumors. The percentages of respondents who informed their patients of a diagnosis of grade 2 astrocytoma, grade 3 or grade 4 glioblastoma were 73%, 57% and 37%, respectively. More than 80% of all glioblastoma patients were only told that they had a malignant brain tumor. Sixty-eight percent of the doctors told the family members, but not the patients, of the real diagnosis. The neurosurgeons' policies and attitudes toward end-of-life care for patients with gliomas were also analyzed., Conclusions: Most neurosurgeons have difficulty disclosing a diagnosis of glioma and providing end-of-life care. This survey will help to develop guidelines regarding disclosure and the decision to pursue end-of-life care for patients with gliomas. (Received : March 19, 2009, Accepted : June 8, 2009)