Optimizing perampanel monotherapy for surgically resected brain tumors.

Perampanel (PER) is an antiseizure medication (ASM) with a unique mechanism of action, which was approved in Japan for use in combination therapy in 2016 and as a monotherapy in 2020. It has exerted antitumor effects against several types of tumors in vitro. However, the efficacy of PER monotherapy for seizure control is not well-established in patients with brain tumor. In the present study, 25 patients with brain tumor treated using PER monotherapy at our institution were analyzed and compared with 45 patients treated using the most commonly prescribed ASM, levetiracetam (LEV). The PER group was younger and had a higher frequency of glioma cases. During drug administration, seizures were observed in two patients from the PER group (8.0%) and five patients from the LEV group (11.1%); however, the difference was not significant. The incidence of adverse effects did not significantly differ between the groups (12.0 and 2.2%, respectively). In the PER group, mild liver dysfunction was observed in two patients and drug rash in one. In the LEV group, a drug-induced rash was observed in one patient. PER monotherapy may be safe and effective for seizure treatment or prophylaxis in patients with brain tumor. Further large-scale clinical studies are warranted.

Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Clinical and Molecular Prognostic Factors for Long-Term Survival of Patients with Glioblastomas in Single-Institutional Consecutive Cohort.

OBJECTIVE: The purpose of this study was to clarify the clinical and molecular characteristics associated with long-term survival in patients with glioblastoma. METHODS: We analyzed the characteristics of 96 glioblastoma patients. Long-term survivors (LTSs) were classified into moderate LTSs (mLTSs), who survived >3 years, and LTSs, who survived >5 years, and compared with short-term survivors (STSs). Clinical and molecular factors were investigated. RESULTS: Younger age, better recursive partitioning analysis class, lack of subventricular zone (SVZ) involvement, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, and loss of 19q were associated with mLTSs as compared with STSs. After adjustment for these factors, younger age and MGMT methylation remained independently associated with mLTSs. Younger age, better recursive partitioning analysis class, lack of SVZ involvement, and loss of 19q were associated with LTSs as compared with STSs. After adjustment, younger age and better preoperative Karnofsky performance scale (KPS) score remained independently associated with LTSs. Kaplan-Meier analyses revealed that younger age (<50 years), better preoperative KPS score (≥70), lack of SVZ involvement, and loss of 19q were associated with longer overall survival. In the multivariate analysis, only age was significantly associated with overall survival. CONCLUSIONS: Younger age and better preoperative KPS score were the characteristics associated with LTSs as compared with STSs. MGMT promoter methylation was associated with mLTSs, but not with LTSs. In addition, lack of SVZ involvement and loss of 19q might be prognostic for longer survival.

Molecular characteristics of pediatric non-ependymal, non­pilocytic gliomas associated with resistance to temozolomide.

Temozolomide constitutes current standard of care for adult patients with high-grade gliomas. However, results for pediatric gliomas are rather disappointing. In order to investigate the molecular differences between pediatric and adult gliomas that could affect sensitivity to temozolomide, we studied 23 pediatric non-ependymal, non-pilocytic gliomas in comparison to 59 consecutive adult gliomas for the expression of O6-methylguanine methyltransferase (MGMT) and the DNA mismatch repair protein, mutS homolog 6 (MSH6) by immunohistochemistry, as well as for the presence or absence of promoter methylation of the MGMT gene by methylation-specific PCR. The expression of MGMT in pediatric gliomas was significantly higher than in adult gliomas, as shown by immunohistochemistry (p=0.00004). This association was conserved if statistical analysis was carried out only in astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma and glioblastoma, p=0.00007), or in oligodendroglial tumors (oligodendroglioma and anaplastic oligodendroglioma, p=0.020). Although methylation-specific PCR was successfully performed only in 15 pediatric gliomas, it also showed a trend toward less frequent methylation in pediatric as opposed to adult gliomas (p=0.242). MSH6 was almost equally expressed in pediatric and adult gliomas. Pediatric gliomas appear to have a distinct molecular profile associated with resistance to temozolomide. Higher expression of MGMT and a trend toward less frequent methylation of the promoter region of MGMT gene may partly account for relative resistance to temozolomide in pediatric gliomas as compared to adult gliomas.

Single-copy gain of chromosome 1q is a negative prognostic marker in pediatric nonependymal, nonpilocytic gliomas.

BACKGROUND: Reports of genetic analyses on pediatric gliomas are few, and those tumors have been far less characterized than adult gliomas. OBJECTIVE: To characterize the genetic and biological features of pediatric gliomas. METHODS: We investigated 23 pediatric nonependymal, nonpilocytic gliomas for chromosomal copy number aberrations (CNAs) by comparative genomic hybridization (CGH), mutations of isocitrate dehydrogenase (IDH) genes by direct sequencing, and proliferative activity and expression of O-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry. RESULTS: The most frequent CNA was single-copy gain of chromosome 1q, with 10 of 20 successfully investigated tumors showing the abnormality (50%). Other CNAs detected by CGH included gain on 7q (+7q) in 6, +9q in 5, +17q in 5, and + 7p in 4 cases. Gain of entire chromosome 7 was rare (2 cases), and codeletion of 1p and 19q was not detected. Gain of 1q was significantly predictive for shorter progression-free survival (PFS) and overall survival (OS), and even more closely associated with poor clinical outcome than histological grade (P = .0009 for PFS, P = .003 for OS by 1q status; P = .004 for PFS, P = .035 for OS by high-grade vs low-grade). Gain of 1q was also significantly correlated with proliferative activity (P = .0002), and tumors with 1q gain showed a trend toward higher MGMT expression (P = .27). Mutation of IDH1 gene was detected in only 2 of 17 tumors successfully analyzed. CONCLUSION: Single copy gain of 1q is associated with biological features of pediatric gliomas, and is a negative prognostic marker in patients with those tumors.