Chang, Edward F.

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C>T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p<0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p<0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.

Abstract INTRODUCTION Glioblastoma has a poor prognosis, further complicated by postoperative seizures. We analyzed various factors associated with postoperative seizures in glioblastoma. METHODS Retrospective chart review of 932 patients who underwent craniotomy for glioblastoma (777=83.4% newly diagnosed; 155=16.6% recurrent) at our institution (2002–2014). Postoperative seizures were defined as those occurring within 14 days of surgery. RESULTS Our cohort consisted of 49.9% (n=465) males with mean age of 55.8 (range 9–91) years. In total, 69 (7.4%) had postoperative seizures with mean time from surgery to seizure of 3.1 days (IQR=1–4). Of 536 patients (57.5%) receiving seizure prophylaxis, those treated with Keppra were more likely to have postoperative seizures compared to those on Dilantin (10.9% vs 5.0%; p=0.022). Primary tumor patients were less likely to seize postoperatively compared to recurrent tumor patients (9.7% vs 19%; p=0.016). Patients presenting with seizure as chief complaint (12.1% vs 5.1%; p=0.025) and those with >20% of Chromosome 10 deletion were more likely to have seizures postoperatively (12.4% vs 6.1%; p=0.0029). Risk factors for postop seizures for newly-diagnosed patients included subtotal resection versus gross total resection (28.0% vs 7.1%; p=0.022). Risk factors for postop seizures for recurrent patients were >5% EGFR amplification (23.5% vs 5.8%; p=0.0021) and hyponatremia within mean 2.5 days (IQR 0–1) after surgery (20.8% vs 7.1%; p=0.035). CONCLUSION We identified several risk factors for postoperative seizures in glioblastoma patients, most of which were clinical (seizure as chief complaint, the antiepileptic chosen for prophylaxis, and extent of resection), while some were molecular and linked to genes whose products have demonstrated links to epileptogeneicity (Chromosome 10, EGFR). These findings may assist physicians in detecting glioblastoma patients that are at higher risk for postoperative seizures and in providing prophylaxis to reduce morbidity.