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Background: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma., Methods: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%., Results: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27-66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4-17.7) and 1.5 (1.4-1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3-4 and 2.0% for Grade 5; most adverse events resolved and were manageable., Conclusions: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types., Clinical Trial Registration: JapicCTI-152967., (© 2021. The Author(s).)

Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.

Isocitrate dehydrogenase (IDH)1/2 mutations have been proposed as a genetic marker for secondary glioblastoma (sGBM). This study aimed to evaluate the impact of the IDH1/2 mutations on the clinical course and genetic alterations of sGBMs, which histopathologically progressed from lower-grade gliomas. We investigated 18 sGBMs, including 8 sGBMs with IDH1/2 mutations (sGBM-Mut) and 10 with wild-type IDH1/2 (sGBM-Wt). The median overall survival time of patients with sGBM-Mut was significantly longer than that of patients with sGBM-Wt (68.2 vs. 25.3 months). The median time from initial diagnosis to sGBM diagnosis was also significantly longer for sGBM-Mut than for sGBM-Wt (50.1 vs. 13.4 months). There was no difference in the median survival time from the sGBM diagnosis between sGBM-Mut and sGBM-Wt (6.75 vs. 6.8 months). All sGBM-Mut (7 of 7) and 6 of 9 sGBM-Wt had TP53 mutations, and the remaining one-thirds of sGBM-Wt had neither TP53 mutations nor 1p/19q codeletion. These observations suggest that IDH1/2 mutations have an impact on the glioma history of sGBM with different genetic pathway. The aggressive progression to sGBM-Wt suggest the need for more intense treatment to the IDH1/2 wild-type tumors.

Glioblastomas, which are the most common primary intracranial tumor, are associated with the poorest survival time, which is typically 1-2 years. Age at initial diagnosis, Karnofsky performance score, and O(6)-methylguanine DNA-methyltransferase (MGMT) promoter methylation status are the most well-documented predictors of survival in patients with newly diagnosed glioblastoma. Few studies have examined prognostic factors in patients with recurrent glioblastomas. At relapse, the pathological features of glioblastomas are affected by tumor regrowth and the influence of chemoradiotherapy during the initial treatment. Morphological transformations at recurrence include quantitative changes in tumor cells, such as the presence of giant cells and gemistocytic cell formation, radiation necrosis, and vascular structural changes. Therefore, we should carefully examine pathological findings at recurrence. In this report, we analyzed MGMT promoter status, the MIB-1 index, and the pathology of tumor samples at the first (primary tumor) and second (recurrent tumor) surgeries and clarified prognostic factors in patients with recurrent cases. In the multivariate analysis, we showed that MIB-1 indexes at the time of the second surgery (p = 0.004) persisted as a significant independent prognostic factor in survival of patients with recurrent glioblastoma.

The naturally occurring mutated form of the epidermal growth factor receptor, deltaEGFR (also named EGFRvIII and de2-7EGFR), greatly enhances glioblastoma (GBM) cell growth in vivo through several activities, such as down-regulating p27 and up-regulating BclX(L) while increasing signaling through the RAS-MAPK and PI3-K cascades. More than half of GBMs, especially of the de novo type, overexpress EGFR, and 50%-70% of these express deltaEGFR. However, little is known about the distribution of deltaEGFR-expressing tumor cells within surgical specimens. In order to address this clinically important issue, we performed immunohistochemical analyses of 53 GBMs obtained during surgery using the anti- deltaEGFR monoclonal antibody, DH8.3. We also simultaneously analyzed wild-type EGFR expression in these tissues using the anti-EGFR monoclonal antibody, EGFR.113. deltaEGFR and wild-type EGFR expression were observed in 20/53 (38%) and 29/53 (55%), respectively. Nineteen (95%) of the deltaEGFR-positive tumors also expressed wild-type EGFR; one case was deltaEGFR-positive but wild-type EGFR-negative. In 13/20 (65%) of the deltaEGFR-positive tumors, tumor cells were scattered diffusely within the tumors, 6/20 showed geographical distribution of deltaEGFR-positive tumor cells, and one case showed homogeneous staining. In the wild-type EGFR-positive cases, almost all tumor cells expressed EGFR. The differential distribution of cells expressing the two receptors observed here may suggest either that deltaEGFR arises at a low frequency from wild-type EGFR-expressing cells, perhaps during the process of gene amplification, or that there is a paracrine-type of interaction between them.