Supratotal Resection of Glioblastoma Allows Better Survival Outcomes Than Gross Total Resection

Objective: Supra-total resection (SupTR) of glioblastoma allows superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe postoperative functional morbidity. This study aimed to analyze institutional cases with respect to the potential survival benefits of additional resection, including lobectomy, as a paradigm for SupTR in patients of glioblastoma.Methods: Between 2014 and 2018, 15 patients with glioblastoma underwent GTR and additional lobectomy at our institution. The postoperative Karnofsky performance score (KPS), progression-free survival (PFS), and overall survival (OS) were analyzed for the patients.Results: Patients with SupTR showed significantly prolonged PFS and OS. The median PFS and OS values for the entire study group were 33.5 months (95% confidence intervals [CI]: 18.5–57.3 months) and 49.1 months (95% CI: 24.7–86.6 months), respectively. Multivariate analysis revealed that O6-DNA-methylguanine methyltransferase (MGMT) promoter methylation status was the only predictor for both superior PFS (p = 0.03, OR 5.7, 95% CI 1.0–49.8) and OS (p = 0.04, OR 6.5, 95% CI 1.1–40.2). There was no significant difference between the pre- and post-operative KPS scores. Conclusions: Our results strongly suggest that SupTR with lobectomy allows superior PFS and OS without negatively affecting the patient performance.

Supratotal Resection of Glioblastoma Allows Better Survival Outcomes than Gross Total Resection

Objective: Supra-total resection (SupTR) of glioblastoma allows superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe postoperative functional morbidity. This study aimed to analyze institutional cases with respect to the potential survival benefits of additional resection, including lobectomy, as a paradigm for SupTR in patients of glioblastoma.Methods: Between 2014 and 2018, 15 patients with glioblastoma underwent GTR and additional lobectomy at our institution. The postoperative Karnofsky performance score (KPS), progression-free survival (PFS), and overall survival (OS) were analyzed for the patients.Results: Patients with SupTR showed significantly prolonged PFS and OS. The median PFS and OS values for the entire study group were 33.5 months (95% confidence intervals [CI]: 18.5–57.3 months) and 49.1 months (95% CI: 24.7–86.6 months), respectively. Multivariate analysis revealed that O6-DNA-methylguanine methyltransferase (MGMT) promoter methylation status was the only predictor for both superior PFS (p = 0.03, OR 5.7, 95% CI 1.0–49.8) and OS (p = 0.04, OR 6.5, 95% CI 1.1–40.2). There was no significant difference between the pre- and post-operative KPS scores. Conclusions: Our results strongly suggest that SupTR with lobectomy allows superior PFS and OS without negatively affecting the patient performance.

Immunohistochemical Analysis of DNA Repair- and Drug-Efflux-Associated Molecules in Tumor and Peritumor Areas of Glioblastoma

Glioblastoma (GBM), the most commonly occurring primary tumor arising within the central nervous system, is characterized by high invasiveness and poor prognosis. In spite of the improvement in surgical techniques, along with the administration of chemo- and radiation therapy and the incessant investigation in search of prospective therapeutic targets, the local recurrence that frequently occurs within the peritumoral brain tissue makes GBM the most malignant and terminal type of astrocytoma. In the current study, we investigated both GBM and peritumoral tissues obtained from 55 hospitalized patients and the expression of three molecules involved in the onset of resistance/unresponsiveness to chemotherapy: O6-methylguanine methyltransferase (MGMT), breast cancer resistance protein (BCRP1), and A2B5. We propose that the expression of these molecules in the peritumoral tissue might be crucial to promoting the development of early tumorigenic events in the tissue surrounding GBM as well as responsible for the recurrence originating in this apparently normal area and, accordingly, for the resistance to treatment with the standard chemotherapeutic regimen. Notably, the inverse correlation found between MGMT expression in peritumoral tissue and patients’ survival suggests a prognostic role for this protein.

PATH-17. NOVEL DUAL HISTONE 3 K27M AND G34R POINT MUTATIONS IN A MIDLINE GLIOMA

BACKGROUND Histone H3 alterations due to mutations on H3F3A and HIST1H3B genes, have in recent years been associated with distinct entities and tumor locations within the context of infiltrative gliomas. H3K27M is associated with a midline location and is included in the WHO 2016 as the diffuse midline glioma H3K27M-mutant, a specific diagnostic entity. H3G34R, thought to be a mutually exclusive alteration, is less common but has been associated with a cerebral hemispheric location. We report the first case to our knowledge with both of these alterations in the same tumor. METHODS Clinical and pathologic records of the patient were reviewed and presented. RESULTS A 39-year-old man presented with acute right face, arm, and leg numbness and mild weakness; examination was notable for right lower motor neuron facial nerve palsy and numbness, along with numbness and subtle slowing of rapid alternating movements in the left arm and leg. A non-enhancing left thalamic mass was identified and stereotactically biopsied. Infiltrative glial neoplasm with moderately-increased cellularity was seen, with ovoid cells, enlarged nuclei, apoptotic bodies, and mitotic figures. No necrosis or microvascular proliferation seen. Immunostain was positive for H3K27M. O6-methylguanine-methyltransferase (MGMT) promoter was not methylated. Next-generation sequencing showed dual in cis H3 point mutations in K27M (HIST1H3B c.83A >T) and G34R (HIST1H3B c.103G >C). Additional alterations were noted in NF1, PIK3CA, ATRX, FGFR3, and NSD1. Isocitrate dehydrogenase (IDH1/2) mutations were not identified. CONCLUSION This case of a young man with a midline glioma is novel for carrying both H3K27M and H3G34R alterations and indicates these alterations are not mutually exclusive. The interaction seen here suggests H3K27M dominance for a midline phenotype.

CTNI-44. INTERIM RESULTS OF PHASE 2 STUDY TO EVALUATE PI3K/mTOR INHIBITOR PAXALISIB (GDC-0084) GIVEN TO NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER

BACKGROUND Paxalisib (GDC-0084) is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). Paxalisib crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. An MTD of 60mg per day has been identified in newly diagnosed glioblastoma (GBM) patient with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. Paxalisib has shown encouraging indications of clinical activity. METHODS This study has a 2-part design: an open-label, dose-escalation phase (Stage 1) to define MTD, followed by an expansion cohort (Stage 2) at the MTD and patients are randomized to take paxalisib, in fed or fasted states. Pharmacokinetic data will be analysed and compared by dose and fed/fasted status. RESULTS Stage 2 (expansion cohort) is fully enrolled and patients are in follow-up. Adverse event profile seems broadly consistent with prior clinical experience and with other PI3K-targeting agents. With analysis including all patients, a sustained PFS signal of 8.5 months is seen and this compares favourably with historical controls. CONCLUSION Paxalisib displays a safety profile consistent with previous data and promising efficacy signals in newly diagnosed GBM. A pivotal study in GBM is planned to commence recruitment later this year.

The Role of CASC2 and miR-21 Interplay in Glioma Malignancy and Patient Outcome

Recently long non-coding RNAs (lncRNAs) were highlighted for their regulatory role in tumor biology. The novel human lncRNA cancer susceptibility candidate 2 (CASC2) has been characterized as a potential tumor suppressor in several tumor types. However, the roles of CASC2 and its interplay with miR-21 in different malignancy grade patient gliomas remain unexplored. Here we screened 99 different malignancy grade astrocytomas for CASC2, and miR-21 gene expression by real-time quantitative polymerase chain reaction (RT-qPCR) in isocitrate dehydrogenase 1 (IDH1) and O-6-methylguanine methyltransferase (MGMT) assessed gliomas. CASC2 expression was significantly downregulated in glioblastomas (p = 0.0003). Gliomas with low CASC2 expression exhibited a high level of miR-21, which was highly associated with the higher glioma grade (p = 0.0001), IDH1 wild type gliomas (p < 0.0001), and poor patient survival (p < 0.001). Taken together, these observations suggest that CASC2 acts as a tumor suppressor and potentially as a competing endogenous RNA (ceRNA) for miR-21, plays important role in IDH1 wild type glioma pathogenesis and patients’ outcomes.

Critical appraisal of MGMT in digestive NET treated with alkylating agents

The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.

Automatic Prediction of MGMT Status in Glioblastoma via Deep Learning-Based MR Image Analysis

Methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is correlated with the effectiveness of the current standard of care in glioblastoma patients. In this study, a deep learning pipeline is designed for automatic prediction of MGMT status in 87 glioblastoma patients with contrast-enhanced T1W images and 66 with fluid-attenuated inversion recovery(FLAIR) images. The end-to-end pipeline completes both tumor segmentation and status classification. The better tumor segmentation performance comes from FLAIR images (Dice score, 0.897±0.007) compared to contrast-enhanced T1WI (Dice score, 0.828±0.108), and the better status prediction is also from the FLAIR images (accuracy, 0.827±0.056; recall, 0.852±0.080; precision, 0.821±0.022; and F1 score, 0.836±0.072). This proposed pipeline not only saves the time in tumor annotation and avoids interrater variability in glioma segmentation but also achieves good prediction of MGMT methylation status. It would help find molecular biomarkers from routine medical images and further facilitate treatment planning.