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We aimed to build a robust classifier for the MGMT methylation status of glioblastoma in multiparametric MRI. We focused on multi-habitat deep image descriptors as our basic focus. A subset of the BRATS 2021 MGMT methylation dataset containing both MGMT class labels and segmentation masks was used. A comprehensive mask fusion approach was developed to select relevant image crops of diseased tissue. These fusion masks, which were guided by multiple sequences, helped collect information from the regions that seem disease-free to radiologists in standard MRI sequences while harboring pathology. Integrating the information in different MRI sequences and leveraging the high entropic capacity of deep neural networks, we built a 3D ROI-based custom CNN classifier for the automatic prediction of MGMT methylation status of glioblastoma in multi-parametric MRI. Single sequence-based classifiers reached intermediate predictive performance with 0.65, 0.71, 0.77, and 0.82 accuracy for T1W, T2W, T1 contrast-enhanced, and FLAIR sequences, respectively. The multiparametric classifier using T1 contrast-enhanced and FLAIR images reached 0.88 accuracy. The accuracy of the four-input model that used all sequences was 0.81. The best model reached 0.90 ROC AUC value. Integrating human knowledge in the form of relevant target selection was a useful approach in MGMT methylation status prediction in MRI. Exploration of means to integrate radiology knowledge into the models and achieve human-machine collaboration may help to develop better models. MGMT methylation status of glioblastoma is an important prognostic marker and is also important for treatment decisions. The preoperative non-invasive predictive ability and the explanation tools of the developed model may help clinicians to better understand imaging phenotypes of MGMT methylation status of glial tumors. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) and ovarian cancer (OC) are rapidly increasing in Saudi Arabia. BRCA1 and MGMT epimutations have been linked to a higher risk of these malignancies. The present research investigated the impact of these epimutations on the prevalence of BC and OC among Saudi women. DNA methylation was evaluated using methylation-specific PCR, whereas mRNA expression levels were assessed using qRT-PCR. We evaluated white blood cell (WBC)–BRCA1 methylation in 1958 Saudi women (908 BC patients, 223 OC patients, and 827 controls). MGMT methylation was determined in 1534 of the 1958 women (700 BC patients, 223 OC patients, and 611 controls). BRCA1 methylation was detected in 8.6% of the controls and 11% of the BC patients. This epimutation was linked to 13.8% of the early-onset BC patients (p = 0.003) and 20% of the triple-negative breast cancer (TNBC) patients (p = 0.0001). BRCA1 methylation was also detected in 14% of the OC patients (p = 0.011), 19.4% of patients aged <55 years (p = 0.0007), and 23.4% of high-grade serous ovarian cancer (HGSOC) patients. In contrast, the BRCA1 mutation was detected in 24% of the OC patients, 27.4% of patients aged ≥55 years, and 26.7% of the HGSOC patients. However, MGMT methylation was detected in 10% of the controls and 17.4% of the BC patients (p = 0.0003). This epimutation was linked to 26.4% of the late-onset BC patients (p = 0.0001) and 11% of the TNBC patients. MGMT methylation was also found in 15.2% of the OC patients (p = 0.034) and 19.1% of HGSOC patients (p = 0.054). Furthermore, 36% of the BRCA1-methylated patients and 34.5% of the MGMT-methylated patients had a family history of cancer, including breast and ovarian cancer. Notably, BRCA1 and MGMT mRNA levels were greater in the WBC RNA of the BC patients and cancer-free methylation carriers than in that of the OC patients. Our data indicate that BRCA1 and MGMT epimutations significantly contribute to the development of breast cancer and ovarian cancer in Saudi cancer patients. These blood-based biomarkers could help identify female patients at high risk of developing TNBC and HGSOC at an early age. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors. Methods: We analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach. Results: We found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient’s survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region. Conclusion: We propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors. Methods: We analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient's survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach. Results: We found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient's survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region. Conclusion: We propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma. [ABSTRACT FROM AUTHOR]

Background and purposeWhile relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions.Methods1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV

Introduction: In 2021, the World Health Organization published a new classification system for central nervous system tumors. This study reclassified the adult diffuse glioma (ADG) into astrocytoma, oligodendroglioma, and glioblastoma (GBM) according to the new tumor classification. Methods: The association of TERT promoter (pTERT) mutation, MGMT methylation, and CD47/TIGIT expression with patient prognosis was investigated. Results: Immunohistochemical analysis showed that the expression levels of CD47 and TIGIT in tumor tissues were significantly higher than those in normal brain tissues. CD47 levels were higher in GBM and grade 4 astrocytoma tissues. TIGIT expression was also higher in patients with GBM. The high expressions of CD47, TIGIT, and CD47/TIGIT were positively correlated with MGMT unmethylation but not pTERT mutation. Moreover, MGMT unmethylation was associated with poor overall survival in astrocytoma. High CD47, TIGIT, and CD47/TIGIT levels were associated with significantly reduced survival in ADG and GBM. GBM, MGMT unmethylation, and high CD47 expression were independent prognostic factors for overall survival in ADG. Discussion: Collectively, these results showed that the MGMT unmethylation and high levels of CD47 and TIGIT are associated with a poor prognosis in ADG. Patients with high CD47 and TIGIT expression may benefit from anti-CD47 and TIGIT immunotherapy. [ABSTRACT FROM AUTHOR]

High grade gliomas are associated with cognitive problems. The aim of the study was to investigate cognitive functioning in a cohort of patients with high grade glioma, according to isocitrate dehydrogenase (IDH) and methyl guanine methyl transferase (MGMT) status and other clinical characteristics.

BackgroundGlioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors.MethodsWe analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach.ResultsWe found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient’s survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region.ConclusionWe propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma.

Purpose: New treatments are needed to improve the overall survival of patients with glioblastoma Metformin is known for anti-tumorigenic effects in cancers, including breast and pancreas cancers. In this study, we assessed the association between metformin use and overall survival in glioblastoma patients. Methods: We retrospectively studied 241 patients who underwent surgery at diagnosis of glioblastoma between 2014 and 2018. Metformin was used for pre-existing type 2 diabetes mellitus or in the prevention or management of glucocorticoid induced hyperglycemia. Kaplan-Meier curves and log-rank p test were used for univariate analysis. Cox-proportional hazards model was used to generate adjusted hazard ratios for multivariate analysis. Results: Metformin use was associated with longer survival in patients with tumors that had a methylated O6-methylguanine DNA methyltransferase gene (MGMT) promoter (484 days 95% CI: 56–911 vs. 394 days 95% CI: 249–538, Log-Rank test: 6.5, p = 0.01). Cox regression analysis shows that metformin associates with lower risk of death at 2 years in patients with glioblastoma containing a methylated MGMT promoter (aHR = 0.497, 95% CI 0.26–0.93, p = 0.028). Conclusion: Our findings suggest a survival benefit with metformin use in patients with glioblastomas having methylation of the MGMT promoter. [ABSTRACT FROM AUTHOR]

Introduction. Recently, the incidence of brain glial tumours has increased significantly worldwide. Gliomas are among the most malignant types of tumours of the central nervous system. Patients diagnosed with glial tumours have a very unfavourable prognosis leading to death, and the course of the disease itself has a negative impact on their physical, mental and social condition. Aim. The aim of this study was to determine the effect of the results of histological and genetic tests as well as the degree of resection of primary CNS tumours on the survival of patients undergoing neurosurgery and complementary oncological treatment — pharmacology and radiotherapy. Material and Methods. The research was carried out on the basis of an analysis of medical records (2019–2021) of 63 adult patients from the Department of Neurosurgery of the Specialist Municipal Hospital of Nicolaus Copernicus in Toruń. The study group included patients who had been diagnosed with a primary brain tumour and had undergone neurosurgery and complementary oncological treatment. The analysis of medical documentation consisted in comparing the results of histopathological tests with the results of specialized molecular tests and correlating them with the survival time of patients. The statistical analysis was carried out using the Pearson correlation, statistical inference was made at the significance level of p=0.05. Results. Based on the obtained results, it was found that the presence of MGMT gene promoter methylation (r=0.30, p=0.018) and IDH mutation (r=0.38, p=0.002) correlated positively with survival. The extent of resection also had a significant impact on patient survival (r=0.55, p

Objective: To investigate whether extending adjuvant temozolomide (TMZ) improved the prognosis of newly diagnosed glioblastoma (GBM) patients with different mutation statuses of O6-methylguanine DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 (IDH1), p53 and different expression level of Ki67. Methods: This study was a retrospective cohort study that postoperative patients with newly diagnosed GBM who did not progress after receiving radiotherapy with concomitant and 6 cycles of adjuvant TMZ were enrolled in control group, and those received more than 6 cycles of adjuvant TMZ were incorporated in extended group. Patients were stratified by MGMT expression, IDH1 mutation, p53 mutation and expression level of Ki67. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Result: A total of 93 postoperative patients with newly diagnosed GBM were included in this study, 40 and 53 cases were included in control group and extended group, respectively. On the whole, extended adjuvant TMZ chemotherapy significantly prolonged OS and PFS of patients with newly diagnosed GBM [median OS (mOS): 29.00 months vs. 16.70 months, P < 0.001; median PFS (mPFS): 13.80 months vs. 9.60 months, P = 0.002]. The results of subgroup analysis showed that patients with methylated MGMT in extended group had significantly longer OS and PFS than those in control group; patients with IDH1 mutation benefited more from extended adjuvant TMZ chemotherapy than those with wild-type IDH1; there was no significant difference in the effect of extended TMZ chemotherapy on OS between GBM patients with wild-type p53 and those with mutant p53; compared with GBM patients with lower expression of Ki67, extended adjuvant TMZ treatment dramatically improved the OS and PFS of those with higher expression of Ki67. Conclusion: The therapeutic schedule of extended adjuvant TMZ significantly prolonged OS and PFS of patients with newly diagnosed GBM regardless of p53 mutation status, and patients with different MGMT methylation, IDH1 mutation and Ki67 expression level benefited differently from extended adjuvant TMZ chemotherapy. [ABSTRACT FROM AUTHOR]

Background: There remains an unmet need to identify molecular biomarkers in ewing sarcoma (ES). We sought to assess the influence of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation on response and progression- free survival (PFS) following initiation of irinotecan and temozolomide (IT), PFS following initiation of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC-IE), and overall survival (OS). Materials and methods: Data of advanced ES patients, treated with IT were retrospectively collected. patients were required to have progression after prior VDC-IE. MGMT promoter methylation was assessed on non-decalcified Formalin-fixed paraffin embedded (FFPE) tissue using methylation sensitive restriction enzyme-quantitative PCR (MSRE-GPCR). survival was estimated by the Kaplan-Meier method. results: A total of 20 ES patients underwent MGMT promoter methylation testing, and were eligible for analysis. Five patients (25%) had methylated MGMT, whereas the remaining (15; 75%) had unmethylated promoter. Five (25%) had objective response to IT, with no observed difference by promoter methylation (p = 0.76). Median PFS from initiation of IT for methylated vs. unmethylated MGMT patients was 4.9 and 1.2 months, respectively, p = 0.69. Median PFS from date of initiation of VDC-IE was significantly superior in the methylated group; 27.8 vs. 8.6 months, p = 0.034. Median OS was superior but not statistically significant in the methylated group. conclusion: MGMT-promoter methylation did not correlate with clinical activity or outcomes following the IT regimen for advanced ES. however, methylated MGMT predicted significantly superior PFS following initiation of the standard VDC-IE protocol. [ABSTRACT FROM AUTHOR]

Abstract Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) neoplasm in adults, and has an almost universally poor prognosis. Recently, an emphasis on genetic and epigenetic profiling has revealed a number of molecular features useful in the diagnostic and prognostic classification of GBM, advancing our understanding of the underlying features that make these tumors so aggressive and providing the rationale for the creation of better targeted therapeutics. One such method, DNA methylation profiling, has recently emerged as an important technique for the classification of CNS tumors, with diagnostic accuracy in some cases surpassing traditional methods. However, how DNA methylation profiles change with the course of the disease remains less understood. Here, we present a case of a 30-year-old male with primary IDH-mutant GBM with widespread recurrence and death two years later. Using unsupervised hierarchical clustering of methylation probes, we created a phylogenetic map to trace the tumor path as it spread from the initial biopsy site throughout the right hemisphere, across the corpus callosum to the contralateral hemisphere, and into the brainstem. We identified molecular divergence between the right and left hemisphere GBM samples marked by distinct copy number profile alterations, alterations in specific methylation sites, and regional loss of MGMT promoter methylation, providing a potential mechanism for treatment resistance in this case. In summary, this case both highlights the molecular diversity in GBM, and illustrates a novel use for methylation profiling in establishing a phylogenetic profile to allow for spatial mapping of tumor progression.

Background Several molecular markers have important roles in glioma management. Mutations in the isocitrate dehydrogenase ( IDH) gene are associated with the grading and prognosis of glioma. Methylation in the promoter region of the O (6)-methylguanine-DNA methyltransferase ( MGMT) gene is an important determinant of glioma sensitivity to alkylating agents. Studies in various cancers indicated that IDH1 mutations and MGMT promoter methylations were associated with smoking habits. However, these associations in gliomas are still unclear. Accordingly, this study aimed to examine the association among smoking, IDH1 mutations, MGMT promoter methylation, and grading in glioma patients. Methods Patients were recruited from Dr. Sardjito General Hospital (a referral hospital in Yogyakarta and Central Java region) and its network hospitals. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples or fresh glioma tissues. Identification of IDH1 mutation was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or DNA sequencing. Methylation-specific real-time PCR was performed to identify MGMT promoter methylation status. Smoking status was obtained by history taken from the patient or family members. Results In total, 122 patients were included in this study. As many as 35 patients (28.7%) had a smoking history. Most smokers (57.1%) smoke less than ten cigarettes per day. However, most of them (68.8%) have been smoking for more than 20 years. Smoking patients have a significantly higher proportion of high-grade glioma than non-smokers (80% vs. 55.2%, p=0.01). Among 122 patients, 24 (19.7%) of them carried IDH1 mutation. Smoking patients have a significantly higher proportion of IDH1 mutation compared with non-smokers (31.4% vs. 14.9%, pIDH1 mutations and glioma grading. No significant association was found between smoking and MGMT promoter methylation. Conclusions In glioma patients, smoking is associated with IDH1 mutations and grading but not with MGMT promoter methylation.

Introduction: Some gene mutations in high grade glioma patients have many implications in prognosis and treatment response. Objectives: To describe the characteristics and associations of IDH, TP53 gene mutations and MGMT methylation status with some characteristics and treatment response in patients with high grade glioma. Methods: A descriptive, prospective, uncontrolled study was conducted, in 52 patients with high-grade glioma. Research variables include age, sex, Karnofsky score, the rate of IDH, P53 mutation, MGMT methylation; the relationship between genes mutation with some characteristics and response to treatment according to the RECIST classification. Results: For IDH gene mutation, grade III patients (23.1%) have a higher positive rate than grade IV (11.5 %); for P53 gene mutation, grade III patients (55.6 %) have a higher positive rate than grade IV (44.1 %); the rate of MGMT promoter methylation occurred in the study group of patients with the rate of 42.3 %. There is a relationship between IDH gene mutation with pathological results and malignancy in studied patients. Patients with the mutant expression of the IDH gene, p53, MGMT methylation status had better RECIST responses than patients without these expressions. Conclusion: High-grade glioma mainly occurs in men, over 40 years old. The presence of mutations in IDH, P53 genes, and MGMT methylation status was a beneficial factor for treatment response as assessed by RECIST.

Purpose: Although the usefulness of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI. Methods: This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74–89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status. Results: The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% < 8.2% had progressive disease after initial chemoradiotherapy administration. Three (50.0%) of six patients with MGMTpm% 8.2% to < 23.9% had stable disease or partial response. Conclusion: Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors. [ABSTRACT FROM AUTHOR]

Background: MGMT promoter methylation has been associated with favorable prognosis and survival outcomes in patients with glioblastoma and WHO grade III glioma. However, the effects of promoter methylation of MGMT in patients with WHO grade II gliomas have not been established. The purpose of the current study is to evaluate the prognostic impact and predictive values of MGMT methylation in patients with grade II glioma. Methods: The National Cancer Database (NCDB) was queried (2004–2016) for patients with newly diagnosed grade II glioma. Demographics and clinical characteristics of these patients were examined. Statistics included Kaplan–Meier overall survival (OS) analysis alongside Cox proportional hazards modeling. Results: A total of 11,223 patients met the selection criteria; 1252 patients (11%) had MGMT testing. Of the patients who had MGMT testing, 58.5% were MGMT methylated (mMGMT), and 43.5% were MGMT unmethylated (uMGMT). mMGMT patients had greater median overall survival (77.3 months) than both uMGMT patients (42.6 months) and patients with no MGMT status reported (61.9 months (p < 0.001 for both). mMGMT was also associated with improved OS, when compared to patients with uMGMT, for patients receiving adjuvant chemoradiation or adjuvant radiation therapy. Conclusions: This is the largest study to date demonstrating both the prognostic and predictive impact of MGMT methylation on patients with grade II glioma. The current results show that mMGMT is a prognostic factor and possibly a predictive biomarker for grade II glioma patients. MGMT methylation status can be used to determine and stratify patients by risk levels, and thus select patients for treatment intensification. Importance of study: The present study is the largest to date examining the prognostic and predictive significance of MGMT methylation (mMGMT) in patients with WHO grade II glioma. The results suggest that mMGMT is prognostic with increasing overall survival rates for patients with mMGMT compared to uMGMT patients. The results also suggest that mMGMT is predictive as shown by improved overall survival in patients receiving gross total resection, adjuvant chemoradiation or adjuvant radiation therapy, but no difference was observed in patients receiving adjuvant chemotherapy or no adjuvant treatment. [ABSTRACT FROM AUTHOR]

Diffuse infiltrating gliomas are a clinically and molecularly heterogeneous group of tumors that are uniformly incurable. Despite our growing knowledge of genomic and epigenomic alterations in gliomas, standard treatments have not changed in the past 2 decades and remain limited to surgical resection, ionizing radiation, and alkylating chemotherapeutic agents. Development of novel therapeutics for diffuse gliomas has been challenging due to inter- and intra-tumoral heterogeneity, diffuse infiltrative nature of gliomas, inadequate tumor/drug concentration due to blood–brain barrier, and an immunosuppressive tumor microenvironment. Given the high frequency of DNA damage pathway alterations in gliomas, researchers have focused their efforts in targeting the DNA damage pathways for the treatment of gliomas. A growing body of data has shed light on the role of poly(ADP-ribose) polymerase (PARP) in combination with radiation and temozolomide in high-grade gliomas. Furthermore, a novel therapeutic strategy in low-grade glioma is the recent elucidation for a potential role of PARP inhibitors in gliomas with IDH1/2 mutations. This review highlights the concepts behind targeting PARP in gliomas with a focus on putative predictive biomarkers of response. We further discuss the challenges involved in the successful development of PARP inhibitors in gliomas, including the intracranial location of the tumor and overlapping toxicities with current standards of care, and promising strategies to overcome these hurdles.

Background and PurposeWhile relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions.Methods1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV

Background: Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor survival rates despite current treatments. The standard of care (SOC) includes surgery, followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide (TMZ). This phase II trial assessed the safety and efficacy of neoadjuvant TMZ (nTMZ) before and during chemoradiotherapy in newly diagnosed GBM patients., Methods: Newly diagnosed GBM patients who underwent maximal safe resection were randomized into 2 groups. One received nTMZ before standard chemoradiotherapy and adjuvant TMZ (intervention). The other received standard chemoradiotherapy followed by adjuvant TMZ (control). Primary endpoints were progression-free survival (PFS) at 6 and 12 months. Secondary endpoints included overall survival, radiological and clinical responses, and adverse events., Results: Of 35 patients, 16 were in the intervention group and 19 in the control group. Median PFS was 9 months (95% CI: 3.93-14.06) versus 3 months (95% confidence interval [CI]: 1.98-4.01) in the control and intervention groups ( P = .737), with a high progression rate (73.4%) during nTMZ treatment. The 6-month PFS rates were 58% versus 25% ( P  = .042), and 12-month PFS rates were 26% versus 25% ( P  = .390) in the control and intervention groups, respectively. Patients with unmethylated O 6 -methylguanine-DNA methyltransferase (MGMT) and those with good performance status (PS) had significantly worse PFS with nTMZ.  However, those who underwent larger extent of resection exhibited significantly better PFS  with nTMZ. Adverse events were similar between groups., Conclusions: Neoadjuvant TMZ before SOC chemoradiotherapy did not improve outcomes for newly diagnosed GBM patients and is unsuitable for those with unmethylated MGMT and good PS. However, It may benefit patients with near or gross total resection. Further research is needed to refine GBM treatment strategies., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM.

• Cerebellar anaplastic astrocytomas are extremely rare entities. • Incidence of IDH-1 mutation in cAA is higher than in cerebellar glioblastomas. • Patients with cAA tend to have a more frequent multifocal presentation at diagnosis. • Overall survival rates for patients with cAA was compatible to the control group with supratentorial anaplastic astrocytomas. Adult cerebellar anaplastic astrocytomas (cAA) are rare entities and their clinical and genetic appearances are still ill defined. Previously, malignant gliomas of the cerebellum were combined and reviewed together (cAA and cerebellar glioblastomas (cGB), that could have possibly affected overall survival (OS) and progression-free survival (PFS). We present characteristics of 15 adult patients with cAA and compared them to a series of 45 patients with a supratentorial AA (sAA) in order to elicit the effect of tumor location on OS and PFS. The mean age at cAA diagnosis was 39.3 years (range 19–72). A history of neurofibromatosis type I was noted in 1 patient (6.7%). An IDH-1 mutation was identified in 6/15 cases and a methylated MGMT promoter in 5/15 cases. Patients in study and control groups were matched in age, sex and IDH-1 mutation status. Patients in a study group tended to present with longer overall survival (50 vs. 36.5 months), but the difference did not reach statistical significance. In both cAA and supratentorial AA groups presence of the IDH-1 mutation remains a positive predictor for the prolonged survival. The present study suggests that adult cAA constitute a group of gliomas with relatively higher rate of IDH-1 mutations and prognosis similar to supratentorial AA. The present study is the first to systematically compare cAA and supratentorial AA with respect to their genetic characteristics and suggests that both groups show a similar survival prognosis. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) neoplasm in adults, and has an almost universally poor prognosis. Recently, an emphasis on genetic and epigenetic profiling has revealed a number of molecular features useful in the diagnostic and prognostic classification of GBM, advancing our understanding of the underlying features that make these tumors so aggressive and providing the rationale for the creation of better targeted therapeutics. One such method, DNA methylation profiling, has recently emerged as an important technique for the classification of CNS tumors, with diagnostic accuracy in some cases surpassing traditional methods. However, how DNA methylation profiles change with the course of the disease remains less understood. Here, we present a case of a 30-year-old male with primary IDH-mutant GBM with widespread recurrence and death two years later. Using unsupervised hierarchical clustering of methylation probes, we created a phylogenetic map to trace the tumor path as it spread from the initial biopsy site throughout the right hemisphere, across the corpus callosum to the contralateral hemisphere, and into the brainstem. We identified molecular divergence between the right and left hemisphere GBM samples marked by distinct copy number profile alterations, alterations in specific methylation sites, and regional loss of MGMT promoter methylation, providing a potential mechanism for treatment resistance in this case. In summary, this case both highlights the molecular diversity in GBM, and illustrates a novel use for methylation profiling in establishing a phylogenetic profile to allow for spatial mapping of tumor progression. [ABSTRACT FROM AUTHOR]

Background: The promoter hypermethylation of the methylguanine-DNA methyltransferase gene is a frequently used biomarker in daily clinical practice as it is associated with a favorable prognosis in glioblastoma patients treated with temozolamide. Due to the absence of adequately standardized techniques, international harmonization of the MGMT methylation biomarker is still an unmet clinical need for the diagnosis and treatment of glioblastoma patients. Results: In this study we carried out a clinical validation of a quantitative assay for MGMT methylation detection by comparing a novel quantitative MSP using double-probe (dp_qMSP) with the conventional MSP in 100 FFPE glioblastoma samples. We performed both technologies and established the best cutoff for the identification of positive-methylated samples using the quantitative data obtained from dp_qMSP. Kaplan–Meier curves and ROC time dependent curves were employed for the comparison of both methodologies. Conclusions: We obtained similar results using both assays in the same cohort of patients, in terms of progression free survival and overall survival according to Kaplan–Meier curves. In addition, the results of ROC(t) curves showed that dp_qMSP increases the area under curve time-dependent in comparison with MSP for predicting progression free survival and overall survival over time. We concluded that dp_qMSP is an alternative methodology compatible with the results obtained with the conventional MSP. Our assay will improve the therapeutic management of glioblastoma patients, being a more sensitive and competitive alternative methodology that ensures the standardization of the MGMT-biomarker making it reliable and suitable for clinical use. [ABSTRACT FROM AUTHOR]

The effect of the MGMT gene methylation in glioblastoma cells on the development of the tumor-induced bystander effect and the modification of sensitivity, due to the impact of ionizing radiation, in the untransformed bystander cells (peripheral blood lymphocytes) was studied. The obtained results showed development of a glioblastoma-induced bystander effect. No association between the manifestation of the tumor-induced bystander effect and the methylation status of the MGMT gene promoter region in tumor cells has been found. After the exposure to radiation, statistically significant (p < 0.01) changes were observed in the apoptotic activity and radiosensitivity of peripheral blood lymphocytes with different statuses of the MGMT gene methylation in the tumor cells of glioblastoma patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to leverage Visually AcceSAble Rembrandt Images (VASARI) radiological features, extracted from magnetic resonance imaging (MRI) scans, and machine-learning techniques to predict glioma grade, isocitrate dehydrogenase (IDH) mutation status, and O6-methylguanine-DNA methyltransferase (MGMT) methylation., Methodology: A retrospective evaluation was undertaken, analyzing MRI and molecular data from 107 glioma patients treated at a tertiary hospital. Patients underwent MRI scans using established protocols and were evaluated based on VASARI criteria. Tissue samples were assessed for glioma grade and underwent molecular testing for IDH mutations and MGMT methylation. Four machine learning models, namely, Random Forest, Elastic-Net, multivariate adaptive regression spline (MARS), and eXtreme Gradient Boosting (XGBoost), were trained on 27 VASARI features using fivefold internal cross-validation. The models' predictive performances were assessed using the area under the curve (AUC), sensitivity, and specificity., Results: For glioma grade prediction, XGBoost exhibited the highest AUC (0.978), sensitivity (0.879), and specificity (0.964), with f6 (proportion of non-enhancing) and f12 (definition of enhancing margin) as the most important predictors. In predicting IDH mutation status, XGBoost achieved an AUC of 0.806, sensitivity of 0.364, and specificity of 0.880, with f1 (tumor location), f12, and f30 (perpendicular diameter to f29) as primary predictors. For MGMT methylation, XGBoost displayed an AUC of 0.580, sensitivity of 0.372, and specificity of 0.759, highlighting f29 (longest diameter) as the key predictor., Conclusions: This study underscores the robust potential of combining VASARI radiological features with machine learning models in predicting glioma grade, IDH mutation status, and MGMT methylation. The best and most balanced performance was achieved using the XGBoost model. While the prediction of glioma grade showed promising results, the sensitivity in discerning IDH mutations and MGMT methylation still leaves room for improvement. Follow-up studies with larger datasets and more advanced artificial intelligence techniques can further refine our understanding and management of gliomas., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health, and Nursing, Dr. Sardjito General Hospital, Universitas Gadjah Mada issued approval KE/FK/1182/EC/2022. The Medical and Health Research Ethics Committee (MHREC) stated that the documents above met the ethical principle outlined in the International and National Guidelines on ethical standards and procedures for researches with human beings. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Setyawan et al.)

Background: O6-methylguanine-DNA methyltransferase (MGMT) methylation status affects tumor chemo-resistance and the prognosis of glioblastoma (GBM) patients. We aimed to investigate the role of MGMT methylation in the regulation of GBM immunophenotype and discover an effective biomarker to improve prognosis prediction of GBM patients.Methods: A total of 769 GBM patients with clinical information from five independent cohorts were enrolled in the present study. Samples from the Cancer Genome Atlas (TCGA) dataset were used as the training set, whereas transcriptome data from the Chinese Glioma Genome Atlas (CGGA) RNA-seq, CGGA microarray, GSE16011, and the Repository for Molecular Brain Neoplasia (REMBRANDT) cohort were used for validation. A series of bioinformatics approaches were carried out to construct a prognostic signature based on immune-related genes, which were tightly related to the MGMT methylation status. In silico analyses were performed to investigate the influence of the signature on immunosuppression and remodeling of the tumor microenvironment. Then, the utility of this immune gene signature was analyzed by the development and evaluation of a nomogram. In vitro experiments were further used to verify the immunologic function of the genes in the signature.Results: We found that MGMT unmethylation was closely associated with immune-related biological processes in GBM. Sixty-five immune genes were more highly expressed in the MGMT unmethylated than the MGMT-methylated group. An immune gene-based risk model was further established to divide patients into high and low-risk groups, and the prognostic value of this signature was validated in several GBM cohorts. Functional analyses manifested a universal up-regulation of immune-related pathways in the high-risk group. Furthermore, the risk score was highly correlated to the immune cell infiltration, immunosuppression, inflammatory activities, as well as the expression levels of immune checkpoints. A nomogram was developed for clinical application. Knockdown of the five genes in the signature remodeled the immunosuppressive microenvironment by restraining M2 macrophage polarization and suppressing immunosuppressive cytokines production.Conclusions:MGMT methylation is strongly related to the immune responses in GBM. The immune gene-based signature we identified may have potential implications in predicting the prognosis of GBM patients and mechanisms underlying the role of MGMT methylation.

Glioblastoma is the most aggressive tumor of the central nervous system. Prognosis is poor, even in the presence of a methylated state of MGMT gene promoter, which represents the biomarker with the highest prognostic/predictive value for the standard treatment of patients. Among patients with a methylated MGMT status, we identified an intermediate range of methylation above the standard 9% cut-off (gray zone) in which the predictive strength of the marker was lost. In an effort to improve the evaluation of the biomarker in clinical decision-making, we are carrying out a retrospective study, performing an in-depth analysis of samples used for diagnosis to understand how molecular heterogeneity, a hallmark of glioblastoma, impacts the evaluation of MGMT gene promoter methylation. Preliminary data from samples belonging to the “gray zone” tend to confirm the hypothesis of a mismatch between methylation values used for clinical decision-making and those included in our in-depth analysis. Confirmation of these data would help to better define the predictive power of MGMT promoter methylation status and greatly facilitate clinical decision-making.

INTRODUCTION: The objective was to evaluate the impact of IDH1 R132H mutation, MGMT methylation and PD-L1 expression in high grade glioma that received standard therapy (surgery, radiation and chemotherapy) to overall survival (OS). METHODS: this is a retrospective study of 35 high grade glioma cases. Genotyping of IDH1 gene alteration on the mutation hotspot R132 (Sanger sequencing method with Applied Biosystems 3500 Genetic Analyzer), EZ DNA Methylation-Gold kit (Zymo Research) is used to study the methylation, Cell line BT549 (ATCC HTB-122) and HCT-116 (ATCC CCL-247) were used as unmethylated control and partially methylated control respectively. Anti-human PD-L1 antibody clone E1L3N® from Cell Signalling Technology (USA) and Rabbit XP® were used to see PDL-1 expression. RESULTS: anaplastic astrocytoma cases had more MGMT promoter methylation (50%) than glioblastoma multiforme (GBM) (20%), more IDH1 R132H mutation (42%) than GBM (4.3%). Immunohistochemistry tumor proportion score method (TPS) identified 17% and 8.7% were PD-L1 positive in AA and GBM groups, respectively. Cases with IDH1 R132H mutation and MGMT methylation still showed better OS although with high PD-L1 expression.

Abstract Background The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported. Methods Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan–Meier analysis was used to assess the rate of disease-free survival (DFS). Results MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ 2 = 7.565, P = 0.006). Conclusions MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

Glioblastoma is the most aggressive tumor of the central nervous system. Prognosis is poor, even in the presence of a methylated state of MGMT gene promoter, which represents the biomarker with the highest prognostic/predictive value for the standard treatment of patients. Among patients with a methylated MGMT status, we identified an intermediate range of methylation above the standard 9% cut-off (gray zone) in which the predictive strength of the marker was lost. In an effort to improve the evaluation of the biomarker in clinical decision-making, we are carrying out a retrospective study, performing an in-depth analysis of samples used for diagnosis to understand how molecular heterogeneity, a hallmark of glioblastoma, impacts the evaluation of MGMT gene promoter methylation. Preliminary data from samples belonging to the "gray zone" tend to confirm the hypothesis of a mismatch between methylation values used for clinical decision-making and those included in our in-depth analysis. Confirmation of these data would help to better define the predictive power of MGMT promoter methylation status and greatly facilitate clinical decision-making. [ABSTRACT FROM AUTHOR]

To explore the epigenetic alterations in response to DNA damage following polycyclic aromatic hydrocarbons (PAHs) exposure and the crosstalk between different epigenetic regulations, we examined trimethylated Lys 36 of histone H3 (H3K36me3) and methylation of 'long interspersed element-1 (LINE-1)' and 'O 6-methylguanine-DNA methyltransferase (MGMT)' in peripheral blood lymphocytes (PBLCs) of 173 coke oven workers (PAH-exposed group) and 94 non-exposed workers (control group). The PAH-exposed group showed higher internal PAH exposure level, enhanced DNA damage and increased MGMT expression (all P < 0.001). Notably, the methylation of LINE-1 and MGMT decreased by 3.9 and 40.8%, respectively, while H3K36me3 level was 1.7 times higher in PBLCs of PAH-exposed group compared to control group (all P < 0.001). These three epigenetic marks were significantly associated with DNA damage degree (all P < 0.001) and PAH exposure level in a dose--response manner (all P < 0.001). LINE-1 hypomethylation is correlated with enhanced H3K36me3 modification (β = -0.198, P = 0.002), indicating a synergistic effect between histone modification and DNA methylation at the whole genome level. In addition, MGMT expression was positively correlated with H3K36me3 modification (r = 0.253, P < 0.001), but not negatively correlated with MGMT methylation (r = 0.202, P < 0.05). The in vitro study using human bronchial epithelial cells treated with the organic extract of coke oven emissions confirmed that H3K36me3 is important for MGMT expression following PAH exposure. In summary, our study indicates that histone modification and DNA methylation might have synergistic effects on DNA damage induced by PAH exposure at the whole genome level and H3K36me3 is more essential for MGMT expression during the course. [ABSTRACT FROM AUTHOR]

Introduction: the objective was to evaluate the impact of IDH1 R132H mutation, MGMT methylation and PD-L1 expression in high grade glioma that received standard therapy (surgery, radiation and chemotherapy) to overall survival (OS). Methods: this is a retrospective study of 35 high grade glioma cases. Genotyping of IDH1 gene alteration on the mutation hotspot R132 (Sanger sequencing method with Applied Biosystems 3500 Genetic Analyzer), EZ DNA Methylation-Gold kit (Zymo Research) is used to study the methylation, Cell line BT549 (ATCC HTB-122) and HCT-116 (ATCC CCL-247) were used as unmethylated control and partially methylated control respectively. Anti-human PD-L1 antibody clone E1L3N®from Cell Signalling Technology (USA) and Rabbit XP®were used to see PDL-1 expression. Results: anaplastic astrocytoma cases had more MGMT promoter methylation (50%) than glioblastoma multiforme (GBM) (20%), more IDH1 R132H mutation (42%) than GBM (4.3%). Immunohistochemistry tumor proportion score method (TPS) identified 17% and 8.7% were PD-L1 positive in AA and GBM groups, respectively. Cases with IDH1 R132H mutation and MGMT methylation still showed better OS although with high PD-L1 expression. Conclusion: IDH1 R132H mutation and MGMT methylation were good prognostic markers. High expression of PD-L1 apparently might not indicate poor overall survival in the presence of IDH1 R132 mutation and MGMT methylation. [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as “elderly”. Several trials with monotherapy have established treatment regimens that offer therapies with reduced side effects but reduced efficacy. We analysed the outcome of elderly glioblastoma patients treated at our facility. Methods We performed a retrospective analysis of 62 consecutive patients older than 65 years treated for a primary glioblastoma at our facility from 2009 to 2015. Results Median age was 69.6 years (range 65.1–85.6 years); median OS of the entire cohort was 10.9 months. ECOG, MGMT and extent of resection but not age and the time from surgery to radiotherapy were associated with longer survival. Patients treated with adjuvant chemotherapy had a significantly longer survival (20.5 vs. 7.8 months). Furthermore, salvage therapies were associated with significant improved survival when compared to Best Supportive Care (22.3 vs. 8.8 months). Conclusion Also elderly patients are likely to benefit from an aggressive treatment after primary diagnosis of glioblastoma.

Gliomas are the most common brain tumors. It is difficult to detect them at early stages of disease and there is a few available therapies providing significant improvement in survival. Mutations of isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) play significant role in gliomogenesis, diagnostics and selection of patient therapy. We tested the distribution of IDH1 and IDH2 mutations in gliomas of different histological types and grades of malignancy by DNA melting analysis using our protocol with a sensitivity of 5 %. The results of this assay were confirmed by conventional Sanger sequencing. IDH1/2 mutations were detected in 74 % of lower grade gliomas (II and III, World Health Organization) and in 14 % of glioblastomas (IV, World Health Organization). Mutation rate in gliomas with oligodendroglioma component were significantly higher then in other glioma types (р = 0.014). The IDH1 mutations was the most common (79 % of general mutation number). IDH1/2 mutations can induce aberrant gene methylation. Detection of methylation rate of the gene encoding for O6-methylguanine-DNA-methyltransferase (MGMT), predictive biomarker for treatment of gliomas with the alkylating agents, has demonstrated a partial association with IDH1/2 mutations. In 73 % of IDH1/2-mutant tumors MGMT promoter methylation were observed. At the same time IDH1/2 mutations were not revealed in 67 % tumors with MGMT promoter methylation. These results indicate existence of another mechanism of MGMT methylation in gliomas. Our data strong support for necessity of both markers testing when patient therapy is selected.

Competing Interests: The authors have no conflict of interest to declare. J.S.B.-S. is a full-time employee of the NIH/NCI. G.C. and K.A.W. are full-time contractors of the NIH/NCI. M.D. is a full-time postdoctoral fellow of the NIH/NCI.

Background: Suprasellar masses commonly include craniopharyngiomas and pituitary adenomas. Suprasellar glioblastoma is exceedingly rare with only a few prior case reports in the literature. Suprasellar glioblastoma can mimic craniopharyngioma or other more common suprasellar etiologies preoperatively., Observations: A 65-year-old male with no significant history presented to the emergency department with a subacute decline in mental status. Work-up revealed a large suprasellar mass with extension to the right inferior medial frontal lobe and right lateral ventricle, associated with significant vasogenic edema. The patient underwent an interhemispheric transcallosal approach subtotal resection of the interventricular portion of the mass. Pathological analysis revealed glioblastoma, MGMT partially methylated, with a BRAF V600E mutation., Lessons: Malignant glioblastomas can mimic benign suprasellar masses and should remain on the differential for a diverse set of brain masses with a broad range of radiological and clinical features. For complex cases accessible from the ventricle where the pituitary complex cannot be confidently preserved via a transsphenoidal approach, an interhemispheric approach is also a practical initial surgical option. In addition to providing diagnostic value, molecular profiling may also reveal therapeutically significant gene alterations such as BRAF mutations.

Introduction: Neurofibromatosis type 1 is an autosomal dominant tumour syndrome with an increased risk of developing central nervous system neoplasms, mostly benign low-grade gliomas involving the optic pathway and the brainstem. High-grade astrocytomas or glioblastoma multiforme (GBM) are rare. Cerebellar GBMs are rarer still, only seven cases NF1 patients have been reported Case description: We report a case of a cerebellar GBM in a 25-year-old male with NF1 who survived 18 months from the initial diagnosis without surgical debulking but only chemo and radiotherapy. Conclusion: A literature review found that the best outcomes were achieved in NF1 patients who didn't undergo gross surgical resection. Possible reasons and future directions are discussed. [ABSTRACT FROM AUTHOR]

Objectives: To build a reliable radiomics model from multiregional and multiparametric magnetic resonance imaging (MRI) for pretreatment prediction of O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status in glioblastoma multiforme (GBM).Methods: In this retrospective multicentre study, 1,705 multiregional radiomics features were automatically extracted from multiparametric MRI. A radiomics model with a minimal set of all-relevant features and a radiomics model with univariately-predictive and non-redundant features were built for MGMT methylation prediction from a primary cohort (133 patients) and tested on an independent validation cohort (60 patients). Predictive models combing clinical factors were built and evaluated. Both radiomics models were assessed on subgroups stratified by clinical factors.Results: The radiomics model with six all-relevant features allowed pretreatment prediction of MGMT methylation (AUC=0.88, accuracy=80 %), which significantly outperformed the model with eight univariately-predictive and non-redundant features (AUC=0.76, accuracy=70 %). Combing clinical factors with radiomics features did not benefit the prediction performance. The all-relevant model achieved significantly better performance in stratified analysis.Conclusions: Radiomics model built from multiregional and multiparameter MRI may serve as a potential imaging biomarker for pretreatment prediction of MGMT methylation in GBM. The all-relevant features have the potential of offering better predictive power than the univariately-predictive and non-redundant features.Key Points: • Multiregional and multiparametric MRI features reliably predicted MGMT methylation in multicentre cohorts. • All-relevant imaging features predicted MGMT methylation better than univariately-predictive and non-redundant features. • Combing clinical factors with radiomics features did not benefit the prediction performance. [ABSTRACT FROM AUTHOR]