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• 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]

The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. Recent advances in the molecular understanding of gliomas suggest some potential reasons for the failure of more targeted therapies in gliomas. Specifically, the histologic-based glioma classification is composed of multiple different molecular subtypes with distinct biology, natural history, and prognosis. As a result of these insights, the diagnosis and classification of gliomas have recently been updated by the World Health Organization. However, these changes and other novel observations regarding glioma biomarkers and subtypes highlight several clinical challenges. First, the field is faced with the difficulty of reinterpreting the results of prior studies and retrospective data using the new classifications to clarify prognostic assessments and treatment recommendations for patients. Second, the new classifications and insights require rethinking the design and stratification of future clinical trials. Last, these observations provide the essential framework for the development and testing of new specific targeted therapies for particular glioma subtypes. This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field. [ABSTRACT FROM AUTHOR]

A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22 GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114 GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1 GSCs: IC 50 = 160 μM; 22 GSCs: IC 50 = 44 μM) compared to MGMT non-expressing (33 GSCs: IC 50 = 1.5 μM; 114 GSCs: IC 50 = 5.2 μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50–500 kHz) with an optimal frequency of 200 kHz. At 200 kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1 GSC: 74 ± 2.9% and 38 ± 3.2%, respectively; 22 GSC: 61 ± 11% and 38 ± 2.6%, respectively; 33 GSC: 56 ± 9.5% and 60 ± 7.1%, respectively; 114 GSC: 79 ± 3.5% and 41 ± 4.3%, respectively). In combination, TTFields (200 kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a grim prognosis. Lobar GBM, notably those localized to the frontal lobe, are generally more amenable to complete surgical resection, and may carry a better prognosis. The biology of differently localized GBM has been reported scarcely in terms of prognostic markers, including isocitrate dehydrogenase 1 (IDH1) mutation and O(6)-methylguanine-methyltransferase (MGMT) methylation. To our knowledge, there has been no evaluation in the literature of different proliferation indexes in different GBM locations in the brain. We performed a retrospective evaluation of our prospectively collected database to assess the rate of IDH1 positivity, MGMT methylation and Ki67 index for GBM located in the frontal lobes alone, lobar GBM in other supra-tentorial lobes and multilobar GBM. IDH1 mutated tumors were localized in the frontal lobes in 50.0%, whereas only 20.3% of IDH1 wild-type tumors were localized in the frontal lobe (p = 0.006); MGMT methylated tumors were localized in the frontal lobe in 32.0% of the cases. Only 13.75% of the MGMT unmethylated tumors were localized to the frontal lobe (p = 0.005); Tumors with higher Ki67 proliferation index were more likely to be localized in the frontal lobe (40.6% vs. 19.5%, p = 0.019). This is the largest cohort of GBM assessed for these purposes in the literature. Frontal lobe GBMs may be intrinsically biologically distinct from GBM in other lobes and from multilobar tumors. [ABSTRACT FROM AUTHOR]

Purpose To establish the frequency of IDH1 mutations and MGMT methylation in primary glioblastomas. Experimental design We screened primary glioblastoma multiforme (GBM) in a population-based study for IDH1 mutations and MGMT methylation and correlated them with clinical data. Results IDH1 mutations were detected in 5 of 40 primary glioblastomas (12,5%). Primary GBM patients carrying IDH1 mutations were significantly younger, mean age of 41 ± 5.06 years, than patients with wild-type IDH1, mean age of 57 ± 2,29 years, p = 0.011. The mean survival time of all GBM patients with and without IDH1 mutations was 19 months (5 cases) and 16 months (35 cases), respectively (p > 0,05). MGMT methylation was detected in 13 of the 40 patients (32,5%). MGMT-promoter methylation did not correlate with overall survival (OS; p > 0,05). Conclusion In summary, our study is the first study to investigate the IDH1 mutation status and MGMT methylation in primary GBMs in Turkish population and confirmed IDH1 mutation as a genetic marker for also primary GBMs. Our data are still insufficient for definite ascertainment; and our preliminary results suggest: IDH1 status shows an association with younger age and there is a lack of association between IDH1 mutation and survival time. Furthermore MGMT promoter methylation had no prognostic value and lower frequency in primary glioblastomas. [ABSTRACT FROM AUTHOR]

Abstract: Background: Very little literature exists on frequency of MGMT methylation status in pituitary adenoma. We assessed the frequency of MGMT methylation and protein expression in pituitary adenoma and correlated with patients’ age group and prognosis. Methods: Tumor tissues from 30 patients with pituitary adenoma were evaluated for MGMT promoter methylation status by methylation specific PCR method. All tumors were also immunostained with MIB-1, anti-p53 and anti-MGMT antibodies. Results: MGMT methylation status was noted in 40% of cases (7/20 non-functioning adenomas and 5/10 functioning adenomas). MGMT protein expression on IHC was noted in 72.2% of unmethylated tumors, while only 41.6% of methylated tumors demonstrated protein expression. The mean labeling index of MGMT protein was higher in unmethylated tumors as compared to the methylated group, though the difference was not statistically significant (18.6% vs 8.8%; p =0.131). Tumor regrowth occurred in four unmethylated tumors as compared to none in methylated group. Even though there was no correlation between patient age and MGMT methylation status (p =0.823), we noted that the frequency of methylation in middle age patients (between 30 and 59 yrs) was 64.7%, which was higher compared to other age groups. Conclusion: This is the first study from India showing MGMT promoter methylation status with protein expression in pituitary adenoma. We noted that tumor regrowth was higher in unmethylated tumors. [Copyright &y& Elsevier]

Background: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O6-methylguanine DNA methyltransferase (MGMT) and Human Mut-L Homologue 1 (MLH1) promoter hypermethylation are associated with APC, KRAS and BRAF mutations among 734 CRC patients. [ABSTRACT FROM PUBLISHER]

In 2016, the World Health Organization recommended that isocitrate dehydrogenase (IDH) mutation status be included in the classification of diffuse astrocytic gliomas. IDH mutations are part of the current definition of oligodendrogliomas and are predictive of a better outcome in diffuse astrocytic gliomas. A few studies, examining the role of routine IDH testing in older patients, came to differing conclusions and made differing recommendations regarding a routine IDH testing algorithm with respect to patient age. The purpose of this study was to examine IDH mutations in a series of diffuse astrocytic gliomas [N = 381; 53 diffuse astrocytomas (WHO grade II), 66 anaplastic astrocytomas (WHO grade III) and 262 glioblastomas (WHO grade IV)], paying particular attention to age of patient and any relationship between age and IDH status. IDH status was evaluated by immunohistochemistry with IDH-1 (R132H) antibody and if negative staining was noted, followup polymerase chain reaction (PCR) testing assessing for IDH-1 and IDH-2 mutations was performed. Overall, IDH mutations were discovered in 50.1% of grade II tumors, 54.4% of grade III tumors and 15.1% of grade IV tumors. Of tumors studied, 224 tumors (58.8%) arose in patients 55 years or older. Higher rates of IDH mutations were observed in the patient group less than 55 years of age versus those 55 years or older. By PCR testing in patients 55 years or older, non IDH-1 (R132H) mutations were noted in 0/4 grade II tumors, 3/11 grade III tumors and 26/37 grade IV tumors. The results of this study suggest that although IDH mutations in diffuse astrocytic gliomas are more frequently encountered in patients less than 55 years of age, a significant subset of older patients have mutations that would not be discovered on routine immunohistochemistry and therefore, followup PCR testing is recommended for all patients whose tumors are negative by immunohistochemistry. • IDH mutations are more frequent in patients less than 55 years of age with fibrillary astrocytomas. • A significant subset of patients with fibrillary astrocytomas over the age of 55 years have IDH mutation. • PCR testing should be done in fibrillary astrocytomas which do not stain with IDH-1 antibody. [ABSTRACT FROM AUTHOR]