Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

Purpose To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. Methods ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Fifty-nine randomized trials focusing on therapeutic management were identified. Recommendations Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMTpromoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.

Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

PURPOSE To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. METHODS ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS Fifty-nine randomized trials focusing on therapeutic management were identified. RECOMMENDATIONS Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines .

NI-10 Reclassification of diffuse gliomas based on molecular diagnosis -evaluation of methionine uptake and treatment outcome-

Object: The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified diffuse gliomas with molecular diagnosis and examined for 11C-methionine uptake and prognosis. Methods. 182 diffuse glioma patients (Grade II in 42 patients, Grade III in 61 patients, Grade IV in 77 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Result. By molecular diagnosis, 11 diffuse astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 diffuse astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. 5 out of 77 grade IV tumors had IDH mutation. 4 tumors were diagnosed as “Diffuse midline glioma, H3 K27M-mutant”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were significantly higher than those in astrocytic tumors with “IDH-mutant”. On the other hand, in tumors with the same genetic background, higher grade tumor has significant higher T/N ratio. Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. IDH wild tumors had significantly worse outcomes.Conclusions. The results indicated that diffuse glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

SPDR-2 Histopathological investigation of the oligodendroglial tumors resected following alkylating agent chemotherapy

Oligodendrogliomas, i.e., lower grade gliomas with 1p/19q codeletion, are often responsive to chemotherapy, however, those tumors eventually recur and life-limiting in the majority of patients despite initial chemotherapeutic response. We have been treating those patients with upfront chemotherapy and subsequent resection following tumor volume decrease since 2006. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in oligodendrogliomas. Fifteen oligodendrogliomas (Grade 2: 12, Grade 3: 3) resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin-eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry. The frequent histological findings following chemotherapy included a sparse glial background, abundant foamy cell infiltration, gliosis, calcification, and nuclear degradation. The Ki-67/MIB-1 index decreased and the number of macrophages increased after chemotherapy. Moreover, the ratio of GSCs to total tumor cells increased after chemotherapy. GSCs and macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in oligodendrogliomas.

NI-8 Molecular diagnostic prediction combining T2-FLAIR mismatch sign, calcification, and methionine PET in grade II and III gliomas

Background: The 2016 WHO Classification classified grade II and III gliomas into three molecular subtypes depending on the presence of IDH mutation and 1p/19q codeletion. We combined T2-FLAIR mismatch sign, tumor calcification, and methionine PET uptake to examine whether molecular diagnosis could be predicted. Methods: 53 grade II and III glioma patients with preoperative MRI, CT, and MET-PET who underwent surgical resection or biopsy during 2000–2019 were included in this study. Out of the 53 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 17, oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 15, and IDH wild tumors (W group) were 21. MR and CT scans were evaluated by 3 independent reviewers to assess presence/absence of T2-FLAIR mismatch sign and calcification in the tumor, respectively. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Results: Out of the 53 cases, T2-FLAIR mismatch sign was present in 6 cases in group A and 9 cases in group W (p=0.008). Calcification in tumor was present in 2 cases in group A, 7 cases in group O, and 3 cases in group W (p=0.046). In the T2-FLAIR mismatch-positive cases, assuming MET-PET T/N>1.401 was group W and <1.401 was group A, sensitivity was 100% and specificity was 67%. In the T2-FLAIR mismatch-negative and calcification-positive cases, assuming those group O, the diagnostic predictive value was 70%. In the T2-FLAIR mismatch-negative and calcification-negative cases, assuming MET-PET T/N>2.349 was group W and <2.349 was group A or O, sensitivity was 60% and specificity was 94%. Conclusions: Combined diagnostic prediction of T2-FLAIR mismatch, calcification, and MET-PET T/N may be useful for preoperative molecular diagnosis of grade II and III gliomas.

PATH-17. POSSIBLE ASSOCIATION BETWEEN OLIGODENDROGLIAL HISTOLOGICAL FEATURES OF IDHMUT/CODEL LOWER GRADE GLIOMAS AND PATIENT'S FAVORABLE PROGNOSIS, BUT NOT IN IDHMUT/NONCODEL AND IDH-WILDTYPE TUMORS

Comprehensive diagnostic using histological and molecular characteristics began to be implemented in WHO 2016 but the relevance of oligodendroglial histological features to patients’ prognoses is still controversial. To elucidate the connection between oligodroglial histology and patient’s prognoses we analyzed 93 LrGGs resected for about 2 decades were reassessed for histological features based on WHO2007 with special interest to pure oligodendroglial diagnosis (namely, oligodendroglioma or anaplastic oligodendroglioma) and presence of classic for oligodendroglioma (CFO) features. Those histological features, patients’ OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q based molecular groups. The reassessed morphology-based diagnosis was shown to be most strict for astrocytic, but loosened for oligodendroglial tumors as compared with the original institutional diagnoses and WHO2016. The pure oligodendroglial diagnosis by reassessment was associated with longer OS in IDHmut/codel group, but not in IDHmut/noncodel and IDH-wildtype groups. The presence of CFO was not associated with patients’ OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any of the 3 molecular groups. NGS of the IDHmut/codel tumors suggested that mutations in the FUBP1 and CIC genes might be associated with poor prognosis. The oligodendroglial histological feature is not independently predictive for either patients’ prognosis or chemotherapeutic response in LrGGs, except the oligodendroglial diagnosis in IDHmut/codel tumors.

Trends in Intracranial Glioma Incidence and Mortality in the United States, 1975-2018

PurposeGlioma incidence in the US seems to have stabilized over the past 20 years. It’s also not clear whether changes in glioblastoma incidence are associated with glioma mortality trends. Our study investigated trends in glioma incidence and mortality according to tumor characteristics.MethodsThis study obtained data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) registries to calculate glioma incidence and mortality trends. Annual percent changes (APC) and 95% CIs were calculated using the Joinpoint program.Results62,159 patients (34,996 males and 55,424 whites) were diagnosed with glioma during 1975-2018, and 31,922 deaths occurred from 1995-2018. Glioblastoma (32,893 cases) and non-glioblastoma astrocytoma (17,406 cases) were the most common histologic types. During the study period, the incidence of glioma first experienced a significant increase (APC=1.8%, [95% CI, 1.3% to 2.3%]) from 1975 to 1987, and then experienced a slight decrease (APC=-0.4%, [95% CI, -0.5% to -0.3%]) from 1987 to 2018, while the APC was 0.8% for glioblastoma, -2.0% for non-glioblastoma astrocytoma, 1.1% for oligodendroglial tumors, 0.7% for ependymoma and -0.3% for glioma NOS during the study period. Glioblastoma incidence increased for all tumor size and tumor extension except for distant. From 1995 to 2018, glioma mortality declined 0.4% per year (95% CI: -0.6% to -0.2%) but only increased in patients older than 80 years [APC=1.0%, (95% CI, 0.4% to 1.6%)].ConclusionSignificant decline in glioma incidence (1987-2018) and mortality (1995-2018) were observed. Epidemiological changes in non-glioblastoma astrocytoma contributed the most to overall trends in glioma incidence and mortality. These findings can improve understanding of risk factors and guide the focus of glioma therapy.

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. We found that DIRAS-1 was strongly downregulated in 65% and DIRAS-2 in 100% of analyzed glioma samples compared to non-neoplastic brain tissue (NNB). Moreover, a significant down-regulation of DIRAS-1 and -2 was detected in glioma data obtained from the TCGA database. Mutational analyses did not reveal any inactivating mutations in the DIRAS-1 and -2 coding regions. Analysis of the DIRAS-1 and -2 promoter methylation status showed significantly higher methylation in IDH-mutant astrocytic and IDH-mutant and 1p/19q-codeleted oligodendroglial tumors compared to NNB. Treatment of U251MG and Hs683 glioblastoma cells lines with 5-azacytidine led to significant re-expression of DIRAS-1 and -2. For IDH-wild-type primary gliomas, however, we did not observe significantly elevated DIRAS-1 and -2 promoter methylation levels, but still detected strong downregulation of both DIRAS family members. Additional analyses revealed that DIRAS-1 and -2 expression was also regulated by histone modifications. We observed a shift towards promoter heterochromatinization for DIRAS-1 and less promoter euchromatinization for DIRAS-2 in IDH-wild-type glioblastomas compared to controls. Treatment of the two glioblastoma cell lines with a histone deacetylase inhibitor led to significant re-expression of DIRAS-1 and -2. Functionally, overexpression of DIRAS-1 and -2 in glioblastoma cells translated into significantly higher sensitivity to lomustine treatment. Analyses of DNA damage markers revealed that DIRAS-1 and -2 may play a role in p53-dependent response to alkylating chemotherapy.

Molecular Classification of Diffuse Gliomas

In 2016 WHO classification of CNS tumors genotypic and phenotypic parameters were integrated to define a new nomenclature of diffuse gliomas on the basis of presence or absence of isocitrate dehydrogenase mutations. This resulted in more homogenous and narrowly defined categories with better accuracy of prognostic information, thus, playing a crucial role in patient management. Broadly, astrocytomas are now histologically and genetically distinct with IDH-mutant, ATRX-mutant, 1p/19q-intact and oligodendroglial tumors has IDH-mutant, ATRX-wildtype and 1p/19q-codeleted profile. Glioblastoma are now classified into primary and secondary on the basis of IDH mutations independent of clinical history.

Ras, TrkB, and ShcA Protein Expression Patterns in Pediatric Brain Tumors

Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in different types of cancers. Their level can be potentially associated with oncogenic processes. We analyzed samples of pediatric brain tumors reflecting different groups such as choroid plexus tumors, diffuse astrocytic and oligodendroglial tumors, embryonal tumors, ependymal tumors, and other astrocytic tumors as well as tumor malignancy grade, in order to characterize the expression profile of Ras, TrkB, and three isoforms of ShcA, namely, p66Shc, p52Shc, and p46Shc proteins. The main aim of our study was to evaluate the potential correlation between the type of pediatric brain tumors, tumor malignancy grade, and the expression patterns of the investigated proteins.