Astrocytoma WHO Grade Research Articles

CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas.

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the glioma cohorts at our institute. We reviewed medical records spanning a 15-year period and examined pathological slides for an updated diagnosis according to the 2021 WHO classification of CNS tumors. We examined the IDH1/2 mutation and CDKN2A deletion using NGS analysis with ONCOaccuPanel®. Further, we examined traditional prognostic factors, including age, WHO performance status, extent of resection, and MGMT promoter methylation status. Results: The mean follow-up duration was 27.5 months (range: 4.1-43.5 months) and mean overall survival (OS) was 20.7 months (SD, ±1.759). After the exclusion of six patients with a poor status of pathologic samples, a total of 136 glioblastoma cases diagnosed by previous WHO classification criteria were newly classified into 29 (21.3%) astrocytoma, IDH-mutant, and CNS WHO grade 4 cases, and 107 (78.7%) glioblastoma, IDH-wildtype, and CNS WHO grade 4 cases. Among them, 61 (56.0%) had CDKN2A deletions. The high-risk group with CDKN2A deletion regardless of IDH1/2 mutation had a mean OS of 16.65 months (SD, ±1.554), the intermediate-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 21.85 months (SD, ±2.082), and the low-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 33.38 months (SD, ±2.946). Multifactor analysis showed that age (≥50 years vs. <50 years; HR 4.645), WHO performance (0, 1 vs. 2; HR 5.002), extent of resection (gross total resection vs. others; HR 5.528), MGMT promoter methylation, (methylated vs. unmethylated; HR 5.078), IDH1/2 mutation (mutant vs. wildtype; HR 6.352), and CDKN2A deletion (absence vs. presence; HR 13.454) were associated with OS independently. Conclusions: The present study suggests that CDKN2A deletion plays a powerful prognostic role in CNS WHO grade 4 gliomas. Even if CNS WHO grade 4 gliomas have mutant IDH1/2, they may have poor clinical outcomes because of CDKN2A deletion.

Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome.

Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated. We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions. Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression.

METB-11. HOW METHYLATION PROFILING HELPS IN DIAGNOSING AND TREATING PEDIATRIC BRAIN TUMORS IN INDONESIA

Abstract BACKGROUNDS Pediatric brain tumors (PBT) exhibit extensive heterogeneity, impacting treatment outcomes. While traditionally classified based on histopathological features, recent WHO classifications have integrated DNA methylation array profiling amongst other molecular characteristics, which improves diagnostic accuracy and thus treatment decisions. However, access to this technology is limited in low- and middle-income countries (LMICs) like Indonesia. As part of the MNP Outreach Consortium, we aimed to introduce methylation profiling in Indonesia to aid in diagnosing and stratifying PBT patients. METHODS In 2023, we conducted a case series involving seven challenging PBT cases from Cipto Mangunkusumo National General Hospital, re-assessing them with methylation profiling. RESULTS Through collaboration with the Institute of Neuropathology Heidelberg and the DKFZ, our centre adopted a discerning approach to re-evaluate histopathological samples from complex cases. This endeavour yielded notable results, reaffirming four initial diagnoses and altering three others Amongst the findings, one case initially diagnosed as anaplastic ependymoma, CNS WHO grade 3, was reclassified as a supratentorial ependymoma with YAP1 fusion gene, based on methylation class. Noteworthy within this latter group, one case initially categorized as low-grade pilocytic astrocytoma was reclassified as high-grade diffuse midline glioma, H3 K27 altered. Moreover identifying the copy number plot could indicate a KIAA1549::BRAF fusion to reclassify a case from diffuse pediatric glioma WHO grade 2 to pilocytic astrocytoma WHO grade 1. The recurrent pigmented neuroectodermal tumor of infancy (MNTI) was reclassified as Medulloblastoma, non-WNT/non-SHH, group 3 subtype II on methylation profiling, highlighting molecular similarities and potential treatment insights. These findings offer insights into genetic mechanisms and guide treatment strategies. CONCLUSION Accurate diagnosis, facilitated by advanced molecular profiling, enhances prognostication and enables personalized treatment plans, even in LMICs. This underscores the importance of expanding access to advanced diagnostic technologies in resource-limited settings.

Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas

BackgroundIsocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown.MethodsPatients undergoing surgery (between 2016–2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2–3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors.ResultsThis multi-center study included 157 patients (mean age 58 years (20–87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response.ConclusionsWHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors.

Concurrent gliomas in patients with multiple sclerosis

BackgroundConcurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives.MethodsA multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients.ResultsMS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation.ConclusionsConcurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.

Artesunate in glioblastoma therapy: Case reports and review of clinical studies

BackgroundArtesunate, a derivative of the active ingredient artemisinin from Artemisia annua L. used for centuries in the traditional Chinese medicine, is being applied as front-line drug in malaria treatment. As it is cytotoxic for cancer cells, trials are ongoing to include this drug as supplement in cancer therapy. In glioblastoma cells, artesunate was shown to induce oxidative stress, DNA base damage and double-strand breaks (DSBs), apoptosis, and necroptosis. It also inhibits DNA repair functions and bears senolytic activity. Compared to ionizing radiation, DNA damages accumulate over the whole exposure period, which makes the agent unique in its genotoxic profile. Artesunate has been used in adjuvant therapy of various cancers. PurposeAs artesunate has been used in adjuvant therapy of different types of cancer and clinical trials are lacking in brain cancer, we investigated its activity in glioma patients with focus on possible side effects. Study designBetween 2014 and 2020, twelve patients were treated with artesunate for relapsing glioma and analyzed retrospectively: 8 males and 4 females, median age 45 years. Histology: 4 glioblastomas WHO grade 4, 5 astrocytomas WHO grade 3, 3 oligodendrogliomas grade 2 or 3. All patients were pretreated with radiation and temozolomide-based chemotherapy. Artesunate 100 mg was applied twice daily p.o. combined with dose-dense temozolomide alone (100 mg/m2 day 1–5/7, 10 patients) or with temozolomide (50 mg/m2 day 1–5/7) plus lomustine (CCNU, 40 mg day 6/7). Blood count, C-reactive protein (CRP), liver enzymes, and renal parameters were monitored weekly. ResultsApart from one transient grade 3 hematological toxicity, artesunate was well tolerated. No liver toxicity was observed. While 8 patients with late stage of the disease had a median survival of 5 months after initiation of artesunate treatment, 4 patients with treatment for remission maintenance showed a median survival of 46 months. We also review clinical trials that have been performed in other cancers where artesunate was included in the treatment regimen. ConclusionsArtesunate administered at a dose of 2 × 100 mg/day was without harmful side effects, even if combined with alkylating agents used in glioma therapy. Thus, the phytochemical, which is also utilized as food supplement, is an interesting, well tolerated supportive agent useful for long-term maintenance treatment. Being itself cytotoxic on glioblastoma cells and enhancing the cytotoxicity of temozolomide as well as in view of its senolytic activity, artesunate has clearly a potential to enhance the efficacy of malignant brain cancer therapy.

Risk Estimation in Non-Enhancing Glioma: Introducing a Clinical Score.

The preoperative grading of non-enhancing glioma (NEG) remains challenging. Herein, we analyzed clinical and magnetic resonance imaging (MRI) features to predict malignancy in NEG according to the 2021 WHO classification and developed a clinical score, facilitating risk estimation. A discovery cohort (2012-2017, n = 72) was analyzed for MRI and clinical features (T2/FLAIR mismatch sign, subventricular zone (SVZ) involvement, tumor volume, growth rate, age, Pignatti score, and symptoms). Despite a "low-grade" appearance on MRI, 81% of patients were classified as WHO grade 3 or 4. Malignancy was then stratified by: (1) WHO grade (WHO grade 2 vs. WHO grade 3 + 4) and (2) molecular criteria (IDHmut WHO grade 2 + 3 vs. IDHwt glioblastoma + IDHmut astrocytoma WHO grade 4). Age, Pignatti score, SVZ involvement, and T2/FLAIR mismatch sign predicted malignancy only when considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A multivariate regression confirmed age and T2/FLAIR mismatch sign as independent predictors (p = 0.0009; p = 0.011). A "risk estimation in non-enhancing glioma" (RENEG) score was derived and tested in a validation cohort (2018-2019, n = 40), yielding a higher predictive value than the Pignatti score or the T2/FLAIR mismatch sign (AUC of receiver operating characteristics = 0.89). The prevalence of malignant glioma was high in this series of NEGs, supporting an upfront diagnosis and treatment approach. A clinical score with robust test performance was developed that identifies patients at risk for malignancy.

Isocitrate-dehydrogenase-mutant lower grade glioma in elderly patients: treatment and outcome in a molecularly characterized contemporary cohort

PurposeLower-grade glioma (LGG) is rare among patients above the age of 60 (“elderly”). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3.MethodsElderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes.Results207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors.ConclusionElderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

NCOG-27. A SINGLE-INSTITUTION RETROSPECTIVE SERIES OF SARS-COV-2 INFECTION IN ADULT GLIOMA PATIENTS

Abstract A subset of cancer patients is particularly vulnerable to SARS-Cov-2 infection; however, real-world outcomes-based data on primary central nervous system tumor patients is sparse. This retrospective case series describes a cohort of adult glioma patients seen at Stanford Cancer Center between 1/20/2020 through 5/24/2022 who contracted SARS-Cov-2. We identified 18 patients with a diagnosis of glioma, with a median age of 54 years, who were infected with Covid-19. One patient contracted Covid-19 twice during this two-year period. Of these patients, four had pathology confirmed low-grade glioma, defined as oligodendroglioma or astrocytoma WHO grade 2, and 14 patients had high-grade glioma, defined as astrocytoma or glioblastoma WHO grade 4. Median KPS at time of infection was 70. Six individuals had notable cardiovascular comorbidities including coronary artery disease, obesity, and/or diabetes. All but one patient was vaccinated against Covid-19, and 6 were taking dexamethasone at the time of infection. Three patients required hospital admission for management of Covid-19 symptoms, although none required ICU-level of care. None died from Covid-related complications; however, two died from complications of their underlying cancer at the end of study. Our data suggest that glioma patients seen at Stanford Cancer Center do not experience an exceptionally high Covid-19 infectivity, hospitalization, or mortality rate, especially when compared to other vulnerable populations such as lung cancer patients. High vaccination rates, fairly low prevalence of cardiovascular comorbidities, and adherence to pandemic precautions among this cohort may have contributed to these results.

CNSC-37. ATYPICAL GERMLINE MUTATIONS AND PRIMARY CNS TUMORS: A SINGLE-CENTER CASE SERIES AND LITERATURE REVIEW

Abstract A growing spectrum of germline mutations and their association with primary CNS tumors has been described over the last decade. These germline mutations are implicated in regulation of DNA integrity and repair, telomere maintenance, and cell cycle regulation resulting in aberrant cellular proliferation and immune surveillance evasion. To date, there are no well-defined guidelines for primary CNS tumor surveillance for these patients. Moreover, the exact role of traditional chemotherapy, immunotherapy, and radiation is unclear. We present a single-institution case series of adult patients with primary CNS tumors with atypical germline mutations and literature review. The most common germline mutations encountered involved heterozygous mutations of one of the mismatch repair (MMR) genes (MSH2, PMS2, MLH1). All patients developed high-grade gliomas defined as astrocytoma or glioblastoma WHO grade 4 based on the WHO 2021 classification. Germline mutations involving RAD51C, POT1, IDH1/2, MutyH, NTHL1, PALB2, and CHEK2 were associated with gliomas of variable grades and molecular subtypes. Non-glial tumors, including atypical rhabdoid tumors, medulloblastomas, hemangioblastomas, and meningiomas were found in association with germline SMARCB1, ATM, BRCA1, and CHEK2 mutations respectively. Review of the existing literature and knowledge obtained from our case series suggests several important concepts: (1) there is an increased risk of both glioma and non-glial tumor types in several atypical germline mutations, (2) multiple risk genes or variants of unknown significance likely contribute to primary brain tumor formation, (3) germline MMR mutations associated with high-grade glioma may be MMR gene-specific with potential increased risk of resistance and/or disease progression in the presence of alkylating agents such as temozolomide, (4) several germline mutations may increase risk of secondary tumor development after radiation, and (5) the role of screening for atypical germline mutations and subsequent disease surveillance remain unanswered.

SURG-14. LOWER-GRADE GLIOMA IN ELDERLY PATIENTS: TREATMENT AND OUTCOMES IN A MOLECULARLY CHARACTERIZED CONTEMPORARY COHORT

Abstract Lower-grade glioma (LGG) is rare among patients above the age of 60. Previous series reported poor outcomes, likely due to a high proportion of missed IDH wildtype astrocytomas which today would be diagnosed as glioblastoma, and thus proposed defensive treatment in elderly patients. We questioned these findings in our contemporary cohort of “true” LGGs, i.e. IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. Patients aged 60 years and older (“elderly”) treated for hemispheric LGG were retrospectively analyzed for demographic, tumor- and treatment-related factors and progression-free survival (PFS) and were compared to a cohort of patients younger than 60 years. Inclusion criteria, amongst others, were availability of molecular data and volumetric assessment of pre- and postoperative tumor burden. 212 patients were analyzed, among those 21 elderlies (9.9%). Elderly patients did not differ from younger ones regarding preoperative tumor volumes, eloquent location, presence of contrast enhancement and clinical presentation (seizures, focal deficits). In both groups (elderly vs. younger), most patients underwent tumor resection (81% vs. 90.6%; p=0.25) with comparable median residual tumor volumes (5.12 cm3 vs. 3.28 cm3; p=0.66). There was a trend towards more aggressive surgical approaches in younger patients, e.g., use of IOM and awake surgery. However, rates of functional deterioration (p=0.2) and revision surgery (p=0.98) were comparable. Oligodendroglioma, in relation to astrocytoma, was more common in the elderly (76.2% vs. 46.1%; p=0.011). Adjuvant radio- and/or chemotherapy was administered in 76.2% of elderly and 59.8% of younger patients (p=0.163). Median PFS was comparable (50 vs. 56 months; p=0.62), regardless of WHO grade (p=0.43) and tumor subtype (p=0.93). In conclusion, favorable surgical and survival outcomes were achieved in our series that were comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

Effects of Long-Term Temozolomide Treatment on Glioblastoma and Astrocytoma WHO Grade 4 Stem-like Cells.

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

IntroductionThe cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear.MethodsWe searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region.ResultsWe identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome.ConclusionsExtent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.

PATH-32. EXTENT, PATTERN, AND PROGNOSTIC VALUE OF MGMT PROMOTOR METHYLATION: DOES IT DIFFER BETWEEN GLIOBLASTOMA AND IDH-WILDTYPE/TERT-MUTATED ASTROCYTOMA?

Abstract INTRODUCTION The cIMPACT-NOW update 6 introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. METHODS We searched the institutional database for patients with: 1.) glioblastoma defined by histopathology; and 2.) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. RESULTS We identified 224 patients with glioblastoma diagnosed based on histopathology, and 71 patients with IDHwt astrocytoma with pTERTmut (32 astrocytomas WHO grade II and 39 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two groups as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two groups. Surgery was associated with improved overall survival in IDHwt astrocytoma with pTERTmut. In patients treated with radiochemotherapy or radiotherapy, higher numbers of methylated CpG sites were associated with favourable outcome in both groups. CONCLUSION Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both groups, higher numbers of methylated CpG sites are associated with favourable outcome when radio/chemotherapy is administered. Surgery may form the basis for favourable outcome.

Evaluation of BRAF Gene Status in Gliomas

Background: Development of different molecular markers has given a new insight in the glioma management. KIAA1549-BRAF gene fusion has a diagnostic and prognostic significance. Aim: The aim of this study was to determine the KIAA1549-BRAF gene fusion in glioma and their correlation with various clinical parameters. Material and Methods: Forty cases of glioma were studied for KIAA1549-BRAF gene fusion by reverse transcription-PCR (RT-PCR). Results: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Children had higher KIAA1549-BRAF fusion (72%; 8/11) as compared to adults (10%; 3/29) and this difference was statistically significant. Cerebellar location of tumor was significantly associated with KIAA1549-BRAF fusion. KIAA1549-BRAF fusion was highest in pilocytic astrocytoma (89%), and this difference was statistically significant. Statistically significant difference was noted between KIAA1549-BRAF fusion expression and WHO grade I glioma. Conclusion: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Childhood age, pilocytic astrocytoma histology, cerebellar location and WHO grade I tumor were significantly associated with KIAA1549-BRAF gene fusion.

Perfusion -Weighted Magnetic Resonance Imaging Techniques and Protocols in the Evaluation of Cerebral Blood Flow, Blood Volume, and Vascular Permeability of Brain Neoplasms

Objective : To identify the efficiency of perfusion, weighted magnetic resonance imaging techniques andprotocols in, evaluation of cerebral blood, flow, blood volume, &amp; vascular, permeability of a tumor in thebrain in correlation with viability of brain neoplastic tissues.Material and Methods : One hundred and fifteen patients with histologically proven brain tumors wereexamined by 1.5 Tesla PHILIPS MR System. For four months, patients who were referred in an MRIassessment were included in this review. Conventional MRIs protocol, (axial T2WI (TSE), Axial T1WI(FSE), axial T2WI FALIR, axial T1WI post contrast). PW-MRI protocol axial Fast Echo –Echo PlannerImage (FE-EPI) Neuro-T2* Perfusion Dynamic Contrast Enhancement agent (DCE-MRI), (Gadolinium(Gd)contrast Magnevist).Results and discussion: Magnetic Resonance Imaging in (10) patients (8.70%) revealed feature consistentwith brain tumors (control cases), the brain has been evaluated by routine study or conventional (protocolC). (105) patients (91.3%) underwent examination with PW-MRI (FE-EPI) Neuro-T2* Perfusion (DCEMRI)( protocol P). (18) patients (15.65%) with the anaplastic astrocytoma WHO grade (III), (17) patients(14.78%) with metastatic brain tumors, (15) patients (13.04%) with non-recurrence of post-operative braintumors, (11) patients (9.57%) with high grade glioma, (10) patients (8.70%) with craniopharyngioma, (9)patients (7.83%) with glioblastoma multiform WHO grade IV, (9) patients (7.83%) with low grade glioma,(8) patients (6.96 %) with meningioma, the agemistocytic astrocytoma WHO grade(II) was the lowestdiagnosed brain tumor (2.61%).

Survival of glioblastoma in relation to tumor location: a statistical tumor atlas of a population-based cohort

PurposePrevious studies on the effect of tumor location on overall survival in glioblastoma have found conflicting results. Based on statistical maps, we sought to explore the effect of tumor location on overall survival in a population-based cohort of patients with glioblastoma and IDH wild-type astrocytoma WHO grade II–III with radiological necrosis.MethodsPatients were divided into three groups based on overall survival: < 6 months, 6–24 months, and > 24 months. Statistical maps exploring differences in tumor location between these three groups were calculated from pre-treatment magnetic resonance imaging scans. Based on the results, multivariable Cox regression analyses were performed to explore the possible independent effect of centrally located tumors compared to known prognostic factors by use of distance from center of the third ventricle to contrast-enhancing tumor border in centimeters as a continuous variable.ResultsA total of 215 patients were included in the statistical maps. Central tumor location (corpus callosum, basal ganglia) was associated with overall survival < 6 months. There was also a reduced overall survival in patients with tumors in the left temporal lobe pole. Tumors in the dorsomedial right temporal lobe and the white matter region involving the left anterior paracentral gyrus/dorsal supplementary motor area/medial precentral gyrus were associated with overall survival > 24 months. Increased distance from center of the third ventricle to contrast-enhancing tumor border was a positive prognostic factor for survival in elderly patients, but less so in younger patients.ConclusionsCentral tumor location was associated with worse prognosis. Distance from center of the third ventricle to contrast-enhancing tumor border may be a pragmatic prognostic factor in elderly patients.

Plasma IL-8 and ICOSLG as prognostic biomarkers in glioblastoma.

BackgroundCNS immune privilege has been challenged in recent years. Glioblastoma (GBM) immune dysfunction includes complex interactions with the immune system outside the CNS. The aim of this study was to determine diagnostic and prognostic potential of immune-related proteins in plasma in GBM and interrogate biomarker presence in the brain tumor microenvironment (TME).MethodsOne hundred and fifty-eight patients with glioma WHO grade II–IV were included. Plasma collected at surgery was screened for 92 proteins using proximity extension assay technology and related to clinical outcome. Secretion and expression of candidate prognostic biomarkers were subsequently analyzed in 8 GBM cell lines and public RNAseq data.ResultsPlasma levels of 20 out of 92 screened proteins were significantly different in patients with GBM compared to patients with astrocytoma WHO grade II–III. High plasma interleukin-8 (IL-8) (hazard ratio [HR] = 1.52; P = .0077) and low CD244 (HR = 0.36; P = .0004) were associated with short progression-free survival and high plasma IL-8 (HR = 1.40; P = .044) and low ICOS ligand (ICOSLG) (HR = 0.17; P = .0003) were associated with short overall survival (OS) in newly diagnosed patients with GBM. A similar trend was found for ICOSLG (HR = 0.34; P = .053) in recurrent GBM. IL-8 was mostly secreted and expressed by mesenchymal GBM cell lines and expressed by vascular cells and immune cells in the TME. This was also the case for ICOSLG, although less consistent, and with additional expression in tumor-associated oligodendrocytes.ConclusionsHigh plasma IL-8 and low ICOSLG at surgery are associated with short OS in newly diagnosed GBM. Source of plasma ICOSLG may be found outside the TME.

Remission of Pediatric Diffuse Intrinsic Pontine Glioma: Case Report and Review of the Literature.

ABSTRACTBackground:Diffuse midline glioma (DMG) is one of the most aggressive pediatric tumors. Approximately 60% of pediatric DMG patients die within the first year of diagnosis. Complete clinical and radiological remission of DMG is extremely rare. The objective of this study was to describe a case of remission of pediatric DMG and to compare with similar cases published so far.Results:DMG was diagnosed in a 2-year-old girl who presented with brainstem and increased intracranial pressure manifestations. Ventriculoperitoneal shunt and chemotherapy-based treatment were offered. From the diagnosis, in spite of progressive enlargement of the tumoral lesion, her clinical condition improved remarkably. After the end of chemotherapy, progressive and gradual imagiological improvements occurred. At the end of the 60th month of follow-up, she was asymptomatic with total remission. Six pediatric DMG cases, from birth to the age of 3, in whom remission occurred were found in the literature. Histology sample was available in two of them (fibrillary astrocytoma—WHO Grade II and anaplastic astrocytoma—WHO Grade III). None received chemotherapy or radiotherapy.Conclusion:Remission of pediatric DMG is extremely rare and reinforces the biological heterogeneity of the tumor. In the absence of reliable predictors of prognosis, offering the best supportive treatment, including neurosurgical interventions should be considered in similar cases.

CTIM-16. INTERSTITIAL PHOTODYNAMIC THERAPY WITH 5-ALA FOR MALIGNANT GLIOMA RECURRENCES

Abstract Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a cytotoxic photosensitizer has been shown to be a feasible treatment option for malignant gliomas. We present outcome measures and a risk profile analysis of salvage iPDT in a large monocentric cohort with local tumor recurrence following standard therapy. This study included consecutive adult patients undergoing salvage iPDT for small, circumscribed, biopsy-proven malignant glioma recurrences not deemed eligible for safe complete resection of contrast enhancing tumor. A modified 3-D treatment-planning software was used to calculate the treatment-volume and the position of the stereotactic light diffusers within the lesion. Outcome measurements included estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and the risk profile of iPDT. Prognostic factors were obtained from logistic regression models. The institutional review board approved the study. A total of 44 patients (median age: 49.4 years, range 33.4–87.0 years, 17 female) were included. Recurrent tumors included 37/44 glioblastomas WHO grade IV and 7/44 anaplastic astrocytomas WHO grade III. Thirty (68.2%) tumors were MGMT methylated. Median treatment volume was 3.3 ccm (range, 0.5–22.8 ccm). A median number of 4 (range: 3–8) laser fibers were used. Median illumination time was 60min (range: 60–167 min). Symptomatic edema (8/44) or intratumoral hemorrhagic imbibition (7/44) did not result in any permanent morbidity. Median TTF was 7.1 months and median PRS was 13.0 months. The 2- and 5-years PRS rates were 25.0% and 4.5%. Treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. In conclusion, iPDT was associated with promising outcome measurements in local malignant glioma recurrences in highly selected patients. Transient neurologic deterioration did not lead to any permanent morbidity. The procedure deserves further prospective evaluation particularly to identify mechanisms of favorable treatment response and prognostic factors associated with long-term survival.