Anaplastic Oligoastrocytoma Research Articles

CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS

Abstract BACKGROUND Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS. METHODS Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO. RESULTS Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented. CONCLUSION These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.

Meningioma and glioma as the first collision brain tumour reported in small animals

We describe the clinical and pathological features of a brain collision tumour consisting of a fibrous meningioma and an anaplastic oligoastrocytoma in a 14-year-old male neutered French Bulldog. Computed tomography of the brain revealed a poorly defined, intra-axial lesion affecting the left frontal lobe. Following euthanasia, histological examination showed an anaplastic oligoastrocytoma invading the brain parenchyma and an adjacent fibrous meningioma. As synchronous intracranial tumours are rare in animals, the aims of this report are to describe the clinical, imaging and histopathological features of an intracranial collision tumour in a dog and highlight the importance of a complete histopathological study despite the imaging findings.

The role of angiogenic factors eNOS / VEGF in the treatment of anaplastic glioma

Introduction: Anaplastic gliomas (AG) account for 6–15 % of all primary brain tumors. These include: anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and rarer forms — anaplastic pleomorphic xanthoastrocytoma and anaplastic ganglioma. According to the data on these factors, endothelial nitric oxide synthase (eNOS) is promising in terms of the prognostic value of the course of the tumor process. It was reported that a number of vascular VEGF factors interact with eNOS, contributing to the formation of an intra-tumor vascular network, which can create conditions for uneven prolonged hypoxia, leading to the emergence of more stable tumor cells. Its role in the development of a higher anaplasia level has not been studied in isolation, which determines the relevance of this study. The prognostic role of changes in endothelial nitric oxide synthase (eNOS) in the continued growth and malignant transformation of anaplastic gliomas was studied. Results: Histological samples of brain tumors of 22 patients at the University Clinic in Nizhny Novgorod from 2017 to 2019 were examined and verified for the presence of high-grade III glioma, according to the data of the World Health Organization. The average age of the patients was 50.7 years. The material was obtained as a result of surgical removal of recurrent tumors after chemo and radiotherapy. Discussion: The microenvironment of anaplastic glioma plays an essential role in its pathogenesis. More importantly, angiogenesis, which causes the supply of glioma cells with oxygen, growth factors, nutrients, and hormones, is a significant process of tumor dissemination and growth. The degree of microvascular proliferation and angiogenesis was associated with poor survival rate, transition from a lower grade to a high grade, and relapse. In high-grade glioma, such as anaplastic glioma, neoangiogenesis is an important physiological process that provides adequate blood supply for the proliferation, survival, and invasion of glioma cells. Conclusion: The high mortality rate in gliomas underscores the urgent need for effective treatment. The glioma pathogenesis is complex and can be caused by various mechanisms, as evidenced by abnormal activation of tumor angiogenesis and mutation of isocitrate dehydrogenase. VEGF acts as a regulator of angiogenesis and is widely recognized as a critical factor in glioma development and progression. Our results suggest that VEGF and eNOS inhibition may be an effective way to control and/or block endothelial barrier damage and prevent tumor progression.

CIMP-positive glioma is associated with better prognosis: A systematic analysis.

Background:CpG island methylator phenotype (CIMP) was closely related to the degree of pathological differentiation of tumors, and it’s an important determinant of glioma pathogenicity. However, the molecular and pathological features of CIMP-positive glioma have not been fully elucidated. In addition, CIMP have been reported to be a useful prognostic marker in several human cancers, yet its prognostic value in gliomas is still controversial. Therefore, we aimed to evaluate gene mutations and pathological features of CIMP-positive glioma and explore the prognostic value of CIMP in gliomas.Methods:We comprehensively searched PubMed, Embase, and MEDLINE for studies describing gene mutations, pathological features and overall survival of gliomas stratified by CIMP status. Odds ratios (OR), hazard ratios (HR), and their 95% confidence intervals (CI) were used to estimate the correlation between CIMP and the outcome parameters.Results:Twelve studies with 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Our results showed that CIMP was more frequent in isocitrate dehydrogenase 1 (IDH1)-mutated gliomas (OR 229.07; 95% CI 138.72–378.26) and 1p19q loss of heterozygosis (LOH) gliomas (OR 5.65; 95% CI 2.66–12.01). Pathological analysis showed that CIMP was common in low-malignant oligodendroglioma (OR 5.51; 95% CI 3.95–7.70) with molecular features including IDH1 mutations and 1p19q LOH, but rare in glioblastoma (OR 0.14; 95% CI 0.10–0.19). However, CIMP showed no obvious correlation with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24–2.00) or oligoastrocytomas (OR 0.79; 95% CI 0.35–1.76). Concerning the prognosis, we found that CIMP-positive gliomas had longer overall survival (HR 0.57; 95% CI 0.97–0.16) than CIMP-negative gliomas.Conclusions:CIMP could be used as a potential independent prognostic indicator for glioma.

Summary of virtual tumor board platforms and implementation in neuro-oncology.

e13604 Background: Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. VTBs are an emerging resource across various cancer care networks in the United States. Methods: We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed Xcures, Genomet, Oncolens, Navify Tumor Board, Medical University of South Carolina [MUSC] Virtual Tumor Board, Virtual Tumor Board Tahoe Forest Cancer Center, UC Davis Health Care Center VTB and MassiveBio. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results: 30% of all VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records were reviewed where the median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose VTB integrated option. 76% of patients in Xcures registry consist primary CNS tumors. With at least 556 patients in tumor registry which included 46% Glioblastoma cases [96% primary;, 4% secondary], 13% Diffuse midline glioma with H3K27M-mutant cases, 5% Diffuse intrinsic pontine glioma cases, 3% Astrocytoma and Diffuse Astrocytoma cases, 3% Anaplastic astrocytoma cases; Glioma and Diffuse Glioma, 1% Anaplastic Oligodendroglioma cases and < 1% Gliosarcoma, Oligodendroglioma, Pilocytic astrocytoma, Anaplastic pleomorphic Xanthoastrocytoma, Fibrillary astrocytoma, Oligoastrocytoma and Pleomorphic Xanthoastrocytoma cases. In the MUSC VTB, 9 neuro-oncology cases were reviewed. They meet weekly, and average response time was within 24hrs of case review.Patient demographics were not recorded. Genomet Virtual Board de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of 5 specialist most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists and neuroradiologists. Participants had an average of 23 cases reviewed. Case review revealed an age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infra-tentorial tumor, < 5% each: pineoblastoma, melanoma, hemangioblastoma and pilocytic astrocytoma. Average response time observed in all cases was ≤24 hours. Detailed metrics for number/percentages of brain tumor cases were not available for most other platforms at time of submission. This will be updated at presentation. Conclusions: VTBs have allowed for quicker expert analysis of cases. This has resulted in an accelerated number of cases reviewed with a shortened communication time. More studies are needed to gain additional insight into user engagement

Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma

Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance.

CTNI-46. PHASE I OPEN-LABEL, SINGLE-CENTER, DOSE ESCALATION STUDY (NCT02423525) OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER

Abstract Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patients were screened and 24 were enrolled (median age 60, 78% male, 87.5% Caucasian, glioblastoma N=16, chordoma N=3, brain metastases N=2, meningioma N=1, anaplastic mixed oligoastrocytoma N=1). Patients had received a median of 2.5 prior treatments. The study proceeded through the 4 dosing cohorts without reaching dose-limiting toxicity: Cohort 1 (80mg every 4 days) N=3; Cohort 2 (120mg every 4 days) N=3; Cohort 3 (180mg every 4 days) N=7, including replacement patients; Cohort 4 (280mg every 7 days) N=11. Diarrhea (75%), rash (75%), nausea/vomiting (37.5%), fatigue (29.2%), anorexia (25%), and limb edema (16.7%) were the most common side effects. There were no CTCAE defined grade 4 toxicities. Grade 3 side effects infrequently occurred in the highest dosing cohort and once in each cohort 2 and 3. These results demonstrate that pulsatile Afatinib at a dose of 280mg every 7 days is safe and tolerable for patients with brain involving cancers.

Abstract 2599: Does tumor volume effect the spectroscopic classification of brain cancer patients

Abstract This study focuses on investigating the link between brain tumor volume and the spectroscopic classification between patients with known gliomas and healthy controls. Discrimination of brain cancer vs. non-cancer patients using serum-based ATR-FTIR diagnostics was first developed by Hands et al. achieving sensitivity and specificity values of 92.8% and 91.5% respectively. Cameron et al. then went on to stratifying between specific brain tumor types and was successful in providing a sensitivity of 90.1% and a specificity of 86.3%. Expanding on these studies, it is vital to determine if the size of a tumor has a direct effect on the sensitivity and specificity and whether or not it was only the larger tumors that were being identified as cancerous. A cohort of 90 patients whose tumor volumes were calculated using their MRI images (either T1-weighted contrast enhanced, T2-weighted or FLAIR images), including patients with high-grade glioblastoma multiforme (GBM), and low-grade gliomas such as anaplastic astrocytoma, astrocytoma, oligoastrocytoma and oligodendroglioma, were used for investigation. Utilizing ATR-FTIR spectroscopy coupled with machine learning algorithms these tumor patients were stratified against 87 healthy controls and were classified as either cancer or non-cancer. From these initial findings' sensitivities, specificities and balanced accuracies were greater than 88% and cancer patients with tumor volumes as small as 0.2 cubic cm were correctly identified, demonstrating that classifications are not affected by tumor volume. Both small and low-grade gliomas were identified which shows great promise for this technique to be used as a screening tool or in diagnostics for early detection of brain tumors. Citation Format: Ashton G. Theakstone, Paul M. Brennan, Matthew J. Baker. Does tumor volume effect the spectroscopic classification of brain cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2599.

HGG-29. A CASE OF CIRCUMSCRIBED HIGH-GRADE ASTROCYTOMA WITH ATRX AND CDKN2A/B ALTERNATIONS WHO WAS INITIALLY DIAGNOSED AS GLIOBLASTOMA AND HAS 20 YEARS SURVIVAL

Pediatric high-grade gliomas are rare and often hard to classify, which grow locally and show longer survival than diffuse high-grade gliomas in adults. We report a case of circumscribed high-grade astrocytoma who was initially diagnosed as glioblastoma and has 20 years survival. A 7-year-old girl suffered from epileptic seizure due to a left occipital lobe tumor. The tumor was resected in another hospital and diagnosed as glioblastoma. The tumor disappeared after extended local irradiation and chemotherapy using nimustine hydrochloride (ACNU) and cisplatin (CDDP). Eighteen years after initial onset, first recurrence was confirmed as the intra-tumoral hemorrhage. The tumor was resected and diagnosed as anaplastic oligoastrocytoma. After 6 courses of temozolomide (TMZ), the tumor disappeared. Twenty years after initial onset, the second local recurrence was confirmed. Although gamma knife and TMZ was performed, the tumor did not disappear. The tumor was surgically resected. Histopathology showed localized growth with some infiltration and mitosis but lacked pseudopallisading and microvascular proliferation. The tumor was diagnosed as circumscribed high-grade astrocytoma. Immunostaining revealed ATRX nuclear loss and CDKN2A / B homozygous deletion. After 10 courses of TMZ, the third local recurrence was confirmed. The tumor was completely removed and has not occurred recurrence more than 3 months after the last operation. Circumscribed high-grade glioma is expected to survive longer than invasive glioma. Pediatric gliomas should differ from adult gliomas in the genes of tumorigenesis. Care should be taken for its diagnosis and treatments. We also need a new classification based on histology and gene profile. HGG-30, ANALYSIS OF PEDIATRIC GLIOMAS IN OUR INSTITUTE Kaoru Tamura, Mai Fujioka, Masae Kuroha, Motoki Inaji, Yoji Tanaka, Tadashi Nariai, and Taketoshi Maehara; Tokyo Medical and Dental University, Tokyo, Japan. PURPOSE: Recent advances in genetic interrogation of pediatric glioma increase the importance of molecular diagnosis using surgical specimen. However, surgical resection may be avoided to preserve quality of life, especially in brain stem glioma cases. We retrospectively examined diagnosis and treatment of pediatric gliomas in our hospital. METHODS: This study includes 14 consecutive glioma patients under the age of 18 who underwent initial treatment at our hospital from 2000 to 2019. Histopathological diagnosis, clinical course and molecular status such as IDH, H3F3A and BRAF were analyzed. RESULTS: 5 patients (1 pilocytic astrocytoma (PA), 3 diffuse astrocytomas, 1 oligodendroglioma were treated only by surgical resection (group A). 7 patients (1 PA, 1 anaplastic oligodendroglioma, 2 diffuse midline gliomas and 3 glioblastomas (GBM)) received radiation and/or chemotherapy after surgical resection (group B). 2 diffuse intrinsic pontine gliomas (DIPG) received radiation and chemotherapy without surgical resection (Group C). No IDH mutation was observed in all pathological specimen obtained cases. BRAF alteration was observed in all PA cases. 1 case of GBM had BRAF V600Emutation and the other had H3K27M mutation. During a median of 7.7 years of follow-up, group A patients have no recurrence. Group B includes various diagnosis and prognosis. 2 group C patients diagnosed DIPG by MRI showed different clinical courses. CONCLUSION: Pediatric gliomas include diverse biological subgroups and show broad range of clinical behavior. Since pediatric glioma has a low incidence and a wide variety of genetic mutations, multicenter study is important to improve the treatment of pediatric glioma.

SURG-39. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 26 CASES

Abstract INTRODUCTION 5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries. MATERIALS AND METHODS Total 26 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection. RESULTS Among the 26 patients, 22 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 4 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect. CONCLUSION 5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.

AYURVEDA AS A CO-THERAPY IN THE MANAGEMENT OF OLIGOASTROCYTOMA: A CASE STUDY

Anaplastic astrocytoma (AA) is a diffusely infiltrating malignant, astrocytic, primary brain tumour with a peak incidence between 40 to 50 years of age is a leading cause of cancer death. Though cancer chemotherapy is highly effective in many cancers, but side-effects of chemotherapy are severe in many patients like myelosuppression, anorexia, weight loss, mucositis, fatigue, nausea, vomiting and diarrhoea. It appears that side effects of chemotherapy are manifestations of aggravated Tridosha as Raktadushti (vitiated blood). Therefore, present case study was undertaken to find effectiveness of Ayurvedic medication as an adjuvant or co-therapy in the management of oligoastrocytoma as well as in minimizing the side effect of chemo-radiotherapy. A female patient of age 40 years with brain cancer (clinically diagnosed case of anaplastic oligoastrocytoma grade 3rd) undergoing oral chemotherapy by irnocam 150 mg, avastin 400mg for 6 cycle and radiotherapy was taken. Patient was given classical Ayurvedic formulation of Rasa sindur 50mg+ Abhrakbhasma 250mg+ Vachachurna 500mg+ Panchamritalauha guggulu 250mg BD with honey, Shatavarighrita 5gm BD with milk, Jyotishmatitaila 5 drops BD with Bataasha and cap SNEC30 (liquid curcumin capsules). After the completion of 6th cycle there were very encouraging results observed with negligible side effects, improvement in all chief complaints, general health condition and quality of life of the patient. Ayurvedic medication appears to have significant effect on reducing side effect of chemo-radiotherapy and improving quality of life in the patient of brain cancer (oligoastrocytoma).

Double extremes of brain tumors – Dilemma of decision-making and pitfalls of image: A case report and literature review

Coexistence of multiple primary intracranial tumors has been reported previously. However, most of simultaneous tumors occurred after intracranial radiotherapy or in high association with heredity. Both primary intracranial tumors arising simultaneously at synchronous discrete sites were introduced without prior radiation or genetic disorders. These tumors showed the same characteristic according to preoperative images. Two distinct tumors, meningioma and anaplastic oligoastrocytoma were revealed by postoperative histopathological findings. We present this unusual case to exhibit the rare possibility that two distinct primary brain tumors can occur in the same patient. Although magnetic resonance image were used to define the tumor patterns in almost cases, some diagnostic pitfalls may occur with coexistent primary brain tumors. Hence, a discrepancy between clinical impressions and radiological findings should raise a further survey for potential different natures. Reviewing the literature, we should remove the symptomatic tumors based on mass effect and presenting symptoms first, whether it is a benign-looking meningioma or a malignant astrocytoma. Surgical priority for two distinct synchronous tumors from each other needs individual evaluation carefully.

Stereotactic Radiosurgery for the Treatment of Recurrent High-grade Gliomas: Long-term Follow-up.

High-grade gliomas (HGG) are the most frequent primary central nervous system tumors; treatment of HCGs includes surgery and post-operative conformal radiotherapy associated with temozolomide (TMZ or procarbazine/lomustine/vincristine [PCV], specifically in patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas). However, recurrence is common. Re-irradiation has been utilized in this setting for years and remains a feasible option, although there is always a concern regarding toxicity. Modern high-precision conformal techniques, including stereotactic radiosurgery (SRS), could improve the therapeutic ratio by delivering high biologically equivalent doses while reducing high-dose radiotherapy (RT) to normal brain tissue. In this paper, we present the results obtained after prolonged follow-up in patients who underwent SRS as a treatment for recurrent high-grade gliomas at San Francisco Hospital in Madrid, Spain

Atypical clinical manifestations and prognosis analysis of pediatric diffuse intrinsic pontine glioma

Objective To analyze the atypical clinical manifestations and clinical prognosis of pediatric diffuse intrinsic pontine glioma (DIPG). Methods A total of 27 patients with complete clinical data of DIPG undergoing clinical treatment at Neurosurgery Department of Beijing Tiantan Hospital, Capital Medical University from November 2015 to November 2017 were retrospectively enrolled into this study. All patients were divided into 2 groups according to the presence of atypical manifestations: atypical clinical manifestation group (17 cases) and the control group (10 cases). Among the 27 cases, 16 patients underwent stereotactic biopsy or open cranial biopsy, and the other 11 patients underwent tumor excision through craniotomy. All the children were followed up clinically or by telephone after operation to study the clinical outcomes. Comparative analysis was conducted on those clinical data. Prognosis was compared between the 2 groups through Kaplan-Meier survival analysis. Results Among the 27 cases, 20 were pathologically identified as high grade gliomas (including 4 cases of diffuse midline glioma, 6 cases of glioblastoma, 6 cases of anaplastic oligoastrocytoma, 4 cases of anaplastic astrocytoma) and 7 as low grade glioma (including 4 cases of oligoastrocytoma and 3 cases of astrocytoma). One child suffered from pneumonia and finally recovered postoperatively. No statistically significant difference (all P>0.05) was identified between 2 groups in the age, gender, clinical manifestation (including cranial nerve palsy, long tract dysfunction and cerebellum signs), clinical imaging features (including lesion enhancement, supratentorial ventricle enlargement and brachium pontis involvement), clinical treatment or pathology. Kaplan-Meier survival analysis showed that patients with atypical clinical manifestation had significantly higher cumulative survival rate than those in the control group (P=0.045). Conclusion Atypical clinical manifestation could be identified in some pediatric DIPG patients, which might be predictive of a better prognosis. Key words: Brainstem tumor; Child; Atypical clinical manifestation

INNV-40. TARGETED NEXT GENERATION SEQUENCING OF PEDIATRIC HIGH-GRADE GLIOMA AND ITS THERAPEUTIC IMPLICATIONS, MD ANDERSON EXPERIENCE

Abstract INTRODUCTION The new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients. MATERIALS AND METHODS An analysis of pediatric patients with HGG treated at UT MD Anderson Cancer Center (MDACC) who underwent molecular genetic profiling using next generation sequencing with different genomic panels (AmpliSeq™Cancer Hotspot and Oncomine Panels – by Thermo Fisher Scientific). RESULTS 27 patients with HGG (median age 14 years, range 3–18 years old) underwent genomic profiling. Primary diagnoses were glioblastoma multiforme (n=22), anaplastic astrocytoma (n = 2), gliosarcoma (n= 1), anaplastic pleomorphic xanthoastrocytoma (n= 1) and anaplastic oligoastrocytoma (n= 1). There are 46 genes common to the panels used. The most common mutation was in TP53 (73%). Other mutations included PIK3CA (19%), IDH1 (11.5%), 7.7% for ATM, EGFR and PTEN, and 3.8% for BRAF, FGFR1 and FGFR2. 24 out of 27 patients were tested at initial diagnosis and 3 upon relapse/progression. Patients at initial diagnosis received standard of care therapy of radiation and temozolomide. Only 5 patients received targeted therapy upon progression/recurrence. Some challenges of genomically-matched therapy included lack of clinical trials accepting pediatric patients, unavailability of a liquid form of a drug, and insurance disapproval for off-label use. CONCLUSION The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. This cohort, though limited by sample size, highlights the opportunity to perform molecular testing and identification of alterations in actionable genes.

SURG-18. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 19 CASES

Abstract BACKGROUND 5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries METHODS Total 19 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection RESULTS Among the 19 patients, 15 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 2 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect. CONCLUSION 5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.

EXTH-45. THERAPEUTIC EFFICACY OF MUTANT ISOCITRATE DEHYDROGENASE 1 (IDH1) INHIBITOR SYC-435 WITH STANDARD THERAPY IN PATIENT-DERIVED IDH1 MUTANT GLIOMA XENOGRAFT MOUSE MODELS

Abstract Mutation in isocitrate dehydrogenase 1 (IDH1) occurs in >70% of WHO grade II/III astrocytomas, oligodendrogliomas and secondary glioblastoma. The mutant enzyme catalyzes the reduction of α-ketoglutaric acid to D-2-hydroxyglutaric acid, leading to cancer initiation. In this study, we examined therapeutic efficacy of SYC-435 (1-hydroxypyridin-2-one), a newly developed mutant IDH1inhibitor, in IDH1 mutant gliomas. IDH1 R132H mutation (homozygous) was detected in BT142 anaplastic oligoastrocytoma (AOA) and R132C mutation (mutant allele frequency 39–50%) in V0914AOA by pyrosequencing. Suppression of cell growth by SYC-435 was observed with more sensitive of mutant over wild-type IDH1. Patient-derived orthotopic xenograft mouse models of BT142AOA and V0914AOA were treated with vehicle, SYC-435 (15 mg/kg/day x 28 days), temozolomide (50 mg/kg/day x 5 days)/fractionated radiation (2 Gy/day x 5 days) (standard therapy), and SYC-435/standard therapy starting 2 weeks after intracranial tumor implantation. Log rank analysis showed SYC-435 alone did not alter survival times. Although standard therapy significantly prolonged survival times in both models (P< 0.0005), SYC-435/standard therapy further extended survival times (P< 0.05) in V0914AOA and exhibited similar trend in BT142AOA. Elevation of 2-HG/α-KG ratio and methylation of H3K4/H3K9 in V0914AOA tumor compared to wild-type model was detected at the end of treatments. SYC-435 with/without standard therapy tended to reduce 2-HG/α-KG ratio and dramatically reduced methylation of H3K4/H3K9. RNA-seq analysis showed sirtuin signaling pathway, mitochondrial dysfunction and oxidative phosphorylation pathways with mitochondrial DNA (mtDNA) encoded molecules were highly affected by all treatments. However, mtDNA regulation did not correlate to survival benefits. In conclusion, SYC-435 possesses anti-tumor effects that are more sensitive in IDH1 mutant gliomas and generated strong synergistic activities with standard therapies for survival benefits with reduced methylation of H3K4/H3K9. Treatments significantly affected mtDNA but significance to survival benefits remains to be elucidated. Our data support the clinical testing of SYC-435 in patients with IDH1 mutant glioma.

Drug loading and the efficiency of nanodiamond-anticancer drug complexes in cancer treatment

We retrospectively investigated the prognostic impact of molecular phenotypes in patients with recurrent anaplastic glioma treated with prolonged administration of temozolomide (TMZ). Malignant gliomas have a dismal prognosis despite the available multimodal treatments. We reviewed 87 patients who were diagnosed with recurrent anaplastic gliomas between March 2004 and June 2010, and 58 were enrolled for analysis. In the cohort, 21 patients had anaplastic oligodendrogliomas, 18 anaplastic oligoastrocytomas and 19 anaplastic astrocytomas. All patients were initially treated with surgical resection or biopsy followed by involved-field radiotherapy. At recurrence, patients were treated with 150–200 mg/m2 of TMZ on days 1–5 in 28 day cycles until disease progression. We evaluated the association of molecular phenotypes, including 1p19q deletion, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase-1 (IDH1) mutation and other clinico-histopathological findings with treatment outcome. During the mean follow-up period of 34.6 months, 33 patients were still alive (56.9%). Median survival from recurrence was 39.7 months (95% confidence interval [CI] 22.7–56.7). Time to progression from administration of TMZ was 6.4 months (95% CI 5.0–7.8). Univariate analysis demonstrated that the presence of the IDH1 mutation was closely associated with treatment response (8.4 versus 3.8 months; p = 0.015). Oligodendroglial lineage, 1p19q deletion status and MGMT promoter methylation status were not independent variables for determining the TMZ treatment outcome. In recurrent anaplastic gliomas, TMZ treatment is an effective modality regardless of MGMT methylation status or histological type. The IDH1 mutation has the most powerful prognostic impact on overall patient survival.

Incidence trends of adult malignant brain tumors in Finland, 1990–2016

Background: Several studies have reported increased incidence trends of malignant gliomas in the late 1900s with a plateau in the 2000s, but also some recent increases have been reported. The purpose of our study was to analyze incidence trends of malignant gliomas in Finland by morphology and tumor location.Material and methods: Data on 4730 malignant glioma patients were obtained from case notifications to the nationwide, population-based Finnish Cancer Registry (FCR), and less detailed data on 3590 patients up to 2016. Age-standardized incidence rates (ASR) and average annual percent changes (APCs) in the incidence rates were calculated by histological subtype and tumor location.Results: The incidence rate of gliomas was 7.7/100,000 in 1990–2006 and 7.3 in 2007–2016. The incidence of all gliomas combined was stable during both study periods, with no departure from linearity. In an analysis by age group, increasing incidence was found only for ages 80 years and older (1990–2006). During both study periods, incidence rates were increasing in glioblastoma and decreasing in unspecified brain tumors. In 1990–2006, rates were also increasing for anaplastic oligodendroglioma, oligoastrocytoma and unspecified malignant glioma, while decreasing for astrocytoma. As for tumor location, incidence in 1990–2006 was increasing for frontal lobe and brainstem tumors, as well as those with an unspecified location, but decreasing for the parietal lobes, cerebrum and ventricles.Conclusions: No increasing incidence trend was observed for malignant gliomas overall. An increasing incidence trend of malignant gliomas was found in the oldest age group during 1990–2006.

Sequencing of Chemotherapy and Radiotherapy for Newly Diagnosed Anaplastic Oligodendroglioma and Oligoastrocytoma.

Adjuvant management of anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs) is guided by 2 seminal phase III trials, one of which utilized radiotherapy (RT) followed by chemotherapy (CT) (RT-CT), and the other in which CT was followed by RT (CT-RT). Both paradigms are endorsed by the National Comprehensive Cancer Network because no direct comparison in the first-line (nonprogressive) setting has been performed to date. This study of a contemporary national database sought to evaluate practice patterns and outcomes between both approaches. The National Cancer Database (NCDB) was queried for newly diagnosed AO/AOA treated with postoperative sequential CT-RT or RT-CT. Multivariable logistic regression ascertained factors independently associated with delivery of a particular paradigm. Overall survival (OS) between cohorts was compared using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling evaluated factors associated with OS. Of 225 patients, 19 (8.4%) received CT-RT and 206 (91.6%) underwent RT-CT. Groups were well-balanced, although CT-RT was more often administered to men (P=0.009) and AOs (P=0.037). Median follow-up was 58 months. Median OS in the CT-RT cohort was 93 months (95% confidence interval, 37-150 mo), and 107 months (95% confidence interval, 72-142 mo) in the RT-CT group (P=0.709). Therapy sequence was not associated with OS on univariate (P=0.709) or multivariate (P=0.257) assessment. In the United States, most AO/AOA patients receiving sequential therapy undergo RT followed by CT. No differences in survival were observed with either approach; this addresses a knowledge gap and confirms that both paradigms are appropriate in the first-line setting.