Astrocytoma Tumors Research Articles

Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors

Abstract We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Characterization of the tumor microenvironment through multi-omics based deconvolution analyses revealed 5 distinct tumor clusters associated with different populations of infiltrating immune cells: Cold-medullo, Cold-mixed, Epithelial, Neuronal and Hot. The two cold-tumor clusters have the lowest immune cell infiltration, one characterized by the enrichment of medulloblastoma tumors; while the other is a mixture of ependymoma, ATRT, HGG and medulloblastoma. The Epithelial group, on the other hand, was enriched in craniopharyngioma samples, an epithelium derived tumor. Interestingly, the RNA levels of PD-1 and CTLA4 were significantly upregulated in this Epithelial group, confirming that craniopharingioma could potentially benefit from anti PD-1 and/or CTLA-4 therapies as previously reported. LLG and ganglioglioma were allocated into two groups of Neuronal and Hot, the former characterized by the presence of neuronal cells, and the latter by the presence of macrophages, microglia, and dendritic cells. Adenosine producers (e.g., ENTPD1 and NT5E), which act as inhibitory immune checkpoint molecular, showed up-regulation in the Hot cluster based on both RNAseq and proteome data, suggesting patients in this group might benefit from adenosine reducing treatments. Among LGG tumors, there is a significant difference between microglial and macrophage polarization across BRAF statuses: BRAF-fusion promoted more pro-regenerative (immune suppressive) microglia than pro-inflammatory microglia, while BRAF-V600E promoted more pro-regenerative macrophages than pro-inflammatory macrophages, implying different immunosuppressive mechanisms in the BRAF-V600E and fusion tumors. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology relating to tumor microenvironment. The incorporation of the proteomic and phosphoproteomic dimension into this large-scale multi-omic study adds functional insight that helps drive translational efforts. Citation Format: Francesca Petralia, Nicole Tignor, Boris Reva, Pichai Raman, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Jiayi Ji, Xiaoyu Song, Yuankun Zhu, Jo Lynne Rokita, Antonio Colaprico, Anna Calinawan, Jeffrey R. Whiteaker, Richard G. Ivey, Zeynep Gumus, Selim Kalayci, Gonzalo L. Garcia, Seungyeul Yoo, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Felipe Leprevost, Hui-Yin Chang, Krutika S. Gaonkar, Elizabeth M. Appert, Ximena Cuellar, Jena Lilly, Jun Zhu, Eric E. Schadt, Medhi Mesri, Emily Boja, Tara Hiltka, Henry Rodriguez, Li Ding, Antonio Iavarone, Maciej Wiznerowicz, Alexey I. Nesvizhskii, David Fenyo, Steven Gygi, Amanda Paulovich, Adam C. Resnick, Phillip B. Storm, Brian Rood, Pei Wang, Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium. Integrated proteogenomic characterization across seven histological types of pediatric brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 445.

Short-term outcome following surgery for rare brain tumor entities in adults: a Swedish nation-wide registry-based study and comparison with SEER database

ObjectiveTo investigate outcomes after surgery for rare brain tumors using the Swedish Brain Tumor Registry (SBTR).MethodsThis is a nationwide study of patient in the SBTR, validated in the Surveillance, Epidemiology, and End Results (SEER) registries. We included all adults diagnosed 2009–2015 with a rare brain tumor entity (n = 216), defined as ependymoma (EP, n = 64), subependymoma (SUBEP, n = 21), ganglioglioma (GGL, n = 54), pilocytic astrocytoma (PA, n = 56) and primitive neuroectodermal tumor (PNET, n = 21). We analyzed symptomatology, tumor characteristics and outcomes.ResultsMean age was 38.3 ± 17.2 years in GGL, 36.2 ± 16.9 in PA, 37.0 ± 19.1 in PNET, 51.7 ± 16.3 in EP and 49.8 ± 14.3 in SUBEP. The most common symptom was focal deficit (39.6–71.4%), and this symptom was most common in GGL patients with 64.2% of GGL presenting with seizures. Most patients had no or little restriction in activity before surgery (Performance Status 0–1), although up to 15.0% of PNET patients had a performance status of 4. Gross total resection was achieved in most (> 50%) tumor categories. Incidence of new deficits was 11.1–34.4%. In terms of postoperative complications, 0–4.8% had a hematoma of any kind, 1.9–15.6% an infection, 0–7.8% a venous thromboembolism and 3.7–10.9% experienced a complication requiring reoperation. There were 3 deaths within 30-days of surgery, and a 1-year mortality of 0–14.3%.ConclusionWe have provided benchmarks for the current symptomatology, tumor characteristics and outcomes after surgery for rare brain tumors as collected by the SBTR and validated our results in an independent registry. These results may aid in clinical decision making and advising patients.

Analysis of Immunoexpression of Programmed Death Ligand 1 (PD-L1) and Proliferation Index Ki-67 on Diffuse Astrocytic Tumours (DAT)

BackgroundDiffuse astrocytic tumours (DAT) is a diffuse infiltrative astrocytoma tumor accompanied by molecular parameters in the form or absence ofIsocitrate Dehydrogenase (IDH) gene mutations. The DAT category without the examination of the IDH gene mutation is classified as NotOtherwise Specified (NOS). Ki-67 is a marker for DAT proliferation so that it can assess the degree of DAT. Diffuse astrocytic tumoursbehavior is influenced by proliferative ability and the presence of a tumor microenvironment. The tumor microenvironment PD-L1 factorinfluences DAT behavior and allows the development of target therapy in DAT cases. This study aimed to analyze the relationship betweenPD-L1 and Ki-67 imunoexpression in the histopathological degree of DAT.MethodsCross-sectional study of 30 paraffin blocks of DAT NOS cases from 2014-2018 in the Department of Anatomical Pathology RSUP dr. HasanSadikin, Bandung. The sample consisted of 15 cases of grade II, 7 cases of grade III and 8 cases of grade IV, carried outimmunohistochemical staining with GFAP, PD-L1 and Ki-67. Assessment of PD-L1 immunoexpression was carried out by the histoscoremethod. The Ki-67 assessment was assessed based on its distribution, which was <10% and ≥10%. PD-L1 and Ki-67 immunoexpressionwith histopathological degrees in DAT were statistically analyzed by Kolmogorof Smirnov test, however association betweenimmunoexpression of PD-L1 and Ki-67 were analyzed by chi-square test.ResultsThere was a significant relationship between PD-L1 immunoexpression and histopathological degree in DAT (p=0.005). There was asignificant relationship between Ki-67 immunoexpression and DAT histopathology degree and with PD-L1 (p=0.001 and p=0.010).ConclusionPD-L1 immunoexpression and proliferation rates affect the degree of DAT. Proliferation rate of DAT is influenced by PD-L1 so that in thisstudy, PD-L1 and Ki-67 can be used as a marker of prognosis predictors.

Characterization of G protein β subunit expression of human brain Glioma tumor.

Proteome indicates the protein content of a genome. Proteome analysis is effective in a new system formulation and prediction, prevention, and treatment based on protein. One of the purposes of proteomics researches is to know and understand the cancer mechanism. In this study, we separated the proteins by the Two-Dimensional Electrophorese method and analyzed and compared protein spots by statistical and software data. The spots were separated and identified by the proteins' Isoelectric PH differences, molecular weights, and data bank. In continuation, the protein profiles were clustered by MALDI-TOF-TOF and the main element was identified and confirmed. We have used site PhosphoSitePlus® to review post-translational modifications. The findings indicated that the G protein Beta subunit rate increased in the astrocytoma, oligodendroglia, and glioblastoma cerebral malignant tumors. The βγ complex formation may prevent and activates many paths of cellular growth. The βγ complex activity control of the changes after the conversion parallel to GTPase activity of this α subunit may be a formulation mechanism for the G signal path (Tab. 5, Fig. 4, Diagram 2, Ref. 29). Keywords: glioma, G protein β subunit, proteomics.

P03.09 Real world management and prognosis of glioma patients:SYSUCC report from China

Abstract Background: The conventional way of patient treatment should be following guidelines. While in clinical practice, patients received treatments very often away from suggested guideline. In this report, we reviewed glioma patients received real world treatment at Sun Yat-sen University Cancer Center (SYSUCC) and results of this patient series. Methods: Total of 1215 glioma patients received surgery at SYSUCC from 2000 to 2017 were enclosed for analysis. The pathologic diagnosis of patients has followed WHO classification (initially 2007 standard, than 2016 standard). Results: A total of 1001 newly diagnosed brain glioma patients were analyzed, including 90 cases WHO grade I, 307 grade II, 239 grade III and 365 grade IV. The median age of onset was 14 (1–75), 35 (2–69), 41 (8–82) and 50 (2–86) years old, respectively, for grade I, II, III and IV glioma patients. Tumor total resection was achieved in 567 patients (57.5%). Among all patients, 331 high-grade gliomas (54.8%) and 159 low-grade glioma (40.1%) received radiotherapy, whereas 285 high-grade gliomas (47.1%) and 80 low-grade tumors (20.2%) received chemotherapy. Among high-grade gliomas, the median OS of glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglial tumors were 17.7 months (15.7–19.7 months), 33.7 months (24.0–43.4 months) and 110.6 months (43.5–177.7 months), respectively, whereas the median OS of low-grade gliomas was not reach. The 5-year survival rate of grade I, II, III and IV gliomas was 94.7%, 73.7%, 45.1% and 18.6%, respectively. Multivariate analysis identified that onset age, Karnofsky performance status, tumor location, preoperative seizure, pathological subtype, resection extent and post-surgical treatment were independent predictors of OS for patients with high-grade gliomas. Patients received post-surgical radiotherapy and (or) chemotherapy had better survival than those without adjuvant treatment (grade III: 53.3 vs. 20.6 months, p =0.012; grade IV: 22.9 vs. 12.3 months, p < 0.001). For low-grade gliomas, patients’ age, Ki-67 index, tumor subtype and resection extent were associated with clinical outcomes. Conclusions: Glioma patients received treatments do not always following guidelines in clinical practice. Although standard care for patients may beneficial for prognosis, personalized treatment may more acceptable for patients and even resulting better outcome which should keep in mind in routine clinical practice.

Metabolomic profiling of blood plasma in patients with primary brain tumours: Basal plasma metabolites correlated with tumour grade and plasma biomarker analysis predicts feasibility of the successful statistical discrimination from healthy subjects - a preliminary study.

The brain tumours represent a complex tissue that has its own characteristic metabolic features and is interfaced with the whole organism. We investigated changes in basal blood plasma metabolites in the presence of primary brain tumour, their correlation with tumour grade, as well as the feasibility of statistical discrimination based on plasma metabolites. Together 60 plasma samples from patients with clinically defined glioblastoma, meningioma, oligodendrioglioma, astrocytoma, and non-specific glial tumour and plasma samples from 28 healthy volunteers without any cancer history were measured by NMR spectroscopy. In blood plasma of primary brain tumour patients, we found significantly increased levels of glycolytic metabolites glucose and pyruvate, and significantly decreased level of glutamine and also metabolites participating in tricarboxylic acid (TCA) cycle, citrate and succinate, when compared with controls. Further, plasma metabolites levels: tyrosine, phenylalanine, glucose, creatine and creatinine correlated significantly with tumour grade. In general, observed changes are parallel to the biochemistry expected for tumourous tissue and metabolic changes in plasma seem to follow the similar rules in all primary brain tumours, with very subtle variations among tumour types. Only two plasma metabolites tyrosine and phenylalanine were increased exclusively in blood plasma of patients with glioblastoma. Based on metabolite levels, an excellent discrimination between plasma from patient's tumours and controls was attainable. The metabolites creatine, pyruvate, glucose, formate, creatinine and citrate were of the highest discriminatory power.

Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor

BackgroundThere are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells.MethodsThe expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models.Results: The IC50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 μM, respectively. A low dose of PB221 (1 μM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 μM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model.ConclusionsThis study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.

Correlations between the expression of hTERT and α and β splice variants in human brain tumors.

Astrocytomas are diffusible infiltrative and aggressive brain tumors that are extensive and heterogeneous clusters of neoplastic growths in the central nervous system (CNS). Meningioma tumors are commonly benign but may demonstrate an invasive pattern with frequent recurrences. Human telomerase reverse transcriptase (hTERT) is an unfavorable prognostic factor for several types of cancers, and there are controversies about its role. In the present study, we investigated the relative expression of hTERT splice variants in 2 groups of brain tumors compared to non-tumor samples. The mRNA of 40 brain tumor samples and 4 control samples was extracted; mRNA expression of hTERT α-deletion and β-deletion variants, as well as the wild type isoform, was quantified using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The α-deletion variant was significantly expressed in primary benign meningeal tumors (p = 0.01). The results indicate a positive correlation between the relative expression of hTERT mRNA transcript and α-deletion and β-deletion variants in both groups of tumors (meningiomas and astrocytomas). A strong association between the expression of the full-length splice variant and the β-deletion variant was observed in astrocytoma tumors (p = 0.045). The most significant correlations were found between the hTERT full-length and β-deletion variants in high-grade meningiomas (p = 0.018, correlation coefficient (CC) = 0.964) and grade II astrocytomas (p = 0.015; CC = 0.580). In addition, in low grades of both types of tumors, the hTERT full-length variant and especially the α-deletion variant were the predominant isoforms. The overexpression of hTERT and β-deletion variants in high grades of these tumors was statistically significant. Our findings indicate that α-deletion and β-deletion isoforms are associated with high levels of full-length hTERT mRNA in both groups of brain tumor patients. Changes in the splicing pattern of hTERT splice variants in brain tumors and their correlation with pathological alterations in cells could be applied as diagnostic or prognostic biomarkers, or possibly as targets for cancer therapy. However, the function and biological role of hTERT splice variants remain to be clarified.

SUN-411 Isolated Central Diabetes Insipidus Due to Astrocytoma: A Case Report

Central diabetes insipidus (CDI) is characterized by a decreased release of antidiuretic hormone (ADH) resulting in a variable degree of polyuria. Patients with central nervous system lesions an impaired thirst mechanism can lead to moderate to severe hypernatremia can develop. Here we report a case of CDI cause by an astrocytoma tumor. This is a 64 year-old female who was found to have multiple cerebellar lesions in MRI as part of dizziness work up. She was admitted to undergo brain biopsy. She became polyuric during the procedure and the immediate post-operative time. Her thirst mechanism was impaired by the anesthesia. Serum sodium increased from 142 to 166 mmol/L (135-146) with a serum osmolality 326 mOsm/kg (275-295), urine specific gravity 1.002 and urine osmolality 131mOsm/kg consistent with diabetes insipidus (DI). The patient received 1mcg of demopressin with resolution of polyuria, polydipsia as well as hypernatremia confirming CDI. Further assessment of the anterior pituitary axis was within normal limits. In the light of the clinical findings, a second review of the imaging confirmed the presence of a pituitary stalk with mild diffuse thickening without nodularity. She eventually recovered her thirst mechanism and her urine output was adequate despite not receiving desmopressin for more than 48 hours. Final pathology revealed Brain astrocytoma, for which she was started on temozolamide. Patient was readmitted a month later with altered mental status, she was found to have an urinary track infection and hypernatremia due to worsening CDI requiring demopressin on the clock. Repeating imaging revealed significant parenchymal disease and leptomenigeal disease affecting the sella, stalk and hypothalamic regions. A wide range of lesions can present as isolated thickening of the pituitary stalk. We could only find 5 other cases of patients with astrocytoma who debuted with isolated CDI. Interestingly we found that Temozolamide has been reported as a rare cause of CDI with only 3 cases reported in the literature, but in our patient CDI was confirmed prior to initiation of chemotherapy.

The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma.

Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of pilocytic astrocytomas. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in pilocytic astrocytoma remains unknown.Experimental Design: The patient-derived pilocytic astrocytoma cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in pilocytic astrocytoma. The model allows for doxycycline-inducible switching between proliferation and OIS. Both states were studied using gene expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary pilocytic astrocytoma tumors were analyzed by GEP and multiplex assay. SASP factors were upregulated in primary human and murine pilocytic astrocytoma and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating pilocytic astrocytoma cells. The SASP factors IL1B and IL6 were upregulated in primary pilocytic astrocytoma, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic BCL2 inhibitors. High IL1B and SASP expression in pilocytic astrocytoma tumors was associated with favorable progression-free survival. We provide evidence for the SASP regulating OIS in pediatric pilocytic astrocytoma, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in patients with pilocytic astrocytoma. Further investigation of the SASP driving the unpredictable growth of pilocytic astrocytomas, and its possible therapeutic application, is warranted.

Epstein-Barr Virus and Astrocytoma.

Epstein-Barr virus (EBV) is an established pathogen linked to a wide range of lymphoproliferative disorders and solid tumors. Astrocytoma is one of the most frequent brain tumors in children, adolescents, and young adults. Astrocyte proliferation usually occurs after brain tissue aggression, which may be of different types, including viral infection. In particular, it has been suggested that EBV may play a role in astrocytoma pathogenesis. This article presents the summarized results of a systematic review of the literature on the relationship between EBV infection and astrocytoma pathophysiology. Although most studies detect the presence of EBV DNA in subsets of astrocytoma tumors, our conclusion is that currently, except for rare cases, there is no clear evidence that EBV plays a role in the development of astrocytoma.

Mathematical skills in children with pilocytic astrocytoma.

Pediatric patients with circumscribed cerebellar pilocytic astrocytoma (PA) tumors generally perform within the normal range on neuropsychological tests after a complete tumor resection. The outcome in academically relevant abilities such as mathematics, which in adults involve some cerebellar functions, is however much less understood. The aim of this study is to retrospectively investigate the neuroplasticity of mathematical skills and associated cognitive functions following cerebellar resection of PA in pediatric patients. Twenty-two children (mean age = 11.2+1.8), including 11 PA patients (females = 6) and 11 healthy controls (females = 6), were administered a battery of mathematical (MaT) and neuropsychological tests. Single-case statistical analyses were carried out (Crawford's t) as well as between-group comparisons (Wilcoxon test). Spearman correlations between MaT and neuropsychological tests were calculated. Thirty-six percent of the patients showed difficulties in some mathematical tasks, 50% of them within a broader cognitive deficit. Verbal working memory was associated with MaT performance both in patients and controls while, crucially, visuospatial memory, and visual-motor integration were associated with MaT in patients only. Among patients, MaT correlated negatively with tumor size and positively with the interval surgery test. The results evince an overall recovery of mathematical abilities despite PA in the majority of patients. This functional reestablishment is supported by visuospatial and visuomotor integration functions that contribute to set up emerging mathematical skills in these patients. Higher levels of compensation are found in more developed tumors as compared to smaller ones.

377PD - Multiplex digital PCR for the diagnostic of pilocytic astrocytoma and glioneuronal tumors

377PD - Multiplex digital PCR for the diagnostic of pilocytic astrocytoma and glioneuronal tumors

Role of MRI in Diagnosis of Medulloblastoma

Background: Brain tumors represent the most common solid neoplasm in children and second most common pediatric malignancy overall. The majority of primary childhood brain tumors occurs in the infratentorial compartment and includes: medulloblastoma, juvenile pilocytic astrocytoma (JPA), ependymoma, brainstem/pontine glioma, and atypical teratoid rhabdoid tumor (ATRT) which is an additional rare but important primary brain tumor of early childhood. Objective: This study aims to provide an overview of the imaging features and appearances of the most common primary posterior fossa brain tumors in children and the diagnosis of medulloblastoma. Patients and Methods: The pool of our study was 25 patients (12 males and 13 females) who presented to diagnostic radiology departments at EL Demerdash Teaching Hospital and National Cancer Institute. They had been diagnosed to have posterior fossa lesions. Patients’ age ranged from 1 to 17 year with mean age of 4.73 years.Results: statistically significant difference between medulloblastoma and other posterior fossa tumors according to location and diffusion. Medulloblastoma is 4th ventricular in location and shows restriction in diffusion weighted images. Conclusion: Medulloblastoma is predominately 4th ventricular in location, Medulloblastoma is restricted in diffusion weighted images.

Role of MRI in Diagnosis of Medulloblastoma

Background: Brain tumors represent the most common solid neoplasm in children and second most common pediatric malignancy overall. The majority of primary childhood brain tumors occurs in the infratentorial compartment and includes: medulloblastoma, juvenile pilocytic astrocytoma (JPA), ependymoma, brainstem/pontine glioma, and atypical teratoid rhabdoid tumor (ATRT) which is an additional rare but important primary brain tumor of early childhood. Objective: This study aims to provide an overview of the imaging features and appearances of the most common primary posterior fossa brain tumors in children and the diagnosis of medulloblastoma. Patients and Methods: The pool of our study was 25 patients (12 males and 13 females) who presented to diagnostic radiology departments at EL Demerdash Teaching Hospital and National Cancer Institute. They had been diagnosed to have posterior fossa lesions. Patients’ age ranged from 1 to 17 year with mean age of 4.73 years.Results: statistically significant difference between medulloblastoma and other posterior fossa tumors according to location and diffusion. Medulloblastoma is 4th ventricular in location and shows restriction in diffusion weighted images. Conclusion: Medulloblastoma is predominately 4th ventricular in location, Medulloblastoma is restricted in diffusion weighted images.

P01.022 Non-measurable speckled contrast-enhancing lesions appearing during course of disease are associated with IDH mutation in high-grade astrocytoma patients

As treatment options at progression are limited for glioma patients, the accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, non-measurable, speckled contrast-enhancing lesions (SCE) without immediate relation to prior immune- or radiotherapy appear relatively frequently during course of disease in glioma patients and challenge the definition of progression based on Response Assessment in Neurooncology (RANO) criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. MRIs of seven hundred forty-six glioma patients included in this study were retrospectively revised for appearance of newly detected SCEs during course of disease. Associations with molecular and clinical baseline parameters as well as their prognostic impact were statistically analyzed and frequency, natural course and location of SCEs described. SCEs occurred more frequently in World Health Organization (WHO) grade II and III astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase (IDH) mutation in WHO grade III astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up MRIs, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated FLAIR abnormalities, but distant appearance also occurred. In glioblastoma patients, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of glioblastoma patients with IDH wildtype status. The data demonstrate a predominantly benign course of SCEs after its appearance and emphasize for cautious definitions of progression as well as for regular clinical and radiographic follow-ups rather than premature initiation of new anti-tumor therapies until progression is confirmed.

Population-based Study Determining Predictors of Cancer-Specific Mortality and Survival in Pediatric High-grade Brainstem Glioma

Pediatric high-grade brainstem gliomas are aggressive tumors with dismal prognoses. Large-scale studies are needed to further characterize these tumors and determine factors influencing cancer-specific mortality and survival at varying time points. We used the SEER (Surveillance Epidemiology and End Results) database to conduct a population-based study of pediatric patients with histologically confirmed anaplastic astrocytoma or glioblastoma tumors located within the brainstem. Multivariate analyses incorporating patient demographics, tumor characteristics, and treatments were used to determine predictors of cancer-specific mortality and survival at 6 months, 9 months, 1 year, and 2 years. We included 154 patients from the SEER database: 72 patients with anaplastic astrocytoma (47%) and 82 (53%) with glioblastoma. Median survival for the entire cohort was 10.0 months. Glioblastoma histology, developmental stage, and large tumor size were significantly associated with cancer-specific mortality. Six-month, 9-month, 1-year, and 2-year survival was 75%, 57%, 42%, and 20%, respectively. Glioblastoma histology was associated with worsened survival at 6 months (odds ratio [OR], 0.19; P= 0.0081), 9 months (OR, 0.18; P < 0.001), 1 year (OR, 0.19; P < 0.001), and 2 years (OR, 0.14; P= 0.0055). Radiation therapy was associated with improved survival at 6 (OR, 8.53; P= 0.0012) and 9 months (OR, 3.58; P=0.035) but not at 1 or 2 years. Radiation therapy was associated with improved survival in glioblastoma (9.0 vs. 3.0 months; P < 0.001). This population-based study showed that glioblastoma histology is associated with a poor prognosis in pediatric patients with high-grade brainstem gliomas. Regardless of histology, radiation therapy improved survival at 6 and 9 months but not long-term.

Nonmeasurable Speckled Contrast-Enhancing Lesions Appearing During Course of Disease Are Associated With IDH Mutation in High-Grade Astrocytoma Patients

Because treatment options at progression are limited for patients with glioma, accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, nonmeasurable, speckled contrast-enhancing lesions (SCEs) without immediate relation to prior immune therapy or radiation therapy appear relatively frequently during the course of disease in patients with glioma and challenge the definition of progression based on Response Assessment in Neuro-oncology criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. Magnetic resonance imaging of 746 patients with glioma included in this study were retrospectively revised for appearance of newly detected SCEs during the course of disease. Associations with molecular and clinical baseline parameters and their prognostic impact were statistically analyzed, and frequency, natural course, and location of SCEs were described. SCEs occurred more frequently in World Health Organization grade 2 and 3 astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase mutation in World Health Organization grade 3 astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up magnetic resonance imaging, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated fluid-attenuated inversion recovery abnormalities, but distant appearance also occurred. In patients with glioblastoma, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of patients with glioblastoma with isocitrate dehydrogenase wildtype status. The data demonstrate a predominantly benign course of SCEs after their appearance and emphasize cautious definitions of progression and regular clinical and radiographic follow-up rather than premature initiation of new antitumor therapies until progression is confirmed.

Abstract 4262: Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype

Abstract Recurring DNA alterations have been recognized as a hallmark of cancer for over a century, and observed in astrocytoma genomes for decades. Only recently, however, a copy-number genotype predictive of an astrocytoma survival phenotype was discovered, and only by using the generalized singular value decomposition (GSVD). We formulated the GSVD as a comparative spectral decomposition that can simultaneously identify the similar and dissimilar between two column-matched matrices, and, therefore, create a single coherent model from two datasets recording different aspects of a single phenomenon (1, 2). In recent comparisons of microarray-profiled patient-matched glioblastoma (GBM) and, separately, lower-grade astrocytoma tumor and normal genomes, the GSVD invariably separated the tumor-exclusive genotype and phenotype from those that occur in the normal genomes and from experimental batch effects. The tumor-exclusive genotype invariably predicted the survival phenotype statistically better than any other indicator of astrocytoma (3). Here we use the GSVD to compare whole-genome sequencing (WGS) read-count profiles of patient-matched astrocytoma tumor and normal DNA. The GSVD uncovers a tumor-exclusive genome-wide pattern of copy-number alterations (CNAs). We find that, first, this WGS astrocytoma pattern is bounded by the microarray GBM and lower-grade astrocytoma patterns. Like the microarray patterns, the WGS pattern is correlated with an approximately one-year median survival time. By filling in gaps in the genome, the WGS pattern reveals that this biologically consistent genotype encodes for transformation via the Notch together with the Ras and Shh signaling pathways. Second, like the GSVDs of the microarray profiles, the GSVD of the WGS profiles separates the tumor-exclusive pattern from normal copy-number variations (CNVs) and from experimental sources of variation. These include the WGS technology-specific effects of guanine-cytosine (GC) content variations across the tumor and normal genomes, which are correlated with experimental batches. Third, by identifying the biologically consistent phenotype among the WGS-profiled tumors, the GBM pattern proves to be a technology-independent predictor of astrocytoma survival and responses to chemotherapy and radiation, statistically better than the patient's age and tumor's grade, the best other indicators of astrocytoma, and existing tests for MGMT promoter methylation and IDH1 mutation. We conclude that by using the complex structure of the data, rather than simplifying them as is commonly done, comparative spectral decompositions, such as the GSVD, underlie a mathematically universal description of the genotype-phenotype relations in cancer that other methods miss.

Abstract LB-376: Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma

Abstract Hypermutated gliomas arising from treatment with alkylating agents, such as temozolomide (TMZ), are genetically distinct, recurrent tumors about which very little is known. Here, we have identified common and subtype-specific patterns in the tumor evolution of IDH-mutant, low-grade astrocytoma (1p/19q-intact) and oligodendroglioma (1p/19q-codeleted) from 57 glioma patients. Hypermutation involved unanimous defects in mismatch repair in both subtypes, with unique mismatch repair alterations differentiating hypermutation events in serial recurrences. Hypermutation was associated with malignant progression in astrocytoma, and can differentiate high-grade regions from low-grade regions within the same tumor. Hypermutated oligodendroglioma tumors associated with newly-arising p53 mutations and mirrored the early branching evolution of astrocytoma tumors. Results from this longitudinal clinical-genomic study suggest prominent roles for MMR and p53 in the establishment and maintenance of hypermutation. The evolution of TMZ-related tumor antigens across serial tumor recurrences will be presented. Citation Format: Matthew R. Grimmer. Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-376.