Low-grade Astrocytomas Research Articles

Radiological Prediction of Isocitrate Dehydrogenase (IDH) Mutational Status and Pathological Verification for Lower-Grade Astrocytomas

Background and objectiveThe isocitrate dehydrogenase (IDH) status of patients with World Health Organization (WHO) grade II or III astrocytoma is essential for understanding its biological features and determining therapeutic strategies. This study aimed to use radiological analysis to predict the IDH status of patients with lower-grade astrocytomas and to verify the pathological implications.MethodsIn this study, 47 patients with grade II (17 cases) or III astrocytomas (30 cases), based on 2016 WHO Classification, underwent methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) on the same day between January 2013 and June 2020. The patients were retrospectively assessed. Immunohistochemistry showed 23 cases of IDH-mutant and 24 of IDH-wildtype. Based on fluid-attenuated recovery inversion (FLAIR)/T2 imaging, three doctors blinded to clinical data independently allocated 18 patients to the clear boundary group between the tumor and the normal brain and 29 to the unclear boundary group. The peak ratios of N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and Cho/NAA and the tumor-to-normal region (T/N) ratio for maximum accumulation in MET-PET were calculated. For statistical analysis, Fisher’s exact test was used to assess associations between two variables, and the Mann-Whitney U test to compare the values between the IDH-wildtype and IDH-mutant groups. The optimal cut-off values of MET T/N ratio and MRS parameters for discriminating IDH-wildtype from IDH-mutant were obtained using receiver operating characteristics curves.ResultsThe unclear boundary group had significantly more IDH-wildtype cases than the clear boundary group (P<0.001). The IDH-wildtype group had significantly lower Cho/Cr (<1.84) and Cho/NAA (<1.62) ratios (P=0.02 and P=0.047, respectively) and a higher MET T/N ratio (>1.44, P=0.02) than the IDH-mutant group. The odds for the IDH-wildtype were 0.22 for patients who fulfilled none of the four criteria, including boundary status and three ratios, and 0.9 for all four criteria.ConclusionsThese results suggest that the combination of MRI, MRS, and MET-PET examination could be helpful for the prediction of IDH status in WHO grade II/III gliomas.

Pituitary adenoma-Gonadotroph type in a 47 years old female patient: A case report

Pituitary adenomas are tumors of the anterior pituitary. Most pituitary tumors are slow-growing and benign. They are classified based on size or cell of origin. Pituitary adenoma can be classified as microadenoma, macroadenoma, and giant tumors based on size.Pituitary adenomas are mostly found incidentally on imaging modalities obtained for other reasons. Mutations in known Oncogenes have little role in the pathogenesis of most sporadic pituitary adenomas. Case presentation : A 47 years old female patient presented with complain of diminished vision , severe headache and dizziness since 1 months.MRI was advised which showed an ill-defined low signal intensity lesion of approximate 3.4x3.2x3 cm noted in clivus, bilateral spenoid sinus and sella region. Histologically, near-signature appearance is that of elongated cells surrounding blood vessels in a pseudorosette-like ependymoma-mimicking pattern. cells with small round nuclei and there is no significant mitotic activity. Conclusion : Pitutary adenoma-gonadotroph type is benign and can cause symptoms from mass effect or by effecting the level of the hormones. Differetial diagnosis includes ependymoma, Pitutary blastoma, Pitutary nodular hyperplasia, dermoid cyst, low grade astrocytoma, meningioma, rathke cleft cyst.

Abstract 5264: Glioblastoma degraded to low-grade astrocytoma two-years after surgical resection: A rare case report

Abstract Background: Glioblastoma (GBM) is the most common and malignant brain tumor. The prognosis of patients with GBM is poor, with a five-year survival rate of 5% and a median overall survival of 12-16 months. In addition, there is a high risk for the recurrence of GBM patient, with the median time of 9.5 months. However, little was reported about the degradation of GBM recurrence. Methods: Immunohistochemistry (IHC) staining and next-generation sequencing (NGS) were conducted to address the histopathological and molecular features of the patient. Results: This patient was firstly diagnosed with GBM in April 2019, followed by surgical resection to completely remove tumor occupancy. IHC staining of the tumor sample showed positive expression of P53, S-100, GFAP, EGFR, MGMT, and a 60% expression of Ki67. Thus, this tumor was clinically classified as WHO grade 4 according to its histopathological features. Then we performed NGS and found that the tumor contained four SNVs (EGFR c.865G&amp;gt;A, EPHA5 c.2152C&amp;gt;T, RB1 c.1615G&amp;gt;T, TP53 c.742C&amp;gt;T), EGFR gene amplification, and without IDH1 or IDH2 mutation. These molecular features of the tumor were classified as WHO grade 4 and were consistent with the histopathological grading. In May 2021, two recurrent tumors were found in this patient and were surgical resected again. However, IHC staining of the tumor sample showed positive expression of P53, S-100, and GFAP, while EGFR and MGMT were undetectable, and expression of Ki67 was only 5%. Thus, these recurrent tumors were diagnosed as low-grade astrocytoma (WHO grade 2) according to their histopathological features. Furthermore, NGS was performed with one of those recurrent tumors and showed that it contained 38 SNVs including those four variants in the primary tumor, EGFR gene amplification, and without IDH1 or IDH2 mutation. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), IDH-wildtype astrocytoma combined with EGFR gene amplification should be classified as IDH-wildtype GBM (WHO grade 4), which was different from the histopathological grading. From our points of view, though these recurrent tumors are actually high-grade glioma from their ‘molecular identity’, maybe they have not developed to high-grade tumors at the time of diagnosis because of our timely follow-up examination. Conclusion: In summary, we reported a rare GBM patient survived for two-years post surgical resection and recurred with a low-grade astrocytoma in histopathological diagnosis. However, the molecular features revealed that the recurrent tumor should be diagnosed as a high-grade glioma, suggesting the clinical importance of combining the molecular and conventional histopathological diagnosis. Moreover, we provided a clinical evidence of histological degradation of GBM, and showed a rare clinical case of inconsistence of histopathological and molecular diagnosis in recurrent GBM. Citation Format: Zhipeng Su, Xiang Zhang, Bella Guo, Ximeng Zhao, Qun Li, Tonghui Ma. Glioblastoma degraded to low-grade astrocytoma two-years after surgical resection: A rare case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5264.

Abstract 1228: Spatial transcriptomics: Data processing revisited to address noise interference

Abstract Background: Spatially resolved transcriptomics is a novel and already highly recognized method that allows RNA sequencing results to be annotated with local tissue phenotypes. The NanoString GeoMx Digital Spatial Profiling (DSP) Platform allows users to collect RNA expression data from manually selected Regions of Interest (ROIs) on FFPE tissue sections. Here, we extensively evaluated data from the DSP platform with its associated pipeline and identify significant background noise interference issues which compromise data interpretation. Alternative and more suitable workflows are presented for correct data analysis. Methods: In this study, 12 paired tumor samples were collected from six glioma patients who underwent two separate resections. For all patients, the first resection was a low grade astrocytoma (WHO grade II or III) and the second resection was a high grade astrocytoma (WHO grade IV). The DSP platform was used to collect expression data of 1,800 genes from 72 ROIs (i.e. 6 per sample). Biological replicates were made of eight tumors from four patients. Gene expression data was normalized with both standard NanoString methods and several alternative methods (e.g. DeSeq2, gamma fit correction and quantile normalization). Weighted Gene Co-expression Network analysis (WGCNA) was used for biological validation. In addition to our own study, six publicly available NanoString DSP datasets were evaluated. Results: Data distributions of all glioma samples, when exposed to standard data processing, were burdened with significant background noise interference. Notably, differences in noise interference were largest between biologically distinct tumor subgroups (i.e. between first and second glioma resections), which was confirmed in replicate experiments. The noise interference patterns were also present in all six publicly available NanoString DSP datasets which will invariably lead to incorrect interpretation of the underlying biology. To correct for noise interference, we tested several normalization methods. The relatively crude quantile normalization method provided the least biased result and showed the highest concordance with bulk RNA sequencing data. To evaluate the biological validity of our alternative approach, we used T cell counts from our tissue regions as an independent parameter, that were quantified using immune fluorescence. Unsupervised WGCNA identified gene clusters enriched for lymphocyte genes that highly correlated with T cell quantities in ROIs, confirming that alternative normalization can extract a biological signal from the DSP platform. Conclusion: The DSP Platform platform suffers from significant noise interference when using standard analysis tools that obscure its results. Here, we revised the workflow and provide an alternative normalization that adequately addresses noise interference and enables correct interpretation of gene expression data. Citation Format: Levi van Hijfte, Marjolein Geurts, Wies R. Vallentgoed, Paul H. Eilers, Peter A. Sillevis Smitt, Reno Debets, Pim J. French. Spatial transcriptomics: Data processing revisited to address noise interference [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1228.

QOL-11. Comparison of Neuropsychological Functioning in Pediatric Posterior Fossa Tumor Survivors: Medulloblastoma, Low-Grade Astrocytoma, and Healthy Controls

BACKGROUND: Neuropsychological comparison of medulloblastoma (MB) and cerebellar low-grade astrocytoma (LGA) survivors to controls can clarify treatment-related neurocognitive late effects. While both brain tumor groups undergo surgery to the posterior fossa, children with MB additionally receive craniospinal irradiation with boost and chemotherapy. This study provides an updated comparison of neuropsychological functioning in these two groups and examines effects of demographic risk factors upon outcomes. PROCEDURE: Forty-two children (16 MB, 9 LGA, 17 controls) completed measures of intellectual functioning, verbal learning/memory, visual-motor integration, and fine motor functioning. The effects of age at diagnosis, time since diagnosis, gender, fatigue, and social status on neuropsychological functioning were examined. RESULTS: MB survivors demonstrated the worst neurocognitive late effects, but they were less severe and extensive than in prior studies. LGA survivors’ mean scores were below normative expectations in working memory, processing speed, and fine motor functioning. Additionally, parents of LGA survivors reported the most difficulty with behavior and cognitive regulation compared to healthy controls and medulloblastoma survivors. In this overall sample, processing speed difficulties were independent of fine motor functioning and fatigue. Higher parental education was associated with better intellectual functioning, working memory, delayed recall, and visual-motor integration. Neuropsychological function was not associated with gender, age at diagnosis, or time since diagnosis. CONCLUSION: The results support that contemporary treatment approaches with craniospinal irradiation plus boost and chemotherapy confer the greatest risk for late effects, while surgical resection is associated with subtle but important neurocognitive difficulties. Ultimately, this study furthers our understanding of factors impacting neuropsychological function in pediatric MB and LGA survivors and contributes to empirical support for close monitoring and targeted interventions into survivorship.

HGG-38. Gliomatosis cerebri/Glioblastoma with discordant histological and molecular profiles - treatment and outcome of a pediatric patient

Gliomatosis cerebri is no longer recognized as a distinctive pathological diagnosis, but a manifestation of diffuse glioma involving at least three cerebral lobes. Lack of understanding in this manifestation of CNS neoplasms limits treatment for this aggressive disease. Here we present a case of stabilization of disease in a pediatric patient with unusual molecular profiles normally associated with aggressive tumor behavior. A nine-year-old male presented with acute onset of right-sided vision changes, headache and numbness of the left arm and leg for one day. He also had a three-month history of an asymptomatic bump on the right temporal skull bone. MRI of the brain was significant for diffuse thickening of the cortex of the entire right hemisphere (temporal>frontal>parietal lobes). No specific enhancing lesion or restricted diffusion was noted. Histologically, the tissue had findings of diffuse low-grade astrocytoma. Molecular genetic testing was notable for TERT and EGFR mutations which are more consistent with adult type high-grade astrocytic tumors. MGMT promoter methylation array was negative. Final diagnosis was glioblastoma, IDH and H3 wildtype. All the molecular features of this tumor were high-grade with an average progression free survival of less than 12 months. Despite the lack of methylation, we opted to include alkylating agents in a maintenance chemotherapy treatment plan following radiation therapy with concurrent temozolomide. Despite poor prognostic factors, the patient is alive without signs of progression 2.5 years post-diagnosis. Targeted agents were not used in upfront treatment for this patient. This is a rare case of stabilization of disease with conventional treatment in a very aggressive tumor. This case is a rare constellation of an ‘adult-type’ molecular profile in a pediatric patient with a low grade, less aggressive behavior profile, and highlights the need to better understand this rare subtype of tumors in children.

LGG-21. Durability of response to targeted therapies in pediatric low-grade gliomas: A multi-institution retrospective review

Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.

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 &lt; 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, &lt; 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

A Cross Sectional Study of Clinical and Histopathological Spectrum of Pediatric Brain Tumours

Introduction: Brain tumors are the most common tumor of the childhood and the second most common malignancies after haematological malignancies. Childhood central nervous system (CNS) tumors differ significantly from adult brain tumors in reference to their sites of origin, clinical presentation, tendency to disseminate early, histological features and their biological behaviour. Aims and Objective: Analyse the Clinical and histopathological spectrum of brain tumors, in pediatric patients ≤18 year of age. Materials and Method: This was a cross sectional study conducted at the department of pathology, SMS medical college, Jaipur from January 2020 to October 2021. This is a laboratory based descriptive type of observational study and data of brain tumors in children equal or less than 18 year of age procured and their clinico-histopathological spectrum were analyszed. Result: In our study, Out of 116 patients 51.8 % were male and 48.2 % were female. Mean age for the male cases were 10.11 and for female cases were 9.78. we observed intracranial pediatric tumors 67 cases (57.7%) were located in infratentorial region and 49 cases (43.3%) were located in supratentorial region and incidence for intracranial tumor was 39(33.62%) cases of astrocytomas followed by 25 (21.55%)cases of medulloblastoma, 20 (17.24%)cases of ependymoma, 13 (11.20%) cases of craniopharyngioma, 5 (4.31%) cases of pituitary adenoma, 4 (3.44%) cases of meningioma, 3 (2.58%) cases of embryonal and choroid plexus tumor, 2 (1.72%) cases of ganglioglioma and 1 (0.86%) case of Schwannoma and PNET. In this article, Based on tumor location, the symptoms of CNS tumors on the supratentorial region were headache (22 cases, 44.8%), impaired vision (10 cases, 20.4%), seizures (6 cases, 12.2%), vomiting (4 cases, 8.1%). Symptoms of CNS tumors on the infratentorial region were headache (48 cases, 71.6%), vomiting (5 cases, 7.4%), impaired vision (4 cases, 5.9%), seizures (3 cases, 4.4%). Conclusion: Infratentorial cases, maximum number of cases were medulloblastomas and supratentorial cases, maximum number of cases were astrocytic tumours. Overall astrocytic tumours in all senses constituted the most common group of CNS tumours. Within astrocytoma, low grade astrocytoma (grade I &amp; II) was most common CNS paediatric tumour.

Patients' Survival with Astrocytoma After Treatment: a Systematic Review and Meta-analysis of Clinical Trial Studies.

About half of the brain tumours are primary and the rest are metastatic. The impact of each of these treatments alone or together on the prognosis of patients with astrocytoma tumours, especially low-grade astrocytoma, is unclear which may pose many challenges in the decision-making of surgeons and patients. Considering the importance of patient's outcomes with astrocytoma and lack of general statistics, this study aimed to determine the survival of patients with high-grade astrocytoma and low-grade astrocytoma after treatments. This study follows a systematic review and a meta-analysis approach. Following a systematic review and meta-analysis method, articles dated from 1982 to March 2020 were extracted from Embase, ScienceDirect, Scopus, PubMed and Web of Science (WoS) international databases. Random effects model was used for analysis, and heterogeneity of studies was investigated considering the I 2 index. Data were analysed using the Comprehensive Meta-Analysis software (version 2). According to a meta-analysis of studies, the mean overall survival in patients with high-grade astrocytoma was 31.9 ± 2.7months, for 2-year survival, 38.1% (95% CI: 27.5-50.1%) and for 5-year survival was 28.6% (95% CI: 24.1-33.4%). Mean overall survival in patients with low-grade astrocytoma was 64.8 ± 7.4months, for 2-year survival was 74.3% (95% CI: 32.6-94.5%) and for 5-year survival was 74.4% (95% CI: 57.9-86%). The highest mean for survival in patients with high-grade astrocytoma and in chemotherapy and radiation therapy treatments was 45.2 ± 5.2months, and also the highest mean for survival in patients with low-grade astrocytoma in surgical treatment was 71.4 ± 8.8months. The results of this study show that the average survival in patients with low-grade astrocytoma is high following the treatment, and in high-grade astrocytoma, there will be the highest survival rate, if the surgical treatment is combined with chemotherapy and radiation therapy. This study summarizes retrospective studies up to 2020 to evaluate the prognosis and survival of patients with brain astrocytoma tumours, and the results of this meta-analysis can be of interest to surgeons and specialists in this field.

Pediatric Astrocytomas and Their Association With Polymorphisms in Embryonic Stem Cell Marker Genes.

Embryonic stem cell markers, such as SOX2, NANOG, and OCT4, are transcription factors expressed in pluripotent stem cells, involved in the mediation of pluripotency and self-renewal. Especially after the discovery of cancer stem cells, these proteins have been associated with several types of neoplasia, including astrocytomas. In the pediatric population, astrocytomas are the most common solid neoplasia and present the highest mortality rates. Our study evaluated 5 polymorphisms in SOX2, NANOG, and POU5F1 genes in 101 pediatric astrocytoma samples. We describe the associations between wild and polymorphic alleles in astrocytomas. In our results, the intronic polymorphic G allele in SOX2 rs77677339 [G/A] had a borderline association with low-grade astrocytomas, and the intronic polymorphic T allele in NANOG rs10845877 [C/T] showed a higher frequency in grade 2, compared to grade 1 astrocytomas, thus showing promising results. Our study is relevant because it shows a potential correlation between polymorphic embryonic stem cell marker genes and pediatric astrocytomas.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3–26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14–26) versus 10 (3–17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify “high-risk” patients and to better individualize treatment.

Risk Factors Associated with Malignant Transformation of Astrocytoma: Competing Risk Regression Analysis.

Background Malignant transformation (MT) of low-grade astrocytoma (LGA) triggers a poor prognosis in benign tumors. Currently, factors associated with MT of LGA have been inconclusive. The present study aims to explore the risk factors predicting LGA progressively differentiated to malignant astrocytoma. Methods The study design was a retrospective cohort study of medical record reviews of patients with LGA. Using the Fire and Gray method, the competing risk regression analysis was performed to identify factors associated with MT, using both univariate and multivariable analyses. Hence, the survival curves of the cumulative incidence of MT of each covariate were constructed following the final model. Results Ninety patients with LGA were included in the analysis, and MT was observed in 14.4% of cases in the present study. For MT, 53.8% of patients with MT transformed to glioblastoma, while 46.2% differentiated to anaplastic astrocytoma. Factors associated with MT included supratentorial tumor (subdistribution hazard ratio [SHR] 4.54, 95% confidence interval [CI] 1.08–19.10), midline shift > 1 cm (SHR 8.25, 95% CI 2.18–31.21), and nontotal resection as follows: subtotal resection (SHR 5.35, 95% CI 1.07–26.82), partial resection (SHR 10.90, 95% CI 3.13–37.90), and biopsy (SHR 11.10, 95% CI 2.88–42.52). Conclusion MT in patients with LGA significantly changed the natural history of the disease to an unfavorable prognosis. Analysis of patients' clinical characteristics from the present study identified supratentorial LGA, a midline shift more than 1 cm, and extent of resection as risk factors associated with MT. The more extent of resection would significantly help to decrease tumor burden and MT. In addition, future molecular research efforts are warranted to explain the pathogenesis of MT.

Clinical and radiographic characteristics of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma: a single institution review.

Genetic analyses of gliomas have identified key molecular features that impact treatment paradigms beyond conventional histomorphology. Despite at-times lower grade histopathologic appearances, IDH-wildtype infiltrating gliomas expressing certain molecular markers behave like higher-grade tumors. For IDH-wildtype infiltrating gliomas lacking traditional features of glioblastoma, these markers form the basis for the novel diagnosis of diffuse astrocytic glioma, IDH-wildtype (wt), with molecular features of glioblastoma (GBM), WHO grade-IV (DAG-G). However, given the novelty of this approach to diagnosis, literature detailing the exact clinical, radiographic, and histopathologic findings associated with these tumors remain in development. Data for 25 patients matching the DAG-G diagnosis were obtained from our institution's retrospective database. Information regarding patient demographics, treatment regimens, radiographic imaging, and genetic pathology were analyzed to determine association with clinical outcomes. The initial radiographic findings, histopathology, and symptomatology of patients with DAG-G were similar to lower-grade astrocytomas (WHO grade 2/3). Overall survival (OS) and progression free survival (PFS) associated with our cohort, however, were similar to that of IDH-wt GBM, indicating a more severe clinical course than expected from other associated features (15.1 and 5.39months respectively). Despite multiple features similar to lower-grade gliomas, patients with DAG-G experience clinical courses similar to GBM. Such findings reinforce the need for biopsy and subsequent analysis of molecular features associated with any astrocytoma regardless of presenting characteristics.

Levels of Coenzyme Q10 and Several COQ Proteins in Human Astrocytoma Tissues Are Inversely Correlated with Malignancy.

In a previous study, we reported the alterations of primary antioxidant enzymes and decreased citrate synthase (CS) activities in different grades of human astrocytoma tissues. Here, we further investigated coenzyme Q10 (CoQ10) levels and protein levels of polyprenyl diphosphate synthase subunit (PDSS2) and several COQ proteins required for CoQ10 biosynthesis in these tissues. We found that the level of endogenous CoQ10, but not of exogenous α-tocopherol, was higher in nontumor controls than in all grades of astrocytoma tissues. The levels of COQ3, COQ5, COQ6, COQ7, COQ8A, and COQ9, but not of COQ4, were lower in Grade IV astrocytoma tissues than in controls or low-grade (Grades I and II) astrocytomas, but PDSS2 levels were higher in astrocytoma tissues than in controls. Correlation analysis revealed that the levels of CoQ10 and COQ proteins were negatively correlated with malignancy degree and positively correlated with CS activity, whereas PDSS2 level was positively correlated with malignancy. Moreover, lower level of mitochondrial DNA-encoded cytochrome c oxidase subunit 2 was not only associated with a higher malignancy degree but also with lower level of all COQ proteins detected. The results revealed that mitochondrial abnormalities are associated with impaired CoQ10 maintenance in human astrocytoma progression.

β-Catenin marks proliferating endothelial cells in glioblastoma

BackgroundAngiogenesis is a key process in the growth and maintenance of tumors. The Wnt signaling pathway is required for angiogenesis of the central nervous system though development of the blood–brain barrier and subsequent proliferation of endothelial cells during tumor growth. However, the specificity of the Wnt pathway in regulating endothelial cells of different central nervous systems remains to be investigated. Materials & methodsPatient-derived tissue samples from 35 paraffin-embedded tumors were used to assess β-catenin immunoexpression. Tumor samples consisted of the following pathologies: grade II diffuse astrocytoma, glioblastoma, hemangioblastoma, and metastatic adenocarcinoma (lung or breast primary). Average percent reactivity was recorded as a mean observed in ten high-power fields. The following scale was used to grade immunoreactivity: 0 = immunonegative, 1 = 1–25% reactive, 2 = 26–50% reactive, 3 = 51–75% reactive, 4 = 76–100% reactive. ResultsWhile we did not observe nuclear expression of β-catenin in any samples, there was uniform cytoplasmic expression of β-catenin within glial tumor cells. There was a clear distinction in tumor endothelial cells whereby diffuse staining was noted in areas of microvascular hyperplasia in GBM and a less immunoreactive profile in low-grade astrocytomas. By contrast, non-glial tumors, contained very minimal cytoplasmic β-catenin expression in tumor and stromal cells and were devoid of immunoreactivity in endothelial cells. Conclusionβ-catenin is unique marker of proliferating endothelial cells in GBM. Therapies targeting the spatial and structural heterogeneity inherent to GBM may prove to be efficacious and result in an improved survivorship.

Distinct metabolic hallmarks of WHO classified adult glioma subtypes.

BackgroundGliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy.MethodsCross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors—oligodendroglioma (n = 31), astrocytoma (n = 31) and glioblastoma (n = 162)—were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2–4, and MGMT promoter methylation.ResultsDistinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides, and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue.ConclusionKey metabolic differences exist across adult glioma subtypes.

Awake Surgery With Visual Pathway Mapping in Low Grade Glioma Surgery

The visual pathway and its defects have been thoroughly studied in clinical correlation to temporal lobe lesions related to epilepsy and traumatic lesions. Nevertheless, its clinical correlation and other decision-making have not been addressed regarding neoplastic lesions. We present a case report of a 28-year-old man with a one-year history of generalized seizures and left superior homonymous quadrantanopia, with no other neurological disturbance on physical examination. According to diffusion tensor imaging tractography, MRI demonstrated a non-enhancing, right temporal lesion disrupting the visual pathway. An awake surgery with direct cortical electrostimulation of visual pathways was performed with subtotal resection of the tumor to preserve visual function, confirmed with postoperative MRI. Histopathological studies revealed a fibrillary astrocytoma.Surgical technique aided with intraoperative cortical and subcortical stimulation involving low-grade gliomas in eloquent areas is an exceptionally suitable procedure for complex cases where the visual pathway is compromised. Our objective is to describe how intraoperative mapping of visual function is performed in our institution and to comment on the relevant technical nuances, which can serve as a practical guideline for young neurosurgeons, as no previous cases have been reported in our country.

Intra-tumoral susceptibility signal: a post-processing technique for objective grading of astrocytoma with susceptibility-weighted imaging

Susceptibility-weighted imaging (SWI) is sensitive to the accumulation of paramagnetic substances, such as hemorrhage and increased venous vasculature, both being frequently found in high-grade tumors. The purpose of this retrospective study is to differentiate high-grade and low-grade astrocytoma by objectively measuring quantitative intra-tumoral susceptibility signals (qITSS) on SWI. Precontrast SWI and 3D contrast-enhanced T1WI of 65 patients with astrocytoma were collected at 1.5 Tesla. All tumors were histologically confirmed and classified into two groups: high grade (WHO grade III and IV, n=50) and low grade (WHO grade II, n=15). After manual delineation of the tumor on T1WI, normalized contrast (NC) was calculated voxel by voxel within the tumor by using the concept of contrast to noise ratio. Thresholding on NC was applied to detect qITSS, and the volumetric percentage of qITSS can be obtained for each tumor. Two-sample t-test was applied to examine significant difference of qITSS percentage between high-grade and low-grade astrocytoma for different NC thresholds, ranging from 4 to 20. Receiver operating characteristic analysis was performed to evaluate the performance of differentiation. P value was less than 0.01 for a large range of NC thresholds [4-20], reflecting significant difference of qITSS percentage between high-grade and low-grade astrocytoma. The area under the receiver operating characteristic curve was larger than 0.9 at NC thresholds from 8 to 16 and peaks at 0.949 with a NC threshold of 14. It was shown that astrocytoma grading by qITSS percentage is successful for a wide range of NC threshold, demonstrating robustness on threshold selection. Without relying on the selection of slice position and at the same time providing objective identification of hypointense signal in SWI, the qITSS percentage can be used to distinguish high-grade and low-grade astrocytoma reliably.

Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.