Search

Purpose: IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood., Experimental Design: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semiautomatic 3D segmentation on all pre- and post-operative MRI scans. Overall survival was assessed with the Cox-proportional hazards model., Results: A total of 383 patients with newly diagnosed IDH-mutant glioma were followed up for a median of 7.2 years. Grades 3 and 4 patients had significantly lower Karnofsky performance, with tumors having more contrast enhancement. Patients also received more aggressive postsurgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR, per cm3 1.19; 95% CI, 1.03-1.39) in IDH-mutant glioma. A separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma but not in oligodendroglioma. Higher age and histologic tumor grade were associated with worse survival in patients with oligodendroglioma but not with astrocytoma., Conclusions: Our data support an initial strategy of extensive resection in patients with oligodendroglioma and astrocytoma. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities., (©2024 American Association for Cancer Research.)

Objective: Query the National Cancer Database (NCDB) to delineate epidemiologic frequency, care patterns, and survival outcomes of pediatric intramedullary spinal cord tumors (IMSCTs)., Methods: IMSCTs included ependymoma, astrocytoma, and hemangioblastoma. We examined data from the NCDB spanning 2004-2018, focusing on IMSCT in children aged 0-21 years. Our analysis included logistic and Poisson regression, Kaplan-Meier survival estimates, and Cox proportional hazards models., Results: This study included 1066 patients aged 0-21 years. 59.4 % of patients were male, while 83.1 % were white. The most common tumor histology was ependymoma (57.5 %), followed by astrocytoma (36.1 %) and hemangioblastoma (6.4 %). 24.9 % of patients received radiotherapy, with radiotherapy utilization being highest among patients aged 6-10 years. Chemotherapy utilization was highest in patients aged 0-5 years. 87.2 % of patients underwent surgical resection, with higher rates in patients aged 16-21 years. Overall survival did not differ significantly between resected and non-resected patients (p = 0.315). Patients in rural areas had worse OS than those in metro areas (HR = 4.42, p = 0.048). Patients with astrocytoma had worse OS compared to other histologies (HR = 2.21, p = 0.003). Astrocytoma patients were over twice as likely to have prolonged LOS compared to ependymoma patients (OR = 2.204, p < 0.001)., Conclusions: In summary, our analysis utilizing the NCDB database provides a comprehensive overview of demographics, care patterns, and outcomes for the largest cohort of pediatric IMSCTs to date. These insights underscore the complexity of managing IMSCTs and emphasize the need for tailored approaches to improve patient outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Anaplastic astrocytoma (AA) is an uncommon primary brain tumor with highly variable clinical outcomes. Our study aimed to develop practical tools for clinical decision-making in a population-based cohort study., Methods: Data from 2997 patients diagnosed with AA between 2004 and 2015 were retrospectively extracted from the Surveillance, Epidemiology, and End Results database. The Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses were applied to select factors and establish prognostic nomograms. The discriminatory ability of these nomogram models was evaluated using the concordance index and receiver operating characteristic curve. Risk stratifications were established based on the nomograms., Results: Selected 2997 AA patients were distributed into the training cohort (70%, 2097) and the validation cohort (30%, 900). Age, household income, tumor site, extension, surgery, radiotherapy, and chemotherapy were identified as independent prognostic factors for both overall survival (OS) and cancer-specific survival (CSS). In the training cohort, our nomograms for OS and CSS exhibited good predictive accuracy with concordance index values of 0.752 (95% CI: 0.741-0.764) and 0.753 (95% CI: 0.741-0.765), respectively. Calibration and decision curve analyses curves showed that the nomograms demonstrated considerable consistency and satisfactory clinical utilities. With the establishment of nomograms, we stratified AA patients into high- and low-risk groups, and constructed risk stratification systems for OS and CSS., Conclusions: We constructed two predictive nomograms and risk classification systems to effectively predict the OS and CSS rates in AA patients. These models were internally validated with considerable accuracy and reliability and might be helpful in future clinical practices., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The introduction of molecular markers in to the diagnosis of gliomas has changed the therapeutic approach to this tumors. The aim of this study was to examine the impact of surgery on anaplastic astrocytomas (AA), which has not previously been fully elucidated., Methods: This was a retrospective study involving a total of 143 patients who underwent surgery for primary AA in our department between 1995 and 2020., Results: Total tumor resection was achieved more often in patients with IDH-mutant tumors (41.09%) than in patients with IDH-wildtype tumors (30.76%). The median PFS was 1876 days for patients with IDH1 mutations and 238 days for patients with IDH-wildtype tumors. The 1-, 3-, 5- and 10-year PFS were longer in patients with total tumor resection and IDH-mutant AA (86.2%, 69%, 65.5% and 44.8%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (83.3%, 55.6%, 41.7% and 25%, respectively) and even longer compared to all IDH-wildtype tumors. The median OS was 2472 days for patients with IDH1 mutations and 434 days for patients with IDH-wildtype tumors. The 3-, 5- and 10-year OS times were longer in patients with total tumor resection and IDH-mutant AA (89.2%, 85.2% and 72.6%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (85.9%, 73.7% and 52.6%, respectively) and were even longer compared to all IDH-wildtype tumors., Conclusion: Total tumor resection is more common with IDH-mutant AA than with IDH-wildtype tumors. Patients with IDH-mutant AA had significantly better PFS and OS after total tumor resection than after subtotal tumor resection and biopsy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low- and high-grade groups. We investigated the utility of the T2-fluid-attenuated inversion recovery (T2-FLAIR) mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization classification., Experimental Design: Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n = 71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed., Results: The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (P < 0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (P = 0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for progression-free survival (P = 0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, copy number variation, and methylation grade, showed trends toward significance for DNA methylation grade with overall survival (P = 0.045) and CDKN2A/B status with progression-free survival (P = 0.052)., Conclusions: The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas., (©2024 American Association for Cancer Research.)

Background: World Health Organization (WHO) grade 4 astrocytoma is a high-grade brain tumour in adults. Tumour treating fields (TTF) has been shown to improve overall survival (OS). Few studies have explored quality-of-life (QoL) in these patients. This study aims to assess the QoL of TTF patients and OS., Methods: This was a prospective multicenter study of adult patients diagnosed with WHO grade 4 astrocytoma from 2018 to 2023 receiving TTF for >1 month after completing standard therapy. A propensity-score matched comparison with a 1:2 ratio with historical control was performed for OS analysis. The patients completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-30/BN20 questionnaires before TTF and at 3-month interval. Primary outcomes included OS, and secondary outcomes included QoL and TTF-associated adverse effects at 3 months., Results: A total of 141 patients were reviewed, with TTF patients (n=47, 33%) and propensity-score matched controls (n=94). The mean duration of TTF use was 10±8 months. The mean age of the TTF group was 54±13 years, and for the control group 52±13 years. Sixty percent (n=28) were male, similar to the control group with 71% (n=67) (P=0.16). Seventy-two percent of TTF patients had preoperative Karnofsky Performance Scale (KPS) score ≥80, while controls had 70% (P=0.79). Five (11%) TTF patients and 8 (9%) controls were IDH1 mutant (P=0.70). Twenty (43%) TTF patients and 42 (45%) controls were O6-methylguanine-DNA methyltransferase promoter (pMGMT) methylated (P=0.81). Twenty-one (45%) of TTF patients and 55 (59%) of controls had gross total resection (P=0.72). After adjusting for independent predictors for OS, the median OS of the TTF group was 22.4 months [interquartile range (IQR): 18.6-26.5 months], significantly longer than the control group (17.2 months; IQR: 12.1-22.3 months) (log-rank test: P=0.01). Forty-seven TTF patients and 40 control patients completed EORTC questionnaires. There was no difference for EORTC functional and symptom scores between the TTF and control group [P=0.45, analysis of variance (ANOVA)] at 3 months. Thirty-two (67%) of TTF patients reported associated RTOG grade I scalp dermatitis., Conclusions: TTF for WHO grade 4 astrocytoma patients is an independent predictor for OS. QoL between the groups was similar, and overall QoL over time for TTF patients was not affected. TTF is a novel and effective outpatient treatment with minimal adverse effects.

Background: Astrocytoma is a type of adult-type diffuse gliomas that includes diffuse astrocytoma (DA) and anaplastic astrocytoma (AA). However, comprehensive investigations into the risk assessment and prognosis of DA and AA using population-based studies remain noticeably scarce., Methods: In this study, we developed 2 predictive nomograms to evaluate the susceptibility and prognosis associated with DA and AA. The study cohort comprised 3837 individuals diagnosed with DA or AA between 2010 and 2019 selected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent predictors were identified and used to construct the nomograms for overall death and cancer-specific death rates. The performance of the models was assessed using C-index, calibration curves, and receiver operating characteristic curve, and the clinical applicability was evaluated using decision curve analysis., Results: The receiver operating characteristic curves in this study show excellent clinical applicability and predictive power. Notably, the area under the curves of the training and verification queues was higher than 0.80, thereby cementing the models' precision. Additionally, the calibration plots demonstrate that the anticipated mortality rates strikingly match the measured values. This alignment of figures is sustained in the validation cohort. Furthermore, the decision curve analysis corroborates the models' translational potential, reinforcing their relevance within real-world clinical settings., Conclusions: The presented nomograms have not only exhibited good predictive performance but also showcased pragmatic clinical utility in prognosticating patient outcomes. Significantly, this will undoubtedly serve as a valuable asset for oncologists, facilitating informed treatment decisions and meticulous follow-up planning., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aim: Glioblastoma multiforme (GBM) is one of the most lethal types of brain cancer with a median survival of only 12 months due to its aggressiveness and lack of effective treatment options. Astrocytomas and oligodendrogliomas are classified as low-grade gliomas (LGG) and have the potential to progress into secondary GBM. YAP1 and TAZ are transcriptional co-activators of the hippo pathway and play an important role in tumorigenesis by controlling cell proliferation and differentiation. The aim of this study was to analyze whether YAP1 and TAZ influence the survival in patients with astrocytoma and oligodendroglioma., Patients and Methods: A total of 22 patient samples of astrocytoma and 11 samples of oligodendroglioma were analyzed using real-time PCR. We utilized open-access data from The Cancer Genome Atlas (TCGA) focusing on "brain lower grade glioma". mRNA expression rates were used to validate our findings on survival analysis., Results: Expression of YAP1 was twice as high in astrocytoma than in oligodendroglioma, whereas there was no difference in TAZ. In oligodendrogliomas, the expression of TAZ was higher in relapsed than in primary tumors. Patients with astrocytoma having a high YAP1 expression had a significantly shorter overall survival than patients with lower expression (median survival 161 vs. 86 months, p=0.0248). These findings were validated with survival analysis of TCGA data., Conclusion: High YAP1 expression shows a high correlation with poorer overall survival in LGG. YAP1 has higher levels of expression in astrocytomas than in oligodendrogliomas., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Intramedullary spinal cord tumors (IMSCTs) are a rare subgroup of neoplasms, encompassing both benign, slow-growing masses, and malignant lesions; radical surgical excision represents the cornerstone of treatment for such pathologies regardless of histopathology, which, on the other hand, is a known predictor of survival and neurologic outcome postsurgery. The present study aims to investigate the relevance of other factors in predicting survival and long-term functional outcomes., Methods: We conducted a review of current literature on functional outcomes of IMSCTs, as well as a 10-years prospective analysis of a wide cohort of patients with diagnosis of IMSCTs who underwent surgical resection at our institution., Results: Our series encompasses 60 patients with IMSCTS, among which 36 ependymomas, 6 cavernous angiomas, 5 hemangioblastomas, 6 WHO Grade I-IV astrocytomas, 3 intramedullary spinal metastases and 4 miscellaneous tumors. GTR was achieved in 76,67% of patients, with high preoperative McCormick grade, syringomyelia and changes at neurophysiologic monitoring being the strongest predictors at multivariate analysis (P = 0.0027, P = 0.0017 and P = 0.001 respectively)., Conclusions: Consistently with literature, preoperative neurologic function is the most important factor predicting long-term functional outcome (0.17, CI 0.069-0.57 with P = 0.0018), advocating for early surgery in the management of IMSCTs, whereas late complications such as myelopathy and neuropathic pain were present regardless of preoperative function., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma., Methods: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts., Results: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534)., Conclusions: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11 C-methionine uptake in astrocytomas with IDH mutations., Methods: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11 C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11 C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis., Results: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11 C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012)., Conclusion: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11 C-methionine uptake in astrocytoma, IDH-mutant., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with either microvascular proliferation and/or necrosis or homozygous deletion of CDKN2A/B as CNS grade 4 (CNS WHO G4), introducing a distinct entity and posing new challenges to physicians for appropriate management and prognostication., Patients and Methods: We retrospectively collected information about patients diagnosed with A IDHm CNS WHO G4 at three reference neuro-oncological Italian centers and correlated them with survival., Results: A total of 133 patients were included. Patients were young (median age 41 years) and most received post-operative treatment including chemo-radiation (n = 101) and/or temozolomide maintenance (n = 112). With a median follow-up of 51 months, the median overall survival (mOS) was 31.2 months, with a 5-year survival probability of 26%. In the univariate analysis, complete resection (mOS: 40.2 versus 26.3 months, P = 0.03), methyl-guaninemethyltransferase (MGMT) promoter methylation (mOS: 40.7 versus 18 months, P = 0.0136), and absence of telomerase reverse transcriptase (TERT) promoter mutation (mOS: 40.7 versus 18 months, P = 0.0003) correlated with better prognosis. In the multivariate models, lack of TERT promoter mutation [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07-0.82, P = 0.024] and MGMT methylation (HR 0.40, 95% CI 0.20-0.81, P = 0.01) remained associated with improved survival., Conclusions: This is the largest experience in Western countries exploring the prognostic signature of patients with A IDHm CNS G4. Our results show that MGMT promoter methylation and TERT promoter mutation may impact clinical outcomes. This may support physicians in prognostication, clinical management, and design of future studies of this distinct diagnostic entity., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults., Methods: ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature., Results: Fifty-nine randomized trials focusing on therapeutic management were identified., Recommendations: Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines., Competing Interests: Reprint Requests: 2318 Mill Road, Suite 800, Alexandria, VA 22314; guidelines@asco.org. Nimish A. MohileResearch Funding: Vascular Biogenics, Boston Biomedical, Quell, Tocagen Na Tosha GatsonHonoraria: NovocureConsulting or Advisory Role: NovocureTravel, Accommodations, Expenses: Novocure Andreas F. HottingerConsulting or Advisory Role: Ideogen (Inst), Bayer Roche (Inst), Novocure (Inst)Research Funding: Novocure (Inst)Travel, Accommodations, Expenses: Celgene, Novocure, Bristol Myers Squibb, Karyopharm Therapeutics Andrew LassmanHonoraria: Abbott MolecularConsulting or Advisory Role: Karyopharm Therapeutics, Sapience Therapeutics, QED Therapeutics, FORMA Therapeutics, Bayer, Orbus Therapeutics, BioClinica, Novocure, Elsevier, Vivacitas OncologyResearch Funding: AbbVie (Inst), Novartis (Inst), Genentech/Roche (Inst), Aeterna Zentaris (Inst), Celldex (Inst), Kadmon (Inst), BeiGene (Inst), VBI Vaccines (Inst), Pfizer (Inst), Millennium (Inst), Oncoceutics (Inst), Karyopharm Therapeutics (Inst), Bayer (Inst), QED Therapeutics (Inst), Agios (Inst), Orbus Therapeutics (Inst), BMS (Inst), RTOG Foundation (Inst)Patents, Royalties, Other Intellectual Property: ElsevierTravel, Accommodations, Expenses: AbbVie, BioClinica, Abbott Molecular, FORMA Therapeutics, Karyopharm Therapeutics, QED Therapeutics, Bayer, Novartis, Pfizer, VBI Vaccines Douglas NeyConsulting or Advisory Role: DNAtrixResearch Funding: Orbus Therapeutics, Denovo Biopharma (Inst) Phioanh Leia NghiemphuConsulting or Advisory Role: AbbVieResearch Funding: Novartis Adriana OlarConsulting or Advisory Role: Guardant Health, Anuncia Inc Jeffery OlsonConsulting or Advisory Role: American Cancer Society David SchiffConsulting or Advisory Role: Orbus Therapeutics, GlaxoSmithKline, PRAResearch Funding: Bayer (Inst) Helen A. ShihHonoraria: UpToDate Roy StrowdConsulting or Advisory Role: Monteris Medical, NovocureResearch Funding: Southeastern Brain Tumor Foundation, Jazz Pharmaceuticals, NIH, American Board of Psychiatry and Neurology, Alpha Omega AlphaOther Relationship: American Academy of Neurology (AAN) Martin van den BentThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: AstraZeneca (I)Consulting or Advisory Role: AbbVie, Bristol Myers Squibb, Celgene, Agios, Boehringer Ingelheim, Bayer, Carthera, Genenta Science, Nerviano Medical Sciences, Boston PharmaceuticalsResearch Funding: AbbVie (Inst) Mateo ZiuStock and Other Ownership Interests: Gilead Sciences Jaishri BlakeleyConsulting or Advisory Role: AbbVie, AstraZeneca, Astellas Pharma, Exelixis, VertexResearch Funding: GlaxoSmithKline (Inst), Lilly (Inst), Sanofi (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: ExelixisUncompensated Relationships: SpringWorks Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/747718No other potential conflicts of interest were reported.

This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma. Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) grade II-IV astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution. Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p < 0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95% CI 1.23-22.8, p = 0.025; glioblastoma: HR 11.52, 95% CI 2.27-58.47, p = 0.0032), preoperative KPS ≥ 80 (HR 0.23, 95% CI 0.09-0.62, p = 0.004), maximum lesion-to-contralateral normal brain tissue (LN max) ≥ 4.03 (HR 0.24, 95% CI 0.08-0.71, p = 0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95% CI 1.81-109.2, p = 0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max ≥ 4.03 (29.3 months) than in patients with LN max < 4.03 (not reached; p = 0.03). OS differed significantly between patients with IDH mutant/LN max < 4.03 and patients with IDH mutant/LN max ≥ 4.03. LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO grade II-IV astrocytic glioma., (© 2022. The Author(s).)

Pleomorphic xanthoastrocytoma (PXA) in its classic manifestation exhibits distinct morphological features and is assigned to CNS WHO grade 2 or grade 3. Distinction from glioblastoma variants and lower grade glial and glioneuronal tumors is a common diagnostic challenge. We compared a morphologically defined set of PXA (histPXA) with an independent set, defined by DNA methylation analysis (mcPXA). HistPXA encompassed 144 tumors all subjected to DNA methylation array analysis. Sixty-two histPXA matched to the methylation class mcPXA. These were combined with the cases that showed the mcPXA signature but had received a histopathological diagnosis other than PXA. This cohort constituted a set of 220 mcPXA. Molecular and clinical parameters were analyzed in these groups. Morphological parameters were analyzed in a subset of tumors with FFPE tissue available. HistPXA revealed considerable heterogeneity in regard to methylation classes, with methylation classes glioblastoma and ganglioglioma being the most frequent mismatches. Similarly, the mcPXA cohort contained tumors of diverse histological diagnoses, with glioblastoma constituting the most frequent mismatch. Subsequent analyses demonstrated the presence of canonical pTERT mutations to be associated with unfavorable prognosis among mcPXA. Based on these data, we consider the tumor type PXA to be histologically more varied than previously assumed. Histological approach to diagnosis will predominantly identify cases with the established archetypical morphology. DNA methylation analysis includes additional tumors in the tumor class PXA that share similar DNA methylation profile but lack the typical morphology of a PXA. DNA methylation analysis also assist in separating other tumor types with morphologic overlap to PXA. Our data suggest the presence of canonical pTERT mutations as a robust indicator for poor prognosis in methylation class PXA., (© 2022. The Author(s).)

Background: Pilocytic astrocytoma(PA) is a relatively benign tumor occurring primarily in the pediatric population. Comparison of characteristics and survival of this tumor between adult and pediatric patients in a single, population-based study is yet to be performed., Objective: We aimed to directly compare the characteristics and survival of pilocytic astrocytoma between pediatric and adult patients in a single, population-based study., Methods: We utilized the SEER database using data from 1983 to 2016. All patients with histologically confirmed, intracranial pilocytic astrocytoma were included and divided into a pediatric(age<18 years) or adult group. Due to lower risk of tumor-specific-mortality, we utilized a competing risk analysis to account for mortality from other causes. Univariable and multivariable competing risk analysis(CRA) was performed, and sub-distribution hazard ratio(SHR) or adjusted SHR(aSHR) was reported., Results: A total of 4357 patients comprised the final cohort, with 3014(69.2%) pediatric patients. As compared to the pediatric group, adult patients were predominantly White(p < 0.01), with PA less likely fully resected(p = 0.01), smaller tumor size(p < 0.01), and were less often located in the cerebellum(p < 0.01). Multivariable CRA revealed a worse prognosis for the adult group(p < 0.01), regional or distal extension(p < 0.01), and non-cerebellar locations including frontal(p < 0.01), parietal(p < 0.01), ventricular(p < 0.01) or brainstem(p < 0.01). Improved prognosis was seen with more recent year-of-diagnosis(2003-2016, p = 0.03), gross-total/total resection(p < 0.01), and biopsy only patients(p = 0.02)., Conclusions: Pilocytic astrocytomas in adult patients have a worse prognosis than pediatric patients. Cumulative incidence of cancer-specific-mortality is higher in adults when adjusted for other factors. PAs with regional or distal extension and non-cerebellar locations carry worse outcomes. Surgery remains an effective treatment and GTR/TR should be achieved when possible., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To investigate incidence and survival of childhood tumours of the central nervous system (CNS) by histological subtype, tumour behaviour and tumour grade., Methods: National, population-based data on all children under 15 years old diagnosed with a CNS tumour between 1983 and 2016 were sourced from the Australian Childhood Cancer Registry. Incidence rate trends were calculated using Joinpoint regression. Relative survival was calculated using the cohort method, with changes in survival over time by cancer type and tumour grade assessed by multivariable flexible parametric survival modelling., Results: The study cohort included 4914 patients, with astrocytoma (n = 2181, 44%) and embryonal tumours (n = 931, 19%) the most common diagnostic subgroups. Almost half (n = 2181, 44%) of all tumours were classified as high grade (III or IV). Incidence rates increased by 29% between 1983 and 2016, with high grade tumours rising by an annual average of + 1.1% (95% CI =  + 0.7%, + 1.5%, p < 0.001). 5-year survival for all patients combined was 72% (95% CI = 71-74%), ranging from 50% (46-54%) for those with other gliomas to 81% (79-83%) for astrocytoma (p < 0.001). Survival improved over time for grade II and III ependymomas but not for patients with astrocytoma irrespective of grade., Conclusion: Improvements in diagnostic technology leading to more precise tumour classification are likely to explain some of the differences in incidence rate trends by histological type and grade. While improvements in survival over time were noted for some tumours, outcomes remained poor among patients with high-grade astrocytoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature., Methods: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression., Results: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression., Conclusion: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Chaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) is reported to be an efficient prognostic biomarker in various cancers, but it is rarely reported in astrocytoma. Thus, this study aimed to evaluate the expression of CCT6A and its correlation with disease features and prognosis in astrocytoma patients., Methods: Totally, 198 astrocytoma patients who received surgery treatment were enrolled. CCT6A protein expression was determined in the tumor tissues fixed in formalin and embedded in paraffin (FFEP) by immunohistochemistry (IHC) assay. In addition, 133 out of 198 astrocytoma patients had fresh tumor tissues frozen in the liquid nitrogen for the determination of CCT6A mRNA expression by reverse transcription-quantitative polymerase chain reaction., Results: Sixty-nine (34.8%), 70 (35.4%), 46 (23.2%), and 13 (6.6%) astrocytoma patients had the CCT6A immunohistochemistry (IHC) score of 0-3, 4-6, 7-9, and 10-12, respectively. CCT6A protein expression was correlated with increased World Health Organization (WHO) grade (P < 0.001) and less isocitrate dehydrogenase (IDH) mutation (P = 0.002); meanwhile, CCT6A mRNA expression was only related to elevated WHO grade (P = 0.001). However, CCT6A protein and mRNA expression were not correlated with other clinical features and subsequent treatment modalities (all P > 0.05). Moreover, CCT6A protein high and CCT6A mRNA high were related to shorter accumulating overall survival (OS; both P < 0.05). CCT6A protein high was an independent factor for predicting the worse OS (hazard ratio: 1.821, P = 0.012)., Conclusion: Chaperonin-containing tailless complex polypeptide 1 subunit 6A correlates with elevated WHO grade and less IDH mutation; besides, CCT6A high expression is independently associated with unfavorable accumulating OS of astrocytoma patients., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

The diagnostic role of Isocitrate Dehydrogenase (IDH) mutation status in adult lower grade astrocytomas was first formally presented within the WHO Classification of Tumours of the Central Nervous System (2016). IDH-mutant astrocytomas are not as common as IDH-wildtype astrocytomas but are of better prognosis. Our previous study provided an evident that IDH-mutant lower grade astrocytomas is not a homogeneous group and could be further stratified by PDGFRA amplification, CDK4 amplification and CDKN2A deletion. In this study, we detected the expressions of DNA mismatch repair (MMR) proteins (PMS2, MLH1, MSH2, MSH6) and PD-L1 by immunohistochemistry in 147 IDH-mutant lower grade astrocytomas and explored their clinical relevance. The loss of was identified in 28.6%, 1.4%, 8.8% and 13.6%, respectively. PD-L1 expression was detected in 1.4% of this cohort. Survival analysis revealed that loss of PMS2 was correlated with shorter OS (p < 0.001) and PFS (p = 0.005). Loss of PMS2 or MLH1 was associated with shorter OS (p < 0.001) and PFS (p = 0.008). In IDH-mutant lower grade astrocytomas without CDKN2A deletion, loss of PMS2 was associated with poorer OS (p < 0.001) and PFS (p = 0.001). Furthermore, among IDH-mutant lower grade astrocytomas lacking the three biomarkers (PDGFRA, CDK4 and CDKN2A), loss of PMS2 was also associated with a poorer OS (p < 0.001) and PFS (p = 0.003). Our data illustrated the potential application of MMR genes in stratification of IDH-mutant lower grade astrocytomas without PDGFRA, CDK4 and CDKN2A copy number alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Optic nerve astrocytomas (ONAs) are neurological neoplasms in the central nervous system (CNS), and they have the highest incidence rate among all the tumor types in the visual pathway. In this study, we conducted a Surveillance, Epidemiology, and End Results (SEER) -based research to explore the demographic, survival, and prognostic factors of patients diagnosed with ONAs., Methods: Utilizing the SEER database, we retrospectively evaluated data of patients diagnosed with ONAs of all ages from 1984 to 2016. We used the Student's t distribution to test variables of patients and various characteristics, and Kaplan-Meier curve to illustrate overall survival (OS) with 95.0% confidence intervals (CIs). We also performed univariate and multivariate analyses to evaluate various variables' validity on overall survival., Results: A total of 1004 cases were analyzed, and revealed that age (P<0.001, hazard ratio (HR) = 8.830, 95% CI: 4.088-19.073), tumor grade (P<0.001, HR = 1.927, 95% CI: 1.516-2.450), diagnostic confirmation (P<0.001, HR = 2.444, 95% CI: 1.632-3.660), and histology type (P = 0.046, HR = 1.563, 95% CI: 1.008-2.424) of the tumor were associated with decreased survival., Conclusions: From this large, comparative study of ONAs, we found that younger age may be considered as a protective indicator, while high-grade astrocytic tumors have a worse prognosis. We also found that diagnostic confirmation and tumor grade were independent prognostic factors in this patient population., (© 2021. The Author(s).)

The characteristics of IDH-wild-type lower-grade astrocytoma remain unclear. According to cIMPACT-NOW update 3, IDH-wild-type astrocytomas with any of the following factors show poor prognosis: combination of chromosome 7 gain and 10 loss (+ 7/- 10), and/or EGFR amplification, and/or TERT promoter (TERTp) mutation. Multiplex ligation-dependent probe amplification (MLPA) can detect copy number alterations at reasonable cost. The purpose of this study was to identify a precise, cost-effective method for stratifying the prognosis of IDH-wild-type astrocytoma. Sanger sequencing, MLPA, and quantitative methylation-specific PCR were performed for 42 IDH-wild-type lower-grade astrocytomas surgically treated at Kyoto University Hospital, and overall survival was analysed for 40 patients who underwent first surgery. Of the 42 IDH-wild-type astrocytomas, 21 were classified as grade 4 using cIMPACT-NOW update 3 criteria and all had either TERTp mutation or EGFR amplification. Kaplan-Meier analysis confirmed the prognostic significance of cIMPACT-NOW criteria, and World Health Organization grade was also prognostic. Cox regression hazard model identified independent significant prognostic indicators of PTEN loss (risk ratio, 9.75; p < 0.001) and PDGFRA amplification (risk ratio, 13.9; p = 0.002). The classification recommended by cIMPACT-NOW update 3 could be completed using Sanger sequencing and MLPA. Survival analysis revealed PTEN and PDGFRA were significant prognostic factors for IDH-wild-type lower-grade astrocytoma., (© 2021. The Author(s).)

The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis., (© 2021. The Japan Society of Brain Tumor Pathology.)

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts.

Astrocytoma is the most common glial tumour of the CNS. The most malignant form is grade IV Astrocytoma, also called Glioblastoma. Due to its heterogeneity, aggressiveness and lethal nature scientists are trying to find less invasive methods for early prediction of tumour onset, recurrence, response to therapy and patients' survival. Here, applying decision tree classification algorithm we performed astrocytoma specific protein profile analysis on serum proteins TIMP-1, active and latent form of TGF-β1, IP-10, ANGPT-1, OPN, and YKL-40 using enzyme-linked immunosorbent detection assay (ELISA). Results have demonstrated that astrocytoma specific profile consisted of three proteins-active form of TGF-β1, TIMP-1 and YKL-40 and was able to correctly classify 78.0% (103/132) of sample and 83.3% (60/72) of astrocytoma sample. Calculating decision tree algorithm associated with astrocytoma patient survival, prediction model reached an accuracy of 83.3% (60/72). All together these results indicate that glioma detection and prediction from patient serum using glioma associated proteins and applying mathematical classification tools could be achieved, and applying more comprehensive research further could be implemented in clinic.

Background: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma., Methods: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis., Results: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma., Conclusion: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.

Chromosomal instability due to mutations in genes guarding the stability of the genome is a well-known mechanism underlying tumorigenesis and malignant progression in numerous cancers. The effect of this process in gliomas is mostly unknown with relatively little research examining the effects of chromosomal instability on patient outcome and therapeutic efficacy, although studies have shown that overall/total copy number variation (CNV) is elevated in higher histologic grades and in cases with more rapid progression and shorter patient survival. Herein, we examine a 70-gene mRNA expression signature (CIN70), which has been previously shown to correlate tightly with chromosomal instability, in 2 independent cohorts of IDH-mutant astrocytomas (total n = 241), IDH-wildtype astrocytomas (n = 228), and oligodendrogliomas (n = 128). Our results show that CIN70 expression levels correlate with total CNV, as well as higher grade, progression-free survival, and overall survival in both IDH-mutant and IDH-wildtype astrocytomas. In oligodendrogliomas, these mRNA signatures correlate with total CNV but not consistently with clinical outcome. These data suggest that chromosomal instability is an underlying factor in aggressive behavior and progression of a subset of diffuse astrocytomas. In addition, chromosomal instability may in part explain the poor response of diffuse gliomas to treatment and may serve as a future therapeutic target., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: Newly emerged molecular markers in gliomas provide prognostic values beyond the capabilities of histologic classification. BRAF mutation, especially BRAF V600E, is common in a subset of gliomas and may represent a potential prognostic marker. The aim of our study is to investigate the potential use of BRAF mutations on the prognosis of low-grade glioma patients., Methods: Four electronic databases were searched for potential articles including PubMed, Web of Science, Embase, and Cochrane. Data of hazard ratio (HR) for overall survival and progression-free survival were directly obtained from original papers or indirectly estimated from the Kaplan-Meier curve. A random effect model weighted by inverse variance method was used to calculate the pooled HR. From 483 articles, we finally included 8 articles with 698 glioma patients for the final analysis. The overall estimates showed that BRAF V600E was associated with an improved overall survival in glioma patients (HR = 0.64; 95% confidence interval = 0.45-0.92)., Results: Results for progression-free survival, however, were not statistically significant (HR = 0.97; 95% confidence interval = 0.7-1.36). In subgroup analyses, BRAF V600E showed its effect in improving survival in pediatric patients but did not have prognostic value in adult. Our meta-analysis provides evidence that BRAF mutation has a favorable prognostic impact in low-grade gliomas, and its prognostic value might be dependent on patient age., Conclusions: This mutation can be used as a prognostic factor in low-grade glioma, but additional studies are required to clarify its prognostic value taking into account other confounding factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The evaluation of the prognosis of gliomas may have great value in individualized treatment., Purpose: To evaluate the value of intravoxel incoherent motion (IVIM) in predicting the survival of patients with astrocytoma and comparing it to apparent diffusion coefficients (ADC)., Material and Methods: Sixty patients with pathologically confirmed cerebral astrocytomas underwent IVIM scans before any treatment was performed. Patients were divided into death group and survival group according to a two-year follow-up. ADC and quantitative parameters of IVIM including D, D*, and f were measured. Independent sample t test was used to compare the two groups of parameters. The accuracy of each parameter for two-year survival rate was analyzed by receiver operating characteristic (ROC) curve and Kaplan-Meier survival curves. The correlation between quantitative parameters and survival days was analyzed by Pearson correlation analysis., Results: The ADC, D*, and f values were statistically significant different between the death and the survival groups ( P  < 0.05). The AUC of the ADC, D*, and f were 0.811, 0.858, and 0.892, respectively. The ADC cut-off value of 0.668 × 10 -3  mm 2 /s corresponded to 82.6% sensitivity and 73% specificity. The D* cut-off value of 3.913 × 10 -3  mm 2 /s corresponded to 78.4% sensitivity and 87% specificity. The f cut-off value of 0.487 corresponded to 83.8% sensitivity and 87% specificity. Significant log rank test was performed for each parameter to predict overall survival ( P  < 0.05). There was a correlation between ADC ( r  = 0.625, P  = 0.023), D* ( r  = -0.655, P  = 0.012), f ( r  = -0.725, P  = 0.000) and survival days., Conclusion: The D* and f values demonstrated great potential in predicting the two-year survival rate for patients with astrocytoma.

Background: Management of WHO grade II gliomas (LGG) can include a combination of observation, surgery, radiotherapy (RT), and chemotherapy; however, optimal management remains unclear in regards to RT., Objective: The current study seeks to investigate the usage of RT in LGG and its effect on survival outcomes., Methods: Patients with diagnosis codes specific for LGG were queried from the National Cancer Database (NCDB) during the years 2004-2016. Kaplan-Meier curves with log-rank testing, univariate and multivariate Cox regression analysis, and comparisons of estimated 3- and 7-year survival were performed to investigate the effect of RT on overall survival., Results: 19,382 patients with LGG were identified with histologically confirmed disease. Kaplan-Meier testing demonstrated RT impacted survival in patients undergoing biopsy or no surgery (p < 0.0001), no chemotherapy (p < 0.0001), and in regimens with early RT (p < 0.0001) and high-dose RT (p < 0.0001). Cox multivariate regression demonstrated RT and age less than 40 (HR 0.93, 95% CI 0.89-0.97, p = 0.001), no chemotherapy (HR 0.82, 95% CI 0.77-0.87, p < 0.001), and astrocytoma histology (HR 0.72, 95% CI 0.66-0.79, p < 0.001) were associated with improved survival. 3-year survival of RT versus non-RT groups showed increased survival rates for age less than 40 years (+ 5.7%, p < 0.0001), no surgery or biopsy (+ 8.1%, p < 0.0001), no chemotherapy (+ 10.3%, p < 0.0001), mixed glioma (+ 6.7%, p < 0.0001), astrocytoma (+ 7.1%, p < 0.0001), and in regimens with early RT (+ 7.6%, p < 0.0001) and high-dose RT (+ 4.7%, p < 0.0001)., Conclusion: This nationwide analysis of LGG patients found that RT was associated with improved survival outcomes in patients less than 40 years of age, with histology subtypes of astrocytoma and mixed glioma, undergoing biopsy or no surgery, and in regimens with early RT and high-dose RT.

Purpose: Studies have evaluated the application of perfusion MR for predicting survival in patients with astrocytic brain tumors, but few of them statistically adjust their results to reflect the impact of the variability of treatment administered in the patients. Our aim was to analyze the association between the perfusion values and overall survival time, with adjustment for various clinical factors, including initial treatments and follow-up treatments., Materials and Methods: This study consisted of 51 patients with astrocytic brain tumors who underwent perfusion-weighted MRI with MultiHance® at a dose of 0.1 mmol/kg prior to initial surgery. We measured the mean rCBV, the 5% & 10% maximum rCBV, and the variation of rCBV in the tumors. Comparisons were made between patients with and without 2-year survival using two-sample t-test or Wilcoxon rank-sum test for the continuous data, or chi-square and Fisher exact tests for categorical data. The multivariate cox-proportional hazard regression was fit to evaluate the association between rCBV and overall survival time, with adjustment for clinical factors., Results: Patients who survived less than 2 years after diagnosis had a higher mean and maximum rCBV and a larger variation of rCBV. After adjusting for clinical factors including therapeutic measures, we found no significant association of overall survival time within 2 years with any of these rCBV values., Conclusions: Although patients who survived less than 2 years had a higher mean and maximum rCBV and a larger variation of rCBV, rCBV itself may not be used independently for predicting 2-year survival of patients with astrocytic brain tumors., Competing Interests: The funding from Bracco Diagnostics, Inc. does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Current guidelines for the treatment of anaplastic astrocytoma (AA) recommend maximal safe resection followed by radiotherapy and chemotherapy. Despite this multimodal treatment approach, patients have a limited life expectancy. In the present study, we identified variables associated with overall survival (OS) and constructed a model score to predict the OS of patients with AA at the time of their primary diagnosis., Methods: We retrospectively evaluated 108 patients with newly diagnosed AA. The patient and tumor characteristics were analyzed for their impact on OS. Variables significantly associated with OS on multivariable analysis were included in our score. The final algorithm was based on the 36-month survival rates corresponding to each characteristic., Results: On univariate analysis, age, Karnofsky performance status, isocitrate dehydrogenase status, and extent of resection were significantly associated with OS. On multivariable analysis all four variables remained significant and were consequently incorporated in the score. The total score ranges from 20 to 33 points. We designated three prognostic groups: A (20-25), B (26-29), and C (30-33 points) with 36-month OS rates of 23%, 71%, and 100%, respectively. The OS rate at 5 years was 8% in group A, 61% in group B and 88% in group C., Conclusions: Our model score predicts the OS of patients newly diagnosed with AA and distinguishes patients with a poor survival prognosis from those with a greater life expectancy. Independent and prospective validation is needed. The upcoming changes of the WHO classification of brain tumors as well as the practice changing results from the CATNON trial will most likely require adaption of the score.

Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.

Glioma is a lethal central nervous system tumor with poor patient survival prognosis. Because of the molecular heterogeneity, it is a challenge to precisely determine the type of the tumor and to choose the most effective treatment. Therefore, novel biomarkers are essential to improve the diagnosis and prognosis of glioma tumors. Class 3 semaphorin proteins (SEMA3) play an important role in tumor biology. SEMA3 transduce their signals by using neuropilin and plexin receptors, which functionally interact with the vascular endothelial growth factor-mediated signaling pathways. Therefore, the aim of this study was to explore the potential of SEMA3 signaling molecules for prognosis of glioma patient survival. The quantitative real-time PCR method was used to evaluate mRNA expression of SEMA3(A-G) , neuropilins ( NRP1 and NRP2 ), plexins ( PLXNA2 and PLXND1 ), cadherins ( CDH1 and CDH2 ), integrins ( ITGB1, ITGB3, ITGA5, and ITGAV ), VEGFA and KDR genes in 59 II-IV grade glioma tissues. Seven genes significantly associated with patient overall survival were used for multi-biomarker construction, which showed 64%, 75%, and 68% of accuracy of predicting the survival of 1-, 2-, and 3-year glioma patients, respectively. The results suggest that the seven-gene signature could serve as a novel multi-biomarker for more accurate prognosis of a glioma patient's outcome.

Background: Due to their rarity, the clinicopathological characteristics and prognostic factors of spinal cord gliomas are still unclear. Here, we aimed to clarify these issues in a cohort of 108 spinal cord astrocytomas., Methods: We characterized the clinicopathological characteristics, including 2016 World Health Organization (WHO) grade, age, sex, location, segment length, resection, pre- and postsurgery, Modified McCormick Scale (MMS), radio- and chemotherapy, and Ki-67 and H3 K27M mutations, in 108 spinal cord astrocytomas through heatmaps. The Cox regression analysis and Kaplan-Meier curves were used to study the prognostic value of these clinicopathological features., Results: There are a total 38 H3 K27M-mutant tumors, including 31 cases with histological grade II/III tumors. The age of low-grade astrocytoma patients (WHO grade I/II, n = 54) was significantly younger (27.0 vs 35.5 years, P = .001) than those with high-grade tumors (WHO grade III/IV, n = 54). All patients underwent surgical resection with neurophysiological monitoring, and the surgery did not result in significant changes in MMS. The presurgery MMS was associated with overall survival in the high-grade subgroup (P = .008) but not in the low-grade subgroup (P = .312). While, the high content of resection improved the survival of only patients with low-grade astrocytomas (P = .016) but not those with high-grade astrocytomas (P = .475). Both the low-grade and high-grade astrocytomas had no obvious benefit from neither adjuvant chemotherapy nor radiotherapy (all P > .05)., Conclusions: We characterized the clinicopathological characteristics and their prognostic values in 108 spinal cord astrocytomas, which could help with evidence-based management of spinal cord astrocytomas., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The aim of this study is to evaluate the survival rate and prognostic factors of anaplastic gliomas according to the 2016 World Health Organization classification, including extent of resection (EOR) as measured by contrast-enhanced T1-weighted magnetic resonance imaging (MRI) and the T2-weighted MRI., Materials and Methods: The records of 113 patients with anaplastic glioma who were newly diagnosed at our institute between 2000 and 2013 were retrospectively reviewed. There were 62 cases (54.9%) of anaplastic astrocytoma, isocitrate dehydrogenase (IDH) wild-type (AAw), 18 cases (16.0%) of anaplastic astrocytoma, IDH-mutant, and 33 cases (29.2%) of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted., Results: The median overall survival (OS) was 48.4 months in the whole anaplastic glioma group and 21.5 months in AAw group. In multivariate analysis, age, preoperative Karnofsky Performance Scale score, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, postoperative tumor volume, and EOR measured from the T2 MRI sequence were significant prognostic factors. The EOR cut-off point for OS measured in contrast-enhanced T1-weighted MRI and T2-weighted MRI were 99.96% and 85.64%, respectively., Conclusion: We found that complete resection of the contrast-enhanced portion (99.96%) and more than 85.64% resection of the non-enhanced portion of the tumor have prognostic impacts on patient survival from anaplastic glioma.

Background: Pleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question., Methods: The National Cancer Database (NCDB) was used to identify adult patients (age ≥ 18 years old) diagnosed with histologically confirmed grade II PXA (2004-2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model., Results: A total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3 %) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (>128.6 months, p < 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR] = 4.28, 95 % confidence interval [CI] = 1.77-10.38, p = .0013). Patients ≥65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54-4.16, p = .006) and had a decreased median OS (26.0 months)., Conclusion: In adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

This study aimed to identify the elderly generation with the worst prognoses for high-grade astrocytoma and find independent predictors of good outcomes. We conducted a retrospective analysis of 91 patients, ≥65 years old, with anaplastic astrocytoma or glioblastoma. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using log-rank test or multivariate Cox regression analysis. We included 21 (23%) and 70 (77%) patients aged 65-69 years and ≥70 years. In the two generations, significant differences were found in the Charlson comorbidity index, extent of resection, chemoradiotherapy (CRT) as adjuvant therapy, and radiation dose (all P < 0.05). The median PFS was 9.9 and 6.9 months in patients aged 65-69 and ≥70 years (P = 0.10). The median OS was 22.8 and 11.6 months in patients aged 65-69 and ≥70 years (P = 0.009). In the multivariate analyzes in patients ≥70 years, only postoperative Karnofsky performance status (KPS) scores ≥70 were significantly related to prolonged PFS (hazard ratio [HR]: 0.48, P = 0.04), and postoperative KPS, CRT as adjuvant therapy, and salvage therapy were significantly related to prolonged OS (HR: 0.45, P = 0.03, HR: 0.38, P = 0.002, and HR: 0.43, P = 0.01, respectively). In conclusion, in patients ≥70 with high-grade astrocytoma, OS was significantly shorter compared to those aged 65-69. Postoperative KPS score was significantly related to prolonged PFS and OS. Postoperative CRT and salvage therapy at recurrence may be effective in the selected elderly., Competing Interests: The authors declare no conflicts of interest.

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8 +  T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

Recent studies showed that peroxisome proliferator-activated receptors (PPARs) had effects on the progression of multiple tumors, but the role of PPARD and PPARG in glioma remains poorly understand. We conducted a case-control study to investigate the association of polymorphisms in PPARD and PPARG with glioma risk and prognosis in the Chinese Han population. Seven polymorphisms (PPARD: rs2016520, rs67056409, rs1053049 and rs2206030; PPARG: rs2920503, rs4073770 and rs1151988) were genotyped using the Agena MassARRAY system in 568 glioma patients and 509 healthy controls. The odd ratios (OR) and 95% confidence interval (CI) were calculated to assess the association of PPARD and PPARG polymorphisms with glioma risk. The Multifactor dimensionality reduction (MDR) method was used to analysis interactions of genetic polymorphisms on glioma risk. Then, we conducted log-rank test, Kaplan-Meier analysis and Cox regression model to evaluate the relationship of PPARD and PPARG polymorphisms with glioma prognosis. We found PPARD polymorphisms (rs2016520, rs67056409, rs1053049) were significantly associated with glioma risk in multiple models (P < 0.05). Stratified analysis showed rs2016520, rs67056409, rs1053049 of PPARD significantly decreased risk of glioma in the subgroup of age > 40 and astrocytoma (P < 0.05). For male, PPARD rs1053049 had a strong relationship with glioma risk in allele (P = 0.041), dominant (P = 0.040) and additive (P = 0.040) models. The effect of PPARG rs2920503 on glioma risk was related to glioma grade (P < 0.05). MDR showed that a seven-locus model was the best polymorphisms interaction pattern. Moreover, surgery and chemotherapy had strongly impact on overall survival and progression free survival of glioma patients. Our findings suggested that PPARD and PPARG polymorphisms were associated with glioma risk and prognosis in the Chinese Han population, and further studies are need to confirm our results.

Purpose: The WHO classification for IDH-mutant grade II and grade III astrocytoma may not be as prognostically meaningful as expected. We aimed to develop a novel classification system based on the DNA damage response signature., Methods: We developed the gene signature of DNA damage response with 115 samples from The Cancer Genome Atlas (TCGA) database. The dataset from Chinese Glioma Genome Atlas (CGGA) database with 41 samples was used as the validation set. Lasso Cox regression model was applied for selection of the best signature. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis were implemented to reveal its biological phenotype., Results: A two-gene DNA damage response signature (RAD18, MSH2) was developed using the lasso Cox regression model based on the TCGA dataset. Its prognostic efficiency was validated in the CGGA cohort. The result of Cox regression analysis showed that the signature has a better predictive accuracy than the WHO grade. The risk score was an independent prognostic factor for the overall survival of the IDH-mutant grade II and grade III astrocytoma. GSEA and GO analysis confirmed enhanced processes related to DNA damage response in high-risk group., Conclusion: We developed a two-gene signature which can effectively predict the prognosis of patients with IDH-mutant grade II and grade III astrocytoma. It suggests a novel classification of astrocytoma with better prognostic accuracy based on the expression of DNA damage response genes.

Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm 2 , and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.

Serum levels of glial fibrillar acidic protein (GFAP) were analyzed in 317 patients with primary and metastatic tumors of the brain, 78 patients with neurological diseases, and 66 normal subjects. A significant increase in the basal level of GFAP was typical of patients with glioblastomas in comparison with other groups (patients with astrocytomas, cerebral metastases, benign tumors, non-tumor diseases, and healthy subjects). An association of GFAP levels with unfavorable prognosis of overall survival in patients with glioblastoma was revealed. The data attest to high specificity and sensitivity of GFAP as a biochemical marker of glioblastoma.

Purpose: The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype., Methods: The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT., Results: A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6‑year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p < 0.001). There was a component of local relapse in 63%, of marginal relapse in 19% and of distant relapse in 37% of relapses. Isolated local, marginal and distant relapse was evident in 51, 9 and 22%, respectively. A distant relapse pattern was more frequent in IDHmut compared to IDHwt patients (26% vs. 45%, p = 0.005), especially within the first 2 years post-IMRT. In multivariate analysis, distant relapse remained associated with AAmut (p < 0.002) and delayed IMRT until the second relapse (p < 0.001)., Conclusion: Although patients with IDH-mutated AG have improved outcomes, there was a higher proportion of distant relapses occurring during the 2 years after IMRT.

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.

High-grade astrocytomas are some of the most common and aggressive brain cancers, whose signs and symptoms are initially non-specific. Up to the present date, there are no diagnostic tools to observe the early onset of the disease. Here, we analyzed the combination of blood serum proteins, which may play key roles in the tumorigenesis and the progression of glial tumors. Fifty-nine astrocytoma patients and 43 control serums were analyzed using Custom Human Protein Antibody Arrays, including ten targets: ANGPT1, AREG, IGF1, IP10, MMP2, NCAM1, OPN, PAI1, TGFβ1, and TIMP1. The decision tree analysis indicates that serums ANGPT1, TIMP1, IP10, and TGFβ1 are promising combinations of targets for glioma diagnostic applications. The accuracy of the decision tree algorithm was 73.5% (75/102), which correctly classified 79.7% (47/59) astrocytomas and 65.1% (28/43) healthy controls. The analysis revealed that the relative value of osteopontin (OPN) protein level alone predicted the 12-month survival of glioblastoma (GBM) patients with the specificity of 84%, while the inclusion of the IP10 protein increased model predictability to 92.3%. In conclusion, the serum protein profiles of ANGPT1, TIMP1, IP10, and TGFβ1 were associated with the presence of astrocytoma independent of its malignancy grade, while OPN and IP10 were associated with GBM patient survival., Competing Interests: The authors declare no conflict of interest.

Background: Pineal region tumors represent challenging surgical lesions with wide ranges of survival reported in different surgical series. In this article, we emphasize the role of complete microsurgical resection (CMR) to obtain a favorable long-term outcome of pineal region tumors., Methods: We report a retrospective study of pineal region tumors operated on in Helsinki Neurosurgery between 1997 and 2015. Information was obtained from the hospital records, and an evaluation of the Finnish population register was conducted in July 2018 to determine the current status of the patients., Results: A total of 76 pineal region tumors were operated on. The survival was 62% at a mean follow-up of 125 ± 105 months (range, 0-588 months), and the disease-related mortality was limited to 14 patients (18.4%). Up to July 2018, 29 patients had died. Two patients died 1 and 3 months after surgery of delayed thalamic infarctions, 12 patients of disease progression, and 15 had non-disease-related deaths. Only 1 patient was lost in the long-term follow-up. Ten of 14 disease-related deaths occurred during the first 5 years of follow-up: 5 diffuse gliomas, 3 germ cell tumors, 1 grade II-III pineal parenchymal tumor of intermediate differentiation, and 1 meningioma. CMR was linked to better tumor-free survival and long-term survival, with the exception of diffuse gliomas., Conclusions: CMR, in the setting of a multidisciplinary management of pineal region tumors, correlates with favorable survival and with minimal mortality. Surgically treated grade II-IV gliomas constitute a particular group with high mortality within the first 5 years independently of the microsurgical resection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: This study was to investigate the relationship of diffusion features with molecule information, and then predict grade and survival in lower-grade gliomas., Methods: 65 patients with primary lower-grade gliomas (WHO Grade II & III) who underwent conventional MRI and diffusion tensor imaging were retrospectively studied. The tumor region was automatically segmented into contrast-enhancing tumor, non-enhancing tumor, edematous and necrotic volumes. Diffusion features, including fractional anisotropy (FA), axial diffusivity, radial diffusivity and apparent diffusion coefficient (ADC), were extracted from each volume using histogram analysis. To estimate molecule biomarkers and predict clinical characteristics of grade and survival, support vector machine, generalized linear model, logistic regression and Cox regression were performed on the related features., Results: The diffusion features in non-enhancing tumor volume showed differences between isocitrate dehydrogenase mutant and wild-type gliomas. And the mean accuracy of support vector machine classifiers was 0.79. Ki-67 labeling index was correlated with these features, which were combined to significantly estimate Ki-67 expression level ( r = 0.657, p < 0.001). These features also showed differences between Grade II and III gliomas. A combination of them for grade classification resulted in an area under the curve of 0.914 (0.857-0.971). Mean FA and fifth percentile of ADC were independently associated with overall survival, with lower FA and higher ADC showing better survival outcome., Conclusion: In lower-grade gliomas, multiparametric and multiregional diffusion features could help predict molecule information, histological grade and survival., Advances in Knowledge: The multi parametric diffusion features in non-enhancing tumor were associated with molecule information, grade and survival in lower-grade gliomas.