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BACKGROUND: After potentially curative cancer treatment, patients may receive procedures for routine monitoring for recurrence or for evaluation of symptoms or signs. OBJECTIVE: We sought to characterize surveillance care guideline-recommended and other procedures performed in cancer survivors according to routine versus diagnostic indications. METHODS: This was a retrospective cohort study of paper and electronic medical records between 1990 and 2000 from a large midwestern U.S. integrated health care delivery system of 500 patients who received curative treatment of breast, colorectal, endometrial, lung, or prostate cancer. Our measures were the indications for potential surveillance procedures as recommended by clinical practice guidelines or otherwise. RESULTS: Among 14,670 procedures of interest received, 82.0% were performed for routine surveillance, whereas 10.6% were performed for diagnostic indications and 7.3% had indeterminate indications. Office visits most were often delivered for routine indications (91.6%), followed by guideline recommended tests for local recurrence (range 74.1-98.4%, depending on the specific test and cancer). In general, tests that were not recommended in established guidelines were for the purposes of detection of metastatic recurrence and were less often delivered for routine indications (overall frequency 59.2%, P<0.0001 compared with recommended testing). CONCLUSION: Office visits and testing for local recurrence of cancer generally are performed for routine surveillance, regardless of recommendation by practice guidelines. Because procedures not recommended by practice guidelines were more often for diagnostic purposes, classification of patients as undergoing intensive surveillance may be misleading and may require record review to confirm. [ABSTRACT FROM AUTHOR]

BACKGROUND: Community surveys have assessed post-traumatic stress disorder (PTSD) in relation to traumatic events designated by respondents as the worst they have ever experienced. An assessment of PTSD in relation to all reported traumas would impose too great a burden on respondents, a considerable proportion of whom report multiple traumas. The 'worst event' method is efficient for identifying persons with PTSD, but may overestimate the conditional probability of PTSD associated with the entire range of PTSD-level traumas. In this report, we evaluate this potential bias. METHOD: The Detroit Area Survey of Trauma (n = 2181) estimated the PTSD risk from two samples of traumas: (1) a representative sample of traumas formed by selecting a random trauma from each respondent's list of traumas; and (2) traumas designated by respondents as the worst (the standard method). RESULTS: Both estimation methods converged on key findings, including identifying trauma types with the highest probability of PTSD and sex differences in the risk of PTSD. Compared to the random events, the 'worst event' method yielded a moderately higher conditional probability for PTSD (0.136 v. 0.092). The bias was due almost entirely to the deviation of the distribution of the worst events from expected values, if all event types had equal prior selection probabilities. Direct adjustment, setting the distribution equal to expected values and applying the observed probabilities of PTSD associated with individual event types brought the estimate close to the unbiased estimate, based on the randomly selected traumas. CONCLUSIONS: Only the 'worst event' method can be used as a short-cut to assessing all traumas. The bias in the estimated risk of PTSD is modest and is attenuated by direct adjustment. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS, which ultimately progresses to secondary progressive MS (SPMS), while primary progressive MS (PPMS) is a type of MS that worsens gradually over time without remissions. There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course, or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GC-GC-MS platform to identify altered metabolites between RRMS, PPMS, and HS. We profiled 235 metabolites in the serum of patients with RRMS (n = 41), PPMS (n = 31), and HS (n = 91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p < 0.05 (false-discovery rate [FDR] = 0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p < 0.05 (FDR = 0.2). Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p < 0.05): (1) galactose metabolism; (2) amino sugar and nucleotide sugar metabolism; (3) phenylalanine, tyrosine, and tryptophan biosynthesis; and (4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) ( p = 0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) ( p = 0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells ( p = 0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS ( p = 0.03). Overall, our study suggests that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for constructing a metabolite panel for progressive autoimmune diseases such as MS.

Purpose: Patient-reported outcome measures (PROMs) provide a direct report of the patient's perspective, complementary to clinician assessment. Currently, understanding the real-time changes in PROM scores near the end of life remains limited. This study evaluated differences in mean PROM scores between patients with cancer within 6 months before death compared with surviving patients with cancer., Methods: This retrospective case-control study uses the National Institutes of Health's Patient-Reported Outcomes Measurement Information System computer adaptive testing instruments to assess pain interference, physical function, fatigue, and depression. Patients dying within 6 months of PROM completion were selected as cases and matched to controls 1:3 by age at PROM completion, sex, cancer disease site, and cancer stage at diagnosis. Generalized estimating equation models assessed the difference in mean PROM score in cases compared with controls., Results: A total of 461 cases and 1,270 controls from September 2020 to January 2023 were included. After adjustment for ethnicity, Charlson Comorbidity Index, and census tract median household income, significant differences in mean scores were demonstrated. Physical function domain showed the largest difference, with cases averaging 6.52 points lower than controls (95% CI, -8.25 to -4.80). Fatigue and pain interference domains showed a rise in PROMs scores by 4.83 points (95% CI, 2.94 to 6.72) and 4.33 points (95% CI, 2.53 to 6.12), respectively., Conclusion: Compared with controls, patients dying within 6 months of PROM completion demonstrated worse PROM scores in the four domains assessed. These findings suggest the utility of routinely collected PROMs as a real-time indicator of the terminal stage of life among patients with cancer to allow for earlier intervention with supportive oncology services.

Background and Purpose: Understanding sex-based differences in patients with glioblastoma is necessary for accurate personalized treatment planning to improve patient outcomes. Our purpose was to investigate sex-specific differences in molecular, clinical, and radiologic tumor parameters, as well as survival outcomes in patients with glioblastoma, isocitrate dehydrogenase-1 wild-type ( IDH1 -WT), grade 4., Materials and Methods: Retrospective data of 1832 patients with glioblastoma, IDH1 -WT with comprehensive information on tumor parameters was acquired from the Radiomics Signatures for Precision Oncology in Glioblastoma consortium. Data imputation was performed for missing values. Sex-based differences in tumor parameters, such as age, molecular parameters, preoperative Karnofsky performance score (KPS), tumor volumes, epicenter, and laterality were assessed through nonparametric tests. Spatial atlases were generated by using preoperative MRI maps to visualize tumor characteristics. Survival time analysis was performed through log-rank tests and Cox proportional hazard analyses., Results: Glioblastoma was diagnosed at a median age of 64 years in women compared with 61.9 years in men (false discovery rate [FDR] = 0.003). Men had a higher KPS (above 80) as compared with women (60.4% women versus 69.7% men, FDR = 0.044). Women had lower tumor volumes in enhancing (16.7 cm 3 versus 20.6 cm 3 in men, FDR = 0.001), necrotic core (6.18 cm 3 versus 7.76 cm 3 in men, FDR = 0.001), and edema regions (46.9 cm 3 versus 59.2 cm 3 in men, FDR = 0.0001). The right temporal region was the most common tumor epicenter in the overall population. Right as well as left temporal lobes were more frequently involved in men. There were no sex-specific differences in survival outcomes and mortality ratios. Higher age, unmethylated O6-methylguanine-DNA-methyltransferase promoter and undergoing subtotal resection increased the mortality risk in both men and women., Conclusions: Our study demonstrates significant sex-based differences in clinical and radiologic tumor parameters of patients with glioblastoma. Sex is not an independent prognostic factor for survival outcomes and the tumor parameters influencing patient outcomes are identical for men and women., (© 2024 by American Journal of Neuroradiology.)

Background Recent advancements, including image processing capabilities, present new potential applications of large language models such as ChatGPT (OpenAI), a generative pretrained transformer, in radiology. However, baseline performance of ChatGPT in radiology-related tasks is understudied. Purpose To evaluate the performance of GPT-4 with vision (GPT-4V) on radiology in-training examination questions, including those with images, to gauge the model's baseline knowledge in radiology. Materials and Methods In this prospective study, conducted between September 2023 and March 2024, the September 2023 release of GPT-4V was assessed using 386 retired questions (189 image-based and 197 text-only questions) from the American College of Radiology Diagnostic Radiology In-Training Examinations. Nine question pairs were identified as duplicates; only the first instance of each duplicate was considered in ChatGPT's assessment. A subanalysis assessed the impact of different zero-shot prompts on performance. Statistical analysis included χ 2 tests of independence to ascertain whether the performance of GPT-4V varied between question types or subspecialty. The McNemar test was used to evaluate performance differences between the prompts, with Benjamin-Hochberg adjustment of the P values conducted to control the false discovery rate (FDR). A P value threshold of less than.05 denoted statistical significance. Results GPT-4V correctly answered 246 (65.3%) of the 377 unique questions, with significantly higher accuracy on text-only questions (81.5%, 159 of 195) than on image-based questions (47.8%, 87 of 182) (χ 2 test, P < .001). Subanalysis revealed differences between prompts on text-based questions, where chain-of-thought prompting outperformed long instruction by 6.1% (McNemar, P = .02; FDR = 0.063), basic prompting by 6.8% ( P = .009, FDR = 0.044), and the original prompting style by 8.9% ( P = .001, FDR = 0.014). No differences were observed between prompts on image-based questions with P values of .27 to >.99. Conclusion While GPT-4V demonstrated a level of competence in text-based questions, it showed deficits interpreting radiologic images. © RSNA, 2024 See also the editorial by Deng in this issue.

Data-intensive research continues to expand with the goal of improving healthcare delivery, clinical decision-making, and patient outcomes. Quantitative scientists, such as biostatisticians, epidemiologists, and informaticists, are tasked with turning data into health knowledge. In academic health centres, quantitative scientists are critical to the missions of biomedical discovery and improvement of health. Many academic health centres have developed centralized Quantitative Science Units which foster dual goals of professional development of quantitative scientists and producing high quality, reproducible domain research. Such units then develop teams of quantitative scientists who can collaborate with researchers. However, existing literature does not provide guidance on how such teams are formed or how to manage and sustain them. Leaders of Quantitative Science Units across six institutions formed a working group to examine common practices and tools that can serve as best practices for Quantitative Science Units that wish to achieve these dual goals through building long-term partnerships with researchers. The results of this working group are presented to provide tools and guidance for Quantitative Science Units challenged with developing, managing, and evaluating Quantitative Science Teams. This guidance aims to help Quantitative Science Units effectively participate in and enhance the research that is conducted throughout the academic health centre-shaping their resources to fit evolving research needs., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors have no conflicts of interest to declare.

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype., Significance: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma., (©2023 The Authors; Published by the American Association for Cancer Research.)

X-linked adrenoleukodystrophy is a severe demyelinating neurodegenerative disease mainly affecting males. The severe cerebral adrenoleukodystrophy (cALD) phenotype has a poor prognosis and underlying mechanism of onset and progression of neuropathology remains poorly understood. In this study we aim to integrate metabolomic and microRNA (miRNA) datasets to identify variances associated with cALD. Postmortem brain tissue samples from five healthy controls (CTL) and five cALD patients were utilized in this study. White matter from ALD patients was obtained from normal-appearing areas, away from lesions (NLA) and from the periphery of lesions- plaque shadow (PLS). Metabolomics was performed by gas chromatography coupled with time-of-flight mass spectrometry and miRNA expression analysis was performed by next generation sequencing (RNAseq). Principal component analysis revealed that among the three sample groups (CTL, NLA and PLS) there were 19 miRNA, including several novel miRNA, of which 17 were increased with disease severity and 2 were decreased. Untargeted metabolomics revealed 13 metabolites with disease severity-related patterns with 7 increased and 6 decreased with disease severity. Ingenuity pathway analysis of differentially altered metabolites and miRNA comparing CTL with NLA and NLA with PLS, identified several hubs of metabolite and signaling molecules and their upstream regulation by miRNA. The transomic approach to map the crosstalk between miRNA and metabolomics suggests involvement of specific molecular and metabolic pathways in cALD and offers opportunity to understand the complex underlying mechanism of disease severity in cALD., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients., (© 2023. Springer Nature Limited.)

Purpose: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas., Methods: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS)., Results: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS., Conclusion: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) ( r 2  = 0.83, p  < 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r 2  = 0.82, p  < 0.00001), hypoxanthine ( r 2  = 0.82, p  < 0.00001), as well as miRNA-432-5p ( r 2  = 0.68, p  < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity., Competing Interests: Potential competing interest for Ali Fatemi: Paid member of drug safety monitoring board – Bluebird Bio, Co‐inventor of Compositions and methods for treatment of peroxisomal disorders and leukodystrophies, Patent #US20170119899A1. Potential competing interest for Bela Rui Turk: Co‐inventor of Compositions and methods for treatment of peroxisomal disorders and leukodystrophies, Patent #US20170119899A1. Laila Marie Poisson, Christina Linnea Nemeth, Jordan Goodman, Richard Owen Jones, and Jordan Goodman have no relevant potential competing interests to report., (© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases., Methods: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET., Results: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets., Conclusions: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy age-matched controls. Of 632 known metabolites detected, 60 were significantly altered in RRMS. Bioinformatics analysis identified an altered metabotype in patients with RRMS, represented by four changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these four pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient-derived peripheral blood mononuclear cells showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the antiinflammatory phenotype of monocytes/macrophage in the central nervous system. Our study provided a proof of principle for how a blood-based metabolomic approach using patient samples could lead to the identification of a therapeutic target for developing potential therapy.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression., Competing Interests: Declaration of interests R.G.W.V. is a co-founder of Boundless Bio and a consultant for Stellanova Therapeutics. M.K. has received research funding from AbbVie and Bristol Myers Squibb, and he is on the advisory board for Janssen; he has received honoraria from the Jackson Laboratory. D.R.O. has received funding from Integra and Agios. F.P.B. has performed consulting for Bristol Myers Squibb. M.W. has received research grants from AbbVie, Adastra, Apogenix, Merck, Sharp & Dohme, Novocure, and Quercis and honoraria for lectures or advisory board participation or consulting from AbbVie, Adastra, Basilea, Bristol Meyer Squibb, Celgene, Medac, Merck, Sharp & Dohme, Merck, Nerviano Medical Sciences, Novartis, Orbus, Philogen, Roche, Tocagen, and yMabs. A.M.E.W. reported receiving institutional financial support for an advisory role from Polyphor, IPSEN, Karyopharm, and Novartis; unrestricted research grants from IPSEN and Novartis; and study budgets from AbbVie, BMS, Genzyme, Karyopharm Therapeutics, and Roche, all outside the submitted work. H.K.G. has performed consulting for AbbVie, and he is a member of the speaker bureau for AbbVie and Igynta. K.P. is a scientific advisory board member and owns stock in Cue BioPharma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.

Background: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches., Methods: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients., Results: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment)., Conclusions: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups., Methods: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings., Results: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors., Conclusions: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Examine the effect of a universal facemask policy for healthcare workers (HCW) and incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity., Methods: Daily number of symptomatic HCW tested, SARS-CoV-2 positivity rates, and HCW job-descriptions were collected pre and post Universal HCW facemask policy (March 26, 2020). Multiple change point regression was used to model positive-test-rate data. SARS-CoV-2 testing and positivity rates were compared for pre-intervention, transition, post-intervention, and follow-up periods., Results: Between March 12 and August 10, 2020, 19.2% of HCW were symptomatic for COVID-19 and underwent SARS-CoV-2 testing. A single change point was identified ∼March 28-30 (95% probability). Before the change point, the odds of a tested HCW having a positive result doubled every 4.5 to 7.5 days. Post-change-point, the odds of a tested HCW having a positive result halved every 10.5 to 13.5 days., Conclusions: Universal facemasks were associated with reducing HCW's risk of acquiring COVID-19., Competing Interests: Wang, O’Neill, Zervos, McKinnon, Allard, Alangaden, Schultz, Poisson, Chu, Kalkanis, and Suleyman have no relationships/conditions/circumstances that present potential conflict of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Background: Clinically relevant glioma subtypes, such as the glioma-CpG island methylator phenotype (G-CIMP), have been defined by epigenetics. In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated. Functional associations of lncRNAs with mRNAs and miRNAs were examined to hypothesize influencing factors of the aggressive phenotype., Methods: RNA-seq data on 250 samples from TCGA's Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes. Functional interpretation of the differential lncRNAs was performed by Ingenuity Pathway Analysis. Spearman rank order correlation estimates between lncRNA, miRNA, and mRNA nominated differential lncRNA with a likely miRNA sponge function., Results: We identified 4371 differentially expressed features (mRNA = 3705; lncRNA = 666; FDR ≤ 5%). From these, the protein-coding gene TP53 was identified as an upstream regulator of differential lncRNAs PANDAR and PVT1 (p = 0.0237) and enrichment was detected in the "development of carcinoma" (p = 0.0176). Two lncRNAs (HCG11, PART1) were positively correlated with 342 mRNAs, and their correlation estimates diminish after adjusting for either of the target miRNAs: hsa-miR-490-3p, hsa-miR-129-5p. This suggests a likely sponge function for HCG11 and PART1., Conclusions: These findings identify differential lncRNAs with oncogenic features that are associated with G-CIMP phenotypes. Further investigation with controlled experiments is needed to confirm the molecular relationships.

Background: Public Health policies related to social distancing efforts during the COVID-19 pandemic helped slow the infection rate. However, individual-level factors associated with social distancing are largely unknown. We sought to examine social distancing during the COVID-19 pandemic in Michigan, an infection "hotspot" state in the United States early in the pandemic., Methods: Two surveys were distributed to Michigan residents via email lists and social media following COVID-19 related state mandates in March; 45,691 adults responded to the first survey and 8512 to the second. Staying home ≥ 3 out of 5 previous days defined having more social distancing. Logistic regression models were used to examine potential factors associated with more social distancing., Results: Most respondents were women (86% in Survey 1, 87% in Survey 2). In Survey 1, 63% reported more social distancing, increasing to 78% in Survey 2. Female sex and having someone (or self) sick in the home were consistently associated with higher social distancing, while increasing age was positively associated in Survey 1 but negatively associated in Survey 2. Most respondents felt social distancing policies were important (88% in Survey 1; 91% in Survey 2)., Conclusions: Michiganders responding to the surveys were both practicing and supportive of social distancing. State-level executive orders positively impacted behaviors early in the COVID-19 pandemic in Michigan. Additional supports are needed to help vulnerable populations practice social distancing, including older individuals.

Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.

(1) Background: Outcomes with coronavirus disease 2019 (COVID-19) have been worse in those with comorbidities and amongst minorities. In our study, we describe outcomes amongst cancer patients in Detroit, a major COVID-19 hotspot with a predominant inner-city population. (2) Methods: We retrospectively analyzed 85 patients with active invasive cancers who were infected with COVID-19. The primary outcome was death or transition to hospice. (3) Results: The majority were males (55.3%, n = 47), ≤70 years old (58.5%, n = 50), and African Americans (65.5%, n = 55). The most common primary site was prostate (18.8%, n = 16). Inpatient admission was documented in 85.5% (n = 73), ICU admission in 35.3% (n = 30), and primary outcome in 43.8% (n = 32) of hospitalized patients. On a multivariate analysis, factors associated with increased odds of a primary outcome included an age of >70 years versus ≤70 years (OR 4.7, p = 0.012) and of male gender (OR 4.8, p = 0.008). Recent cancer-directed therapy was administered in 66.7% (n = 20) of ICU admissions versus 39.5% (n = 17) of general floor admissions (Chi-square p -value of 0.023). (4) Conclusions: High rates of mortality/transition to hospice and ICU utilization were noted amongst our patients with active invasive cancer, following a COVID-19 infection. Men and those of >70 years of age had a greater than four-fold increase in odds of death or transition to hospice.

Background and Purpose: Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories., Materials and Methods: We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status., Results: For isocitrate dehydrogenase ( IDH ) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P  < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P  < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P  = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P  = .013), margins ( P  = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P  = .030) were associated with overall survival. For IDH -mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P  = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P  = .042) were associated with overall survival., Conclusions: MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas., (© 2020 by American Journal of Neuroradiology.)

Purpose of Review: Real-world data (RWD) applications in healthcare that support learning health systems and pragmatic clinical trials are gaining momentum, largely due to legislation supporting real-world evidence (RWE) for drug approvals. Clinical notes are thought to be the cornerstone of RWD applications, particularly for conditions with limited effective treatments, extrapolation of treatments from other conditions, or heterogenous disease biology and clinical phenotypes., Recent Findings: Here, we discuss current issues in applying RWD captured at the point-of-care and provide a framework for clinicians to engage in RWD collection. To achieve clinically meaningful results, RWD must be reliably captured using consistent terminology in the description of our patients. RWD complements traditional clinical trials and research by informing the generalizability of results, generating new hypotheses, and creating a large data network for scientific discovery. Effective clinician engagement in the development of RWD applications is necessary for continued progress in the field.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear 1,2 . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Background: Oropharyngeal cancer survivors experience difficulty returning to work after treatment. To better understand specific barriers to returning to work, we investigated factors associated with discontinuing employment among older and working-age survivors., Methods: The sample included 675 oropharyngeal cancer survivors (median: 6 years posttreatment) diagnosed from 2000 to 2013 and employed at diagnosis. Relative risk models were constructed to examine the independent associations of demographic and health factors, and symptom experiences per the MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) with posttreatment employment, overall and by age (<60 years vs ≥60 years at survey)., Results: Symptom interference was not statistically significantly associated with posttreatment employment status among respondents ≥60 years. Among working-age respondents <60 years, symptom interference was strongly associated with posttreatment employment., Conclusions: Efforts to assess and lessen symptom burden in working-age survivors should be evaluated as approaches to support regaining core functions needed for continued employment., (© 2019 Wiley Periodicals, Inc.)

Purpose: There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features., Methods: Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis., Results: There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393)., Conclusions: Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS. Graphical Abstract Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH -mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine., Competing Interests: The authors declare no competing interests.

Background and Purpose: Few studies have shown MR imaging features and ADC correlating with molecular markers and survival in patients with glioma. Our purpose was to correlate MR imaging features and ADC with molecular subtyping and survival in adult diffuse gliomas., Materials and Methods: Presurgical MRIs and ADC maps of 131 patients with diffuse gliomas and available molecular and survival data from The Cancer Genome Atlas were reviewed. MR imaging features, ADC (obtained by ROIs within the lowest ADC area), and mean relative ADC values were evaluated to predict isocitrate dehydrogenase ( IDH ) mutation, 1p/19q codeletion status, MGMT promoter methylation, and overall survival., Results: IDH wild-type gliomas tended to exhibit enhancement, necrosis, and edema; >50% enhancing area ( P < .001); absence of a cystic area ( P = .013); and lower mean relative ADC (median, 1.1 versus 1.6; P < .001) than IDH -mutant gliomas. By means of a cutoff value of 1.08 for mean relative ADC, IDH -mutant and IDH wild-type gliomas with lower mean relative ADC (<1.08) had poorer survival than those with higher mean relative ADC (median survival time, 24.2 months; 95% CI, 0.0-54.9 months versus 62.0 months; P = .003; and median survival time, 10.4 months; 95% CI, 4.4-16.4 months versus 17.7 months; 95% CI, 11.6-23.7 months; P = .041, respectively), regardless of World Health Organization grade. Median survival of those with IDH -mutant glioma with low mean relative ADC was not significantly different from that in those with IDH wild-type glioma. Other MR imaging features were not statistically significant predictors of survival., Conclusions: IDH wild-type glioma showed lower ADC values, which also correlated with poor survival in both IDH -mutant and IDH wild-type gliomas, irrespective of histologic grade. A subgroup with IDH -mutant gliomas with lower ADC had dismal survival similar to that of those with IDH wild-type gliomas., (© 2018 by American Journal of Neuroradiology.)

Background and Purpose: The World Health Organization has recently placed new emphasis on the integration of genetic information for gliomas. While tissue sampling remains the criterion standard, noninvasive imaging techniques may provide complimentary insight into clinically relevant genetic mutations. Our aim was to train a convolutional neural network to independently predict underlying molecular genetic mutation status in gliomas with high accuracy and identify the most predictive imaging features for each mutation., Materials and Methods: MR imaging data and molecular information were retrospectively obtained from The Cancer Imaging Archives for 259 patients with either low- or high-grade gliomas. A convolutional neural network was trained to classify isocitrate dehydrogenase 1 ( IDH1 ) mutation status, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase ( MGMT ) promotor methylation status. Principal component analysis of the final convolutional neural network layer was used to extract the key imaging features critical for successful classification., Results: Classification had high accuracy: IDH1 mutation status, 94%; 1p/19q codeletion, 92%; and MGMT promotor methylation status, 83%. Each genetic category was also associated with distinctive imaging features such as definition of tumor margins, T1 and FLAIR suppression, extent of edema, extent of necrosis, and textural features., Conclusions: Our results indicate that for The Cancer Imaging Archives dataset, machine-learning approaches allow classification of individual genetic mutations of both low- and high-grade gliomas. We show that relevant MR imaging features acquired from an added dimensionality-reduction technique demonstrate that neural networks are capable of learning key imaging components without prior feature selection or human-directed training., (© 2018 by American Journal of Neuroradiology.)

Background and Purpose: Idiopathic intracranial hypertension is a complex neurologic disorder resulting from increased intracranial pressure. Our aim was to determine whether a correlation exists between the CSF pressure-volume relationship, specifically the craniospinal elastance and pressure-volume index, in patients with idiopathic intracranial hypertension and whether opening pressure affects this relationship., Materials and Methods: Lumbar punctures performed for suspected idiopathic intracranial hypertension from 2006 to 2017 were identified. Opening and closing pressures, CSF volume removed, and clinical diagnosis of idiopathic intracranial hypertension were obtained from the medical records. The craniospinal elastance (pressure change per milliliter of CSF removed) and pressure-volume index were calculated, and the Pearson correlation coefficients between both the craniospinal elastance and pressure-volume index and opening pressure were determined. Linear regression models of craniospinal elastance and the pressure-volume index and interaction terms with opening pressure were assessed for covariate influence on this association., Results: One hundred sixteen patients were included in the final analysis. The mean craniospinal elastance according to opening pressure group was 0.52 ± 0.18 for <20 cm H 2 O, 0.57 ± 0.20 for 20-29 cm H 2 O, 0.91 ± 0.28 for 30-39 cm H 2 O, and 1.20 ± 0.25 for ≥40 cm H 2 O. There was a positive linear association between opening pressure and craniospinal elastance with a 0.28 cm H 2 O/mL increase in craniospinal elastance (standard error = 0.03, P < .001) for every 10 cm H 2 O increase in opening pressure. Of the covariables analyzed, only age older than 50 years and total volume of CSF removed affected this association., Conclusions: As opening pressure increases, the craniospinal elastance increases in a linear fashion while the pressure-volume index decreases. Further studies are needed to determine whether these changes relate to the underlying pathophysiology of idiopathic intracranial hypertension or simply represent established CSF volume pressure dynamics., (© 2018 by American Journal of Neuroradiology.)

To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA was unevenly inherited by offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during GBM evolution, independently of chromosomal DNA alterations.

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes. Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database ( n = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2-FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort ( n = 82) was analyzed to validate the T2-FLAIR mismatch sign. Results: Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ κ = 0.234 (0.111-0.358)], T2-FLAIR mismatch sign [ κ = 0.728 (0.538-0.918)], lesion margins [ κ = 0.292 (0.135-0.449)], and peritumoral edema [ κ = 0.173 (0.096-0.250)]. All 15 cases that were positive for the T2-FLAIR mismatch sign were IDH -mutant, 1p/19q non-codeleted tumors ( P < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2-FLAIR mismatch sign [ κ = 0.747 (0.536-0.958)]; all 10 cases positive for the T2-FLAIR mismatch sign were IDH -mutant, 1p/19q non-codeleted tumors ( P < 0.00001; PPV = 100%, NPV = 76%). Conclusions: Among lower-grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH -mutant, 1p/19q non-codeleted molecular subtype. Clin Cancer Res; 23(20); 6078-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.

We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p < 0.05, false discovery rate <0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including α-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, including ω-3 and ω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite of ω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

In neurosurgical applications, a tool capable of distinguishing grey matter, white matter, and areas of tumor and/or necrosis in near-real time could greatly aid in tumor resection decision making. Raman spectroscopy is a non-destructive spectroscopic technique which provides molecular information about the tissue under examination based on the vibrational properties of the constituent molecules. With careful measurement and data processing, a spatial step and repeat acquisition of Raman spectra can be used to create Raman images. Forty frozen brain tissue sections were imaged in their entirety using a 300-µm-square measurement grid, and two or more regions of interest within each tissue were also imaged using a 25 µm-square step size. Molecular correlates for histologic features of interest were identified within the Raman spectra, and novel imaging algorithms were developed to compare molecular features across multiple tissues. In previous work, the relative concentration of individual biomolecules was imaged. Here, the relative concentrations of 1004, 1300:1344, and 1660 cm(-1), which correspond primarily to protein and lipid content, were simultaneously imaged across all tissues. This provided simple interpretation of boundaries between grey matter, white matter, and diseased tissue, and corresponded with findings from adjacent hematoxylin and eosin-stained sections. This novel, yet simple, multi-channel imaging technique allows clinically-relevant resolution with straightforward molecular interpretation of Raman images not possible by imaging any single peak. This method can be applied to either surgical or laboratory tools for rapid, non-destructive imaging of grey and white matter.

Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Both SPARC and p53 regulate glioma cell survival by inverse effects on apoptotic signaling. Therefore, during glioma formation, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival. This study determined whether the loss of Sparc in astrocytes that are null for p53 would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation, but a loss of tumorigenicity. At 7 days after intracranial implantation, Sparc-null tumors had decreased tumor cell survival, proliferation and reduced tumor size. The loss of Sparc promoted microglia/macrophage activation and phagocytosis of tumor cells. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance., (© 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas., Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes., Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma., Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Background: Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library., Results: We observed 288 identified metabolites, of which 179 were found to be significantly different (t-test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered., Conclusion: Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.

Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM.

Raman spectroscopy provides a molecular signature of the region being studied. It is ideal for neurosurgical applications because it is non-destructive, label-free, not impacted by water concentration, and can map an entire region of tissue. The objective of this paper is to demonstrate the meaningful spatial molecular information provided by Raman spectroscopy for identification of regions of normal brain, necrosis, diffusely infiltrating glioma and solid glioblastoma (GBM). Five frozen section tissues (1 normal, 1 necrotic, 1 GBM, and 2 infiltrating glioma) were mapped in their entirety using a 300-µm-square step size. Smaller regions of interest were also mapped using a 25-µm step size. The relative concentrations of relevant biomolecules were mapped across all tissues and compared with adjacent hematoxylin and eosin-stained sections, allowing identification of normal, GBM, and necrotic regions. Raman peaks and peak ratios mapped included 1003, 1313, 1431, 1585, and 1659 cm(-1). Tissue maps identified boundaries of grey and white matter, necrosis, GBM, and infiltrating tumor. Complementary information, including relative concentration of lipids, protein, nucleic acid, and hemoglobin, was presented in a manner which can be easily adapted for in vivo tissue mapping. Raman spectroscopy can successfully provide label-free imaging of tissue characteristics with high accuracy. It can be translated to a surgical or laboratory tool for rapid, non-destructive imaging of tumor margins.

Purpose: To correlate patient survival with morphologic imaging features and hemodynamic parameters obtained from the nonenhancing region (NER) of glioblastoma (GBM), along with clinical and genomic markers., Materials and Methods: An institutional review board waiver was obtained for this HIPAA-compliant retrospective study. Forty-five patients with GBM underwent baseline imaging with contrast material-enhanced magnetic resonance (MR) imaging and dynamic susceptibility contrast-enhanced T2*-weighted perfusion MR imaging. Molecular and clinical predictors of survival were obtained. Single and multivariable models of overall survival (OS) and progression-free survival (PFS) were explored with Kaplan-Meier estimates, Cox regression, and random survival forests., Results: Worsening OS (log-rank test, P = .0103) and PFS (log-rank test, P = .0223) were associated with increasing relative cerebral blood volume of NER (rCBVNER), which was higher with deep white matter involvement (t test, P = .0482) and poor NER margin definition (t test, P = .0147). NER crossing the midline was the only morphologic feature of NER associated with poor survival (log-rank test, P = .0125). Preoperative Karnofsky performance score (KPS) and resection extent (n = 30) were clinically significant OS predictors (log-rank test, P = .0176 and P = .0038, respectively). No genomic alterations were associated with survival, except patients with high rCBVNER and wild-type epidermal growth factor receptor (EGFR) mutation had significantly poor survival (log-rank test, P = .0306; area under the receiver operating characteristic curve = 0.62). Combining resection extent with rCBVNER marginally improved prognostic ability (permutation, P = .084). Random forest models of presurgical predictors indicated rCBVNER as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline. A multivariable model containing rCBVNER, age at diagnosis, and KPS can be used to group patients with more than 1 year of difference in observed median survival (0.49-1.79 years)., Conclusion: Patients with high rCBVNER and NER crossing the midline and those with high rCBVNER and wild-type EGFR mutation showed poor survival. In multivariable survival models, however, rCBVNER provided unique prognostic information that went above and beyond the assessment of all NER imaging features, as well as clinical and genomic features.