Publications by authors named "Mark R Gilbert"

339 Publications

Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics.

Neuro Oncol 2021 Sep 23. Epub 2021 Sep 23.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases.

Methods: An integrated diagnostic approach was employed for a consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA methylation profiling and classification using the DKFZ/Heidelberg CNS tumor classifier was performed, as well as unsupervised analyses of methylation data. Ancillary testing, where relevant, was performed.

Results: Among the received cases in consultation, a high confidence methylation classifier score (>0.84) was reached in 66.4% of cases. The classifier impacted the diagnosis in 46.5% of these high-confidence classifier score cases, including a substantially new diagnosis in 26.9% cases. Among the 289 cases received with only a descriptive diagnosis, methylation was able to resolve approximately half (144, 49.8%) with high-confidence scores. Additional methods were able to resolve diagnostic uncertainty in 41.6% of the low-score cases. Tumor purity was significantly associated with classifier score (p = 1.15e-11). Deconvolution demonstrated that suspected GBMs matching as control/inflammatory brain tissue could be resolved into GBM methylation profiles, which provided a proof-of-concept approach to resolve tumor classification in the setting of low tumor purity.

Conclusions: This work assesses the impact of a methylation classifier and additional methods in a consultative practice by defining the proportions with concordant vs. change in diagnosis in a set of diagnostically challenging CNS tumors. We address approaches to low-confidence scores and confounding issues of low tumor purity.
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http://dx.doi.org/10.1093/neuonc/noab227DOI Listing
September 2021

Adenosine A2A receptor activation enhances blood-tumor barrier permeability in a rodent glioma model.

Mol Cancer Res 2021 Sep 14. Epub 2021 Sep 14.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke

The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma (GBM). Poor drug entry across the BTB allows infiltrative glioma stem cells (GSC) to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier (BBB) in non-tumor bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, down-regulation of junctional protein expression by 4 hours, and re-establishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide (TMZ) concentrations, yet no increased survival noted with combined TMZ therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes amongst glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance CNS treatment delivery to aggressive brain tumors. Implications: This study provides insight on the use of a vasoactive agent to increase exposure of the blood-tumor barrier to chemotherapy with intention to improve glioma treatment efficacy.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0995DOI Listing
September 2021

Effects of Cognitive Reserve on Cognition in Individuals With Central Nervous System Disease.

Cogn Behav Neurol 2021 Sep 10. Epub 2021 Sep 10.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland NIH Library/Office of Research Services, National Institutes of Health, Bethesda, Maryland.

Cognitive reserve (CR) has been proposed to account for functional outcome differences in brain pathology and its clinical manifestations. The purpose of our paper is to systematically review the effects of CR on cognitive outcomes in individuals with neurodegenerative and structural CNS diseases. We performed a systematic search of PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PsychInfo using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Seventeen studies met the predetermined inclusion criteria and were selected for review. Education level was the most commonly used measure for CR, and various neuropsychological tests were used to measure cognitive outcomes. Regardless of the CNS disease of the individuals, almost all of the studies reported a positive association between CR and cognitive outcomes when they were evaluated cross-sectionally. However, when evaluated longitudinally, CR had either no effect on, or a negative association with, cognitive outcomes. Based on studies across a broad spectrum of CNS diseases, our findings suggest that CR may serve as a predictor of cognitive outcomes in individuals with CNS diseases. However, studies to date are limited by a lack of imaging analyses and standardized assessment strategies. The ability to use a standardized measure to assess the longitudinal effects of CR may allow for the development of more targeted treatment methods, resulting in improved disease outcomes for individuals.
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http://dx.doi.org/10.1097/WNN.0000000000000282DOI Listing
September 2021

Convolutional Neural Networks for Challenges in Automated Nuclide Identification.

Sensors (Basel) 2021 Aug 3;21(15). Epub 2021 Aug 3.

School of Physics and Astronomy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Improvements in Radio-Isotope IDentification (RIID) algorithms have seen a resurgence in interest with the increased accessibility of machine learning models. Convolutional Neural Network (CNN)-based models have been developed to identify arbitrary mixtures of unstable nuclides from gamma spectra. In service of this, methods for the simulation and pre-processing of training data were also developed. The implementation of 1D multi-class, multi-label CNNs demonstrated good generalisation to real spectra with poor statistics and significant gain shifts. It is also shown that even basic CNN architectures prove reliable for RIID under the challenging conditions of heavy shielding and close source geometries, and may be extended to generalised solutions for pragmatic RIID.
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http://dx.doi.org/10.3390/s21155238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347253PMC
August 2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Acta Neuropathol 2021 Nov 5;142(5):827-839. Epub 2021 Aug 5.

Institute of Neuropathology, University of Giessen, Giessen, Germany.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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http://dx.doi.org/10.1007/s00401-021-02356-6DOI Listing
November 2021

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab073. Epub 2021 Jun 1.

Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA.

Background: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO).

Methods: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression.

Results: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT ( = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT ( = .24). RANO-PFS was significantly shorter than clinical PFS overall ( = .001) and for both the IMRT ( = .01) and PT ( = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria.

Conclusions: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.
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http://dx.doi.org/10.1093/noajnl/vdab073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320688PMC
June 2021

Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies.

Front Oncol 2021 15;11:719091. Epub 2021 Jul 15.

Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, United States.

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3 T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.
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http://dx.doi.org/10.3389/fonc.2021.719091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320893PMC
July 2021

Living with a central nervous system (CNS) tumor: findings on long-term survivorship from the NIH Natural History Study.

Neurooncol Pract 2021 Aug 10;8(4):460-474. Epub 2021 Apr 10.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Primary central nervous system (CNS) tumors are often associated with high symptom burden and a poor prognosis from the time of diagnosis. The purpose of this study is to describe patient-reported outcomes (PRO) data from long-term survivors (LTS; ≥5-year survival post-diagnosis).

Methods: Clinical/treatment/molecular characteristics and PROs (symptom burden/interference (MDASI-BT/SP), perceived cognition (Neuro-QoL), anxiety/depression (PROMIS), and general health status (EQ-5D-3L)) were collected on 248 adult LTS between 9/2016 and 8/2019. Descriptive statistics and regression analysis were used to report results.

Results: Participants had a median age of 47 years (19-82) and were primarily White (83%) males (51%) with high-grade tumors (59%) and few mutations. Forty-two percent of the 222 brain tumor LTS reported no moderate-to-severe symptoms, whereas 45% reported three or more; most common symptoms were fatigue (40%), difficulty remembering (29%), and drowsiness (28%). Among spine tumor LTS (n = 42), nearly half reported moderate-to-severe weakness, pain, fatigue, and numbness/tingling, with 72% experiencing activity-related interference. Severe anxiety, depression, and cognitive symptoms were reported in up to 23% of the sample. Brain tumor LTS at higher risk for severe symptoms were more likely to be young, unemployed, and have poor KPS (Karnofsky Performance Status), whereas high symptom-risk spinal cord tumor LTS had poor KPS and received any tumor treatment.

Conclusions: Findings indicate LTS fall into distinct cohorts with no significant symptoms or very high symptom burden, regardless of tumor grade or mutational profile. These LTS data demonstrate the need for survivorship care programs and future studies to explore the symptom trajectory of all CNS tumor patients for prevention and early interventions.
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http://dx.doi.org/10.1093/nop/npab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278352PMC
August 2021

Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.

Neurooncol Pract 2021 Aug 13;8(4):417-425. Epub 2021 Feb 13.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.

Methods: A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.

Results: A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).

Conclusion: Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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http://dx.doi.org/10.1093/nop/npab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278354PMC
August 2021

Targeting CDK9 for the Treatment of Glioblastoma.

Cancers (Basel) 2021 Jun 18;13(12). Epub 2021 Jun 18.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.
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http://dx.doi.org/10.3390/cancers13123039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234280PMC
June 2021

Association of Circadian Clock Gene Expression with Glioma Tumor Microenvironment and Patient Survival.

Cancers (Basel) 2021 Jun 2;13(11). Epub 2021 Jun 2.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.

Circadian clock genes have been linked to clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established markers that predict the prognosis, including mutations in Isocitrate Dehydrogenase (), which characterize the majority of lower-grade gliomas and secondary high-grade gliomas. To demonstrate the connection between circadian clock genes and glioma outcomes while accounting for the mutational status, we analyzed multiple publicly available gene expression datasets. The unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas showed distinct molecular subtypes representing different disease states and showed the differential prognosis of these groups by a Kaplan-Meier analysis. Further analyses of these groups showed that a low period () gene expression was associated with the negative prognosis and enrichment of the immune signaling pathways. These findings prompted the exploration of the relationship between the microenvironment and clock genes in additional datasets. Circadian clock gene expression was found to be differentially expressed across the anatomical tumor location and cell type. Thus, the circadian clock expression is a potential predictive biomarker in glioma, and further mechanistic studies to elucidate the connections between the circadian clock and microenvironment are warranted.
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http://dx.doi.org/10.3390/cancers13112756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199552PMC
June 2021

Nonmalignant meningioma and vestibular schwannoma incidence trends in the United States, 2004-2017.

Cancer 2021 Oct 23;127(19):3579-3590. Epub 2021 Jun 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Given concerns about risks associated with the growing use of mobile phones over recent decades, the authors analyzed temporal trends in incidence rates of nonmalignant meningioma and vestibular schwannoma in the United States.

Methods: The incidence of nonmalignant meningioma and vestibular schwannoma among adults in the Surveillance, Epidemiology, and End Results 18 registries during 2004 through 2017 was evaluated according to the method of diagnosis: microscopically (MC) or radiographically confirmed (RGC). Annual percent changes (APCs) and 95% CIs were estimated using log-linear models.

Results: Overall meningioma rates (n = 108,043) increased significantly from 2004 to 2009 (APC, 5.4%; 95% CI, 4.4%-6.4%) but subsequently rose at a slower pace through 2017 (APC, 1.0%; 95% CI, 0.6%-1.5%). Rates for MC meningiomas changed little from 2004 to 2017 (APC, -0.3%; 95% CI, -0.7%, 0.1%) but rose rapidly for RGC meningiomas until 2009 (APC, 9.5%; 95% CI, 7.8%-11.1%) and rose more modestly thereafter (APC, 2.3%; 95% CI, 1.5%-3.0%). Overall vestibular schwannoma rates (n = 17,475) were stable (APC, 0.4%; 95% CI, -0.2%, 1.0%), but MC vestibular schwannoma rates decreased (APC, -1.9%; 95% CI, -2.7%, -1.1%), whereas RGC vestibular schwannoma rates rose (2006-2017: APC, 1.7%; 95% CI, 0.5%-3.0%). For each tumor, the trends by diagnostic method were similar for each sex and each racial/ethnic group, but RGC diagnosis was more likely in older patients and for smaller tumors. Meningioma trends and the proportion of RGC diagnoses varied notably by registry.

Conclusions: Overall trends obscured differences by diagnostic method in this first large, detailed assessment, but the recent stable rates argue against an association with mobile phone use. Variation among registries requires evaluation to improve the registration of these nonmalignant tumors.

Lay Summary: The etiology of most benign meningiomas and vestibular schwannomas is poorly understood, but concerns have been raised about whether mobile phone use contributes to risk of developing these tumors. Descriptive studies examining temporal trends could provide insight; however, globally, few registries collect these nonmalignant cases. In the United States, reporting benign meningiomas and vestibular schwannomas became required by law in 2004. This was the first large, systematic study to quantify and characterize incidence trends for meningioma and vestibular schwannoma according to whether the tumors were diagnosed microscopically or only radiographically. Differential trends across registries and by diagnostic method suggest that caution should be used when interpreting the patterns.
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http://dx.doi.org/10.1002/cncr.33553DOI Listing
October 2021

Using first-principles calculations to predict the mechanical properties of transmuting tungsten under first wall fusion power-plant conditions.

J Phys Condens Matter 2021 Jul 1;33(34). Epub 2021 Jul 1.

Department of Mechanical Engineering, Villanova University, Villanova, PA 19085, United States of America.

Tungsten and tungsten alloys are being considered as leading candidates for structural and functional materials in future fusion energy devices. The most attractive properties of tungsten for the design of magnetic and inertial fusion energy reactors are its high melting point, high thermal conductivity, low sputtering yield and low long-term disposal radioactive footprint. Yet, despite these relevant features, tungsten also presents a very low fracture toughness, mostly associated with inter-granular failure and bulk plasticity, that limits its applications. Significant neutron-induced transmutation happens in these tungsten components during nuclear fusion reactions, creating transmutant elements including Re, Os and Ta. Density functional theory (DFT) calculations that allow the calculation of defect and solute energetics are critical to better understand the behavior and evolution of tungsten-based materials in a fusion energy environment. In this study, we present a novel computational approach to perform DFT calculations on transmuting materials. In particular, we predict elastic and plastic mechanical properties (such as bulk modulus, shear modulus, ductility parameter, etc) on a variety of W-X compositions that result when pure tungsten is exposed to the EU-DEMO fusion first wall conditions for ten years.
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http://dx.doi.org/10.1088/1361-648X/ac08b8DOI Listing
July 2021

Making a Cold Tumor Hot: The Role of Vaccines in the Treatment of Glioblastoma.

Front Oncol 2021 10;11:672508. Epub 2021 May 10.

Neuro-Oncology Branch, CCR, NCI, National Institutes of Health, Bethesda, MD, United States.

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically "cold," implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients.
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http://dx.doi.org/10.3389/fonc.2021.672508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141615PMC
May 2021

Impact of age on the circadian visual system and the sleep-wake cycle in mus musculus.

NPJ Aging Mech Dis 2021 May 4;7(1):10. Epub 2021 May 4.

Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Age plays a critical role in disease development and tolerance to cancer treatment, often leading to an increased risk of developing negative symptoms including sleep disturbances. Circadian rhythms and sleep become disrupted as organisms age. In this study, we explored the behavioral alterations in sleep, circadian rhythms, and masking using a novel video system and interrogate the long-term impact of age-based changes in the non-image forming visual pathway on brain anatomy. We demonstrated the feasibility and utility of the novel system and establish that older mice have disruptions in sleep, circadian rhythms, and masking behaviors that were associated with major negative volume alterations in the non-imaging forming visual system, critical for the induction and rhythmic expression of sleep. These results provide important insights into a mechanism, showing brain atrophy is linked to age in distinct non-image forming visual regions, which may predispose older individuals to developing circadian and sleep dysfunction when further challenged by disease or treatment.
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http://dx.doi.org/10.1038/s41514-021-00063-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096965PMC
May 2021

Synthetic lethality-mediated precision oncology via the tumor transcriptome.

Cell 2021 04 14;184(9):2487-2502.e13. Epub 2021 Apr 14.

Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.
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http://dx.doi.org/10.1016/j.cell.2021.03.030DOI Listing
April 2021

Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma.

Int J Mol Sci 2021 Mar 26;22(7). Epub 2021 Mar 26.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms.
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http://dx.doi.org/10.3390/ijms22073455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037428PMC
March 2021

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas.

Clin Cancer Res 2021 Jun 30;27(12):3298-3306. Epub 2021 Mar 30.

Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.

Patients And Methods: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.

Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the (rs2470890) polymorphism was associated with higher AUC value.

Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197750PMC
June 2021

Molecularly Targeted Clinical Trials.

Neurosurg Clin N Am 2021 Apr 18;32(2):191-210. Epub 2021 Feb 18.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Glioblastoma remains incurable despite advances in surgery, radiation, and chemotherapy, underscoring the need for new therapies. The genetic heterogenicity, presence of redundant molecular pathways, and the blood-brain barrier have limited the applicability of molecularly targeted agents. The therapeutic benefit seen with a small subset of patients suggests, however, that patient selection is critical. Recent investigations show that molecularly targeted synthetic lethality is a promising complementary approach. The article provides an overview of the challenges of molecularly targeted therapy in adults with glioblastoma, including current trials and future therapeutic directions.
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http://dx.doi.org/10.1016/j.nec.2020.12.002DOI Listing
April 2021

Induction of Immune Response Against Metastatic Tumors via Vaccination of Mannan-BAM, TLR Ligands and Anti-CD40 Antibody (MBTA).

Adv Ther (Weinh) 2020 Sep 9;3(9). Epub 2020 Jun 9.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.

Emerging evidence is demonstrating the extent of T-cell infiltration within the tumor microenvironment has favorable prognostic and therapeutic implications. Hence, immunotherapeutic strategies that augment the T-cell signature of tumors hold promising therapeutic potential. Recently, immunotherapy based on intratumoral injection of mannan-BAM, toll-like receptor ligands and anti-CD40 antibody (MBTA) demonstrated promising potential to modulate the immune phenotype of injected tumors. The strategy promotes the phagocytosis of tumor cells to facilitate the recognition of tumor antigens and induce a tumor-specific adaptive immune response. Using a syngeneic colon carcinoma model, we demonstrate MBTA's potential to augment CD8 T-cell tumor infiltrate when administered intratumorally or subcutaneously as part of a whole tumor cell vaccine. Both immunotherapeutic strategies proved effective at controlling tumor growth, prolonged survival and induced immunological memory against the parental cell line. Collectively, our investigation demonstrates MBTA's potential to trigger a potent anti-tumor immune response.
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http://dx.doi.org/10.1002/adtp.202000044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942838PMC
September 2020

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

Neuro Oncol 2021 08;23(8):1337-1347

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM).

Methods: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs).

Results: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02).

Conclusions: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.
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http://dx.doi.org/10.1093/neuonc/noab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328012PMC
August 2021

Magnetic resonance spectroscopy for the study of cns malignancies.

Prog Nucl Magn Reson Spectrosc 2021 02 2;122:23-41. Epub 2020 Dec 2.

Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institute of Health, Bethesda, United States. Electronic address:

Despite intensive research, brain tumors are amongst the malignancies with the worst prognosis; therefore, a prompt diagnosis and thoughtful assessment of the disease is required. The resistance of brain tumors to most forms of conventional therapy has led researchers to explore the underlying biology in search of new vulnerabilities and biomarkers. The unique metabolism of brain tumors represents one potential vulnerability and the basis for a system of classification. Profiling this aberrant metabolism requires a method to accurately measure and report differences in metabolite concentrations. Magnetic resonance-based techniques provide a framework for examining tumor tissue and the evolution of disease. Nuclear Magnetic Resonance (NMR) analysis of biofluids collected from patients suffering from brain cancer can provide biological information about disease status. In particular, urine and plasma can serve to monitor the evolution of disease through the changes observed in the metabolic profiles. Moreover, cerebrospinal fluid can be utilized as a direct reporter of cerebral activity since it carries the chemicals exchanged with the brain tissue and the tumor mass. Metabolic reprogramming has recently been included as one of the hallmarks of cancer. Accordingly, the metabolic rewiring experienced by these tumors to sustain rapid growth and proliferation can also serve as a potential therapeutic target. The combination of C tracing approaches with the utilization of different NMR spectral modalities has allowed investigations of the upregulation of glycolysis in the aggressive forms of brain tumors, including glioblastomas, and the discovery of the utilization of acetate as an alternative cellular fuel in brain metastasis and gliomas. One of the major contributions of magnetic resonance to the assessment of brain tumors has been the non-invasive determination of 2-hydroxyglutarate (2HG) in tumors harboring a mutation in isocitrate dehydrogenase 1 (IDH1). The mutational status of this enzyme already serves as a key feature in the clinical classification of brain neoplasia in routine clinical practice and pilot studies have established the use of in vivo magnetic resonance spectroscopy (MRS) for monitoring disease progression and treatment response in IDH mutant gliomas. However, the development of bespoke methods for 2HG detection by MRS has been required, and this has prevented the wider implementation of MRS methodology into the clinic. One of the main challenges for improving the management of the disease is to obtain an accurate insight into the response to treatment, so that the patient can be promptly diverted into a new therapy if resistant or maintained on the original therapy if responsive. The implementation of C hyperpolarized magnetic resonance spectroscopic imaging (MRSI) has allowed detection of changes in tumor metabolism associated with a treatment, and as such has been revealed as a remarkable tool for monitoring response to therapeutic strategies. In summary, the application of magnetic resonance-based methodologies to the diagnosis and management of brain tumor patients, in addition to its utilization in the investigation of its tumor-associated metabolic rewiring, is helping to unravel the biological basis of malignancies of the central nervous system.
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http://dx.doi.org/10.1016/j.pnmrs.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910526PMC
February 2021

Randomized, Double-Blind, Placebo-Controlled Phase II Study of Yeast-Brachyury Vaccine (GI-6301) in Combination with Standard-of-Care Radiotherapy in Locally Advanced, Unresectable Chordoma.

Oncologist 2021 05 9;26(5):e847-e858. Epub 2021 Mar 9.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial-to-mesenchymal transition. GI-6301 is a recombinant, heat-killed Saccharomyces cerevisiae yeast-based vaccine targeting brachyury. A previous phase I trial of GI-6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI-6301 vaccine plus radiation.

Materials And Methods: Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo-controlled trial. Patients received three doses of GI-6301 (80 × 10 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity.

Results: Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive-free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7-37.5 months) and 25.9 months (95% CI, 9.2-30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38-2.71). Vaccine was well tolerated with no vaccine-related serious adverse events. Preexisting brachyury-specific T cells were detected in most patients in both arms. Most patients developed T-cell responses during therapy, with no difference between arms in frequency or magnitude of response.

Conclusion: No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual.

Implications For Practice: Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast-brachyury vaccine (GI-6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.
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http://dx.doi.org/10.1002/onco.13720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100546PMC
May 2021

Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q.

Neuro Oncol 2021 08;23(8):1360-1370

Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification.

Methods: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival.

Results: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group.

Conclusions: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
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http://dx.doi.org/10.1093/neuonc/noab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328032PMC
August 2021

Case Report: Single-Cell Transcriptomic Analysis of an Anaplastic Oligodendroglioma Post Immunotherapy.

Front Oncol 2020 14;10:601452. Epub 2021 Jan 14.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy.
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http://dx.doi.org/10.3389/fonc.2020.601452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841290PMC
January 2021

Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825).

Neuro Oncol 2021 07;23(7):1125-1138

Department of Radiation Oncology, University of Maryland, Baltimore, Maryland, USA.

Background: Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints.

Methods: NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated.

Results: A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference.

Conclusion: The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.
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http://dx.doi.org/10.1093/neuonc/noab011DOI Listing
July 2021

Clinical correlates for immune checkpoint therapy: significance for CNS malignancies.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa161. Epub 2020 Nov 27.

Neuro-Oncology Branch, CCR, NCI, National Institutes of Health, Bethesda, Maryland, USA.

Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy. Most commonly, inhibitors of PD-1 and CTLA4 are used having received approval for the treatment of many cancers like melanoma, non-small-cell lung carcinoma, and leukemia. In contrast, to date, clinical studies conducted in patients with CNS malignancies have not demonstrated promising results. However, patients with CNS malignancies have several underlying factors such as treatment with supportive medications like corticosteroids and cancer therapies including radiation and chemotherapy that may negatively impact response to ICIs. Although many clinical trials have been conducted with ICIs, measures that reproducibly and reliably indicate that treatment has evoked an effective immune response have not been fully developed. In this article, we will review the history of ICI therapy and the correlative biology that has been performed in the clinical trials testing these therapies in different cancers. It is our aim to help provide an overview of the assays that may be used to gauge immunologic response. This may be particularly germane for CNS tumors, where there is currently a great need for predictive biomarkers that will allow for the selection of patients with the highest likelihood of responding.
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http://dx.doi.org/10.1093/noajnl/vdaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813206PMC
November 2020

IDH1 mutations induce organelle defects via dysregulated phospholipids.

Nat Commun 2021 01 27;12(1):614. Epub 2021 Jan 27.

Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1) acquire a different tumor biology and clinical manifestation from those that are IDH1. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1-specific cellular apoptosis. Collectively, these results suggest that IDH1-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.
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http://dx.doi.org/10.1038/s41467-020-20752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840755PMC
January 2021

Developmental vascular malformations in EPAS1 gain-of-function syndrome.

JCI Insight 2021 03 8;6(5). Epub 2021 Mar 8.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.
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http://dx.doi.org/10.1172/jci.insight.144368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021124PMC
March 2021
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