Publications by authors named "Dimitris G Placantonakis"

75 Publications

Volumetric growth rates of untreated cavernous sinus meningiomas.

J Neurosurg 2021 Aug 20:1-8. Epub 2021 Aug 20.

2Department of Neurosurgery, NYU Langone Medical Center, New York, New York.

Objective: Meningiomas that arise primarily within the cavernous sinus are often believed to be more indolent in their growth pattern. Despite this perceived growth pattern, disabling symptoms can arise even with small tumors. While research has been done on cavernous sinus meningiomas (CSMs) and their treatment, very little is known about their natural growth rates. With a better understanding of the growth rate of CSM, patient treatment and guidance can be can optimized and individualized. The goal of this study was to determine volumetric growth rates of untreated CSMs.

Methods: Thirty-seven patients with 166 MR images obtained between May 2004 and September 2019 were reviewed, with a range of 2-13 MR images per patient (average of 4.5 MR images per patient). These scans were obtained over an average follow-up period of 45.9 months (median 33.8, range 2.8-136.9 months). All imaging prior to any intervention was included in this analysis. Volumetric measurements were performed and assessed over time.

Results: The estimated volumetric growth rate was 23.3% per year (95% CI 10.2%-38.0%, p < 0.001), which is equivalent to an estimated volume doubling time (VDT) of 3.3 years (95% CI 2.1-7.1 years). There was no significant relationship between growth rate and patient age (p = 0.09) or between growth rate and patient sex (p = 0.78). The median absolute growth rate was 41% with a range of -1% to 1793%. With a definition of "growth" as an increase of greater than 20% during the observed period, 65% of tumors demonstrated growth within their observation interval. Growth rates for each tumor were calculated and tumors were segmented based on growth rate. Of 37 patients, 22% (8) demonstrated no growth (< 5% annual growth, equivalent to a VDT > 13.9 years), 32% (12) were designated as slow growth (annual growth rate 5%-20%, VDT 3.5-13.9 years), 38% (14) were found to have medium growth (annual growth rate 20%-100%, VDT 0.7-3.5 years), and 8% were considered fast growing (annual growth rate > 100%, VDT < 0.7 years).

Conclusions: This study evaluated CSM volumetric growth rates. A deeper understanding of the natural history of untreated CSMs allows for better counseling and management of patients.
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http://dx.doi.org/10.3171/2021.2.JNS203485DOI Listing
August 2021

The H3K36me2 writer-reader dependency in H3K27M-DIPG.

Sci Adv 2021 Jul 14;7(29). Epub 2021 Jul 14.

Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.
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http://dx.doi.org/10.1126/sciadv.abg7444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279504PMC
July 2021

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

Mol Cancer Ther 2021 09 17;20(9):1584-1591. Epub 2021 Jun 17.

Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland.

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients ( = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419097PMC
September 2021

Cerebrospinal fluid from COVID-19 patients with olfactory/gustatory dysfunction: A review.

Clin Neurol Neurosurg 2021 08 12;207:106760. Epub 2021 Jun 12.

Department of Neurology, NYU Langone Medical Center, New York, NY 10016, USA; Department of Neurosurgery, NYU Langone Medical Center, New York, NY 10016, USA.

Objective: We reviewed the literature on cerebrospinal fluid (CSF) testing in patients with altered olfactory/gustatory function due to COVID-19 for evidence of viral neuroinvasion.

Methods: We performed a systematic review of Medline and Embase to identify publications that described at least one patient with COVID-19 who had altered olfactory/gustatory function and had CSF testing performed. The search ranged from December 1, 2019 to November 18, 2020.

Results: We identified 51 publications that described 70 patients who met inclusion criteria. Of 51 patients who had CSF SARS-CoV-2 PCR testing, 3 (6%) patients had positive results and 1 (2%) patient had indeterminate results. Cycle threshold (Ct; the number of amplification cycles required for the target gene to exceed the threshold, which is inversely related to viral load) was not provided for the patients with a positive PCR. The patient with indeterminate results had a Ct of 37 initially, then no evidence of SARS-CoV-2 RNA on repeat testing. Of 6 patients who had CSF SARS-CoV-2 antibody testing, 3 (50%) were positive. Testing to distinguish intrathecal antibody synthesis from transudation of antibodies to the CSF via breakdown of the blood-brain barrier was performed in 1/3 (33%) patients; this demonstrated antibody transmission to the CSF via transudation.

Conclusion: Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare in patients with altered olfactory/gustatory function. While pathology studies are needed, our review suggests it is unlikely that these symptoms are related to viral neuroinvasion.
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http://dx.doi.org/10.1016/j.clineuro.2021.106760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196517PMC
August 2021

COVID-19 associated brain/spinal cord lesions and leptomeningeal enhancement: A meta-analysis of the relationship to CSF SARS-CoV-2.

J Neuroimaging 2021 09 8;31(5):826-848. Epub 2021 Jun 8.

Department of Neurology, NYU Langone Medical Center, New York, New York, USA.

Background And Purpose: We reviewed the literature to evaluate cerebrospinal fluid (CSF) results from patients with coronavirus disease 2019 (COVID-19) who had neurological symptoms and had an MRI that showed (1) central nervous system (CNS) hyperintense lesions not attributed to ischemia and/or (2) leptomeningeal enhancement. We sought to determine if these findings were associated with a positive CSF severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR).

Methods: We performed a systematic review of Medline and Embase from December 1, 2019 to November 18, 2020. CSF results were evaluated based on the presence/absence of (1) ≥ 1 CNS hyperintense lesion and (2) leptomeningeal enhancement.

Results: In 117 publications, we identified 193 patients with COVID-19 who had an MRI of the CNS and CSF testing. There were 125 (65%) patients with CNS hyperintense lesions. Patients with CNS hyperintense lesions were significantly more likely to have a positive CSF SARS-CoV-2 PCR (10% [9/87] vs. 0% [0/43], p = 0.029). Of 75 patients who had a contrast MRI, there were 20 (27%) patients who had leptomeningeal enhancement. Patients with leptomeningeal enhancement were significantly more likely to have a positive CSF SARS-CoV-2 PCR (25% [4/16] vs. 5% [2/42], p = 0.024).

Conclusion: The presence of CNS hyperintense lesions or leptomeningeal enhancement on neuroimaging from patients with COVID-19 is associated with increased likelihood of a positive CSF SARS-CoV-2 PCR. However, a positive CSF SARS-CoV-2 PCR is uncommon in patients with these neuroimaging findings, suggesting they are often related to other etiologies, such as inflammation, hypoxia, or ischemia.
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http://dx.doi.org/10.1111/jon.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242764PMC
September 2021

Cerebrospinal fluid findings in patients with seizure in the setting of COVID-19: A review of the literature.

Seizure 2021 Jul 17;89:99-106. Epub 2021 May 17.

Department of Neurology, NYU Langone Medical Center, New York, NY, USA; Department of Neurosurgery, NYU Langone Medical Center, New York, NY, USA.

We reviewed the literature on cerebrospinal fluid (CSF) studies in patients who had a seizure in the setting of COVID-19 infection to evaluate for evidence of viral neuroinvasion. We performed a systematic review of Medline and Embase to identify publications that reported one or more patients with COVID-19 who had a seizure and had CSF testing preformed. The search ranged from December 1st 2019 to November 18th 2020. We identified 56 publications which described 69 unique patients who met our inclusion criteria. Of the 54 patients whose past medical history was provided, 2 (4%) had epilepsy and 1 (2%) had a prior seizure in the setting of hyperglycemia, but the remaining 51 (94%) had no history of seizures. Seizure was the initial symptom of COVID-19 for 15 (22%) patients. There were 26 (40%) patients who developed status epilepticus. SARS-CoV-2 PCR testing was performed in the CSF for 45 patients; 6 (13%) had a positive CSF SARS-CoV-2 PCR, only 1 (17%) of whom had status epilepticus. The cycle thresholds were not reported. Evaluation for CSF SARS-CoV-2 antibodies (directly or indirectly, via testing for CSF oligoclonal bands or immunoglobulins) was performed in 26 patients, only 2 (8%) of whom had evidence of intrathecal antibody synthesis. Of the 11 patients who had CSF autoimmune antibody panels tested, 1 had NMDA antibodies and 1 had Caspr-2 antibodies. Detection of SARS-CoV-2 in the CSF of patients with seizures who have COVID-19 is uncommon. Our review suggests that seizures in this patient population are not likely due to direct viral invasion of the brain.
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http://dx.doi.org/10.1016/j.seizure.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127527PMC
July 2021

Functional impact of intramolecular cleavage and dissociation of adhesion G protein-coupled receptor GPR133 (ADGRD1) on canonical signaling.

J Biol Chem 2021 Jan-Jun;296:100798. Epub 2021 May 20.

Department of Neurosurgery, NYU Grossman School of Medicine, New York, New York, USA; Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, New York, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, New York, USA; Brain and Spine Tumor Center, NYU Grossman School of Medicine, New York, New York, USA; Neuroscience Institute, NYU Grossman School of Medicine, New York, New York, USA. Electronic address:

GPR133 (ADGRD1), an adhesion G protein-coupled receptor (GPCR) whose canonical signaling activates G-mediated generation of cytosolic cAMP, has been shown to be necessary for the growth of glioblastoma (GBM), a brain malignancy. The extracellular N terminus of GPR133 is thought to be autoproteolytically cleaved into N-terminal and C- terminal fragments (NTF and CTF, respectively). However, the role of this cleavage in receptor activation remains unclear. Here, we used subcellular fractionation and immunoprecipitation approaches to show that the WT GPR133 receptor is cleaved shortly after protein synthesis and generates significantly more canonical signaling than an uncleavable point mutant GPR133 (H543R) in patient-derived GBM cultures and HEK293T cells. After cleavage, the resulting NTF and CTF remain noncovalently bound to each other until the receptor is trafficked to the plasma membrane, where we demonstrated NTF-CTF dissociation occurs. Using a fusion of the CTF of GPR133 and the N terminus of thrombin-activated human protease-activated receptor 1 as a controllable proxy system to test the effect of intramolecular cleavage and dissociation, we also showed that thrombin-induced cleavage and shedding of the human protease-activated receptor 1 NTF increased intracellular cAMP levels. These results support a model wherein dissociation of the NTF from the CTF at the plasma membrane promotes GPR133 activation and downstream signaling. These findings add depth to our understanding of the molecular life cycle and mechanism of action of GPR133 and provide critical insights that will inform therapeutic targeting of GPR133 in GBM.
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http://dx.doi.org/10.1016/j.jbc.2021.100798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215292PMC
August 2021

Adhesion G protein-coupled receptors in glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab046. Epub 2021 Mar 23.

Department of Neurosurgery, NYU Grossman School of Medicine, New York, New York, USA.

Background: Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma.

Methods: Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.
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http://dx.doi.org/10.1093/noajnl/vdab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086243PMC
March 2021

Epstein-Barr Virus-Positive Primary Central Nervous System Lymphoma in a 40-Year-Old Immunocompetent Patient.

Cureus 2021 Jan 17;13(1):e12754. Epub 2021 Jan 17.

Neurosurgery, New York University (NYU) Grossman School of Medicine, New York, USA.

Epstein-Barr virus-positive (EBV+) primary central nervous system lymphoma (PCNSL) is a clinical entity rarely reported in young immunocompetent patients. Here, we present the case of a 40-year-old female with no history of immunosuppression or immunodeficiency, who presented with a ring-enhancing lesion in the right basal ganglia. The tumor generated significant vasogenic edema and mass effect, causing midline shift, symptoms of increased intracranial pressure, and rapidly progressive neurologic dysfunction. She underwent gross total resection of the tumor through a tubular retractor. Her tumor was of the diffuse large B cell lymphoma (DLBCL) subtype of PCNSL and was positive for EBV. No immunodeficiency or extracranial disease was identified. After adjuvant therapy with high-dose methotrexate, rituximab, and temozolomide, she remains disease-free two years after initial presentation. EBV+ PCNSL, although rare in young immunocompetent adults, poses unique clinical challenges and may require surgical intervention in the acute setting in some cases.
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http://dx.doi.org/10.7759/cureus.12754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886623PMC
January 2021

Cerebrospinal fluid in COVID-19: A systematic review of the literature.

J Neurol Sci 2021 02 10;421:117316. Epub 2021 Jan 10.

Department of Neurology, NYU Langone Medical Center, New York, NY 10016, USA; Department of Neurosurgery, NYU Langone Medical Center, New York, NY 10016, USA.

Objective: We sought to review the literature on cerebrospinal fluid (CSF) testing in patients with COVID-19 for evidence of viral neuroinvasion by SARS-CoV-2.

Methods: We performed a systematic review of Medline and Embase between December 1, 2019 and November 18, 2020 to identify case reports or series of patients who had COVID-19 diagnosed based on positive SARS-CoV-2 polymerase chain reaction (PCR) or serologic testing and had CSF testing due to a neurologic symptom.

Results: We identified 242 relevant documents which included 430 patients with COVID-19 who had acute neurological symptoms prompting CSF testing. Of those, 321 (75%) patients had symptoms that localized to the central nervous system (CNS). Of 304 patients whose CSF was tested for SARS-CoV-2 PCR, there were 17 (6%) whose test was positive, all of whom had symptoms that localized to the central nervous system (CNS). The majority (13/17, 76%) of these patients were admitted to the hospital because of neurological symptoms. Of 58 patients whose CSF was tested for SARS-CoV-2 antibody, 7 (12%) had positive antibodies with evidence of intrathecal synthesis, all of whom had symptoms that localized to the CNS. Of 132 patients who had oligoclonal bands evaluated, 3 (2%) had evidence of intrathecal antibody synthesis. Of 77 patients tested for autoimmune antibodies in the CSF, 4 (5%) had positive findings.

Conclusion: Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare. Most neurological complications associated with SARS- CoV-2 are unlikely to be related to direct viral neuroinvasion.
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http://dx.doi.org/10.1016/j.jns.2021.117316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833669PMC
February 2021

Awake Laser Ablation for Patients With Tumors in Eloquent Brain Areas: Operative Technique and Case Series.

Cureus 2020 Dec 20;12(12):e12186. Epub 2020 Dec 20.

Neurosurgery, New York University (NYU) Grossman School of Medicine, New York, USA.

Background Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (LITT) is a minimally invasive treatment modality that has been gaining traction in neuro-oncology. Laser ablation is a particularly appealing treatment option when eloquent neurologic function at the tumor location precludes conventional surgical excision. Although typically performed under general anesthesia, LITT in awake patients may help monitor and preserve critical neurologic functions. Objective To describe intraoperative workflow and clinical outcomes in patients undergoing awake laser ablation of brain tumors. Methods We present a cohort of six patients with tumors located in eloquent brain areas that were treated with awake LITT and report three different workflow paradigms involving diagnostic or intraoperative MRI. In all cases, we used NeuroBlate® (Monteris Medical, Plymouth, MN) fiberoptic laser probes for stereotactic laser ablation of tumors. The neurologic status of patients was intermittently assessed every few minutes during the ablation. Results The mean preoperative tumor volume that was targeted was 12.09 ± 3.20 cm, and the estimated ablation volume was 12.06 ± 2.75 cm. Performing the procedure in awake patients allowed us close monitoring of neurologic function intraoperatively. There were no surgical complications. The length of stay was one day for all patients except one. Three patients experienced acute or delayed worsening of pre-existing neurologic deficits that responded to corticosteroids. Conclusion We propose that awake LITT is a safe approach when tumors in eloquent brain areas are considered for laser ablation.
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http://dx.doi.org/10.7759/cureus.12186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815262PMC
December 2020

Breaking Tradition to Bridge Bench and Bedside: Accelerating the MD-PhD-Residency Pathway.

Acad Med 2021 04;96(4):518-521

J. Cangiarella is associate dean, Education and Faculty, associate professor of pathology, and director, the Accelerated 3-Year MD Pathway, New York University Grossman School of Medicine, New York, New York; ORCID: https://orcid.org/0000-0002-9364-2672.

Problem: Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are mainly MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates.

Approach: To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated 3-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program.

Outcomes: Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by 1 year and reduces the MD training phase to 3 years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success.

Next Steps: The authors and institutional leaders plan to increase the number of trainees who are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.
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http://dx.doi.org/10.1097/ACM.0000000000003920DOI Listing
April 2021

SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients.

Front Neurol 2020 11;11:587384. Epub 2020 Dec 11.

NYU Grossman School of Medicine and NYU Langone Health, New York, NY, United States.

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.
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http://dx.doi.org/10.3389/fneur.2020.587384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759491PMC
December 2020

COVID-19-Induced Neurovascular Injury: a Case Series with Emphasis on Pathophysiological Mechanisms.

SN Compr Clin Med 2020 22;2(11):2109-2125. Epub 2020 Oct 22.

Department of Pathology, Division of Neuropathology, NYU Langone Health, 550 First Avenue, New York, NY 10016 USA.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.
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http://dx.doi.org/10.1007/s42399-020-00598-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577845PMC
October 2020

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.

Elife 2020 09 10;9. Epub 2020 Sep 10.

Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
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http://dx.doi.org/10.7554/eLife.52253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556869PMC
September 2020

Treatment of sellar metastases with gamma knife radiosurgery in patients with advanced cancer.

Pituitary 2020 Dec;23(6):665-671

Department of Neurosurgery, NYU Langone Medical Center, New York, NY, USA.

Purpose: Metastases should be considered in a patient with a cancer history and a sellar/suprasellar lesion, as this diagnosis can change the management strategy in such patients. Once the diagnosis is established, stereotactic radiosurgery (SRS) can be a safe and effective approach for these patients.

Methods: This case series describes five patients with pituitary metastases managed with GKRS at a single institution, taken from our prospective registry. All patients had SRS using the Gamma Knife Perfexion or Icon (Elekta), according to our standard institutional protocol. The optic nerves and chiasm were contoured, and the plan was adjusted to restrict dose to the optic apparatus as necessary. The tumor margin doses delivered were 11 Gy, 12 Gy, 14 Gy, 18 Gy (3 sessions of 6 Gy), and 12 Gy at the 50% isodose line.

Results: In this series, all sellar metastases were treated successfully with good radiographic and clinical response. The histology of the tumors included endometrial, gastrointestinal, and lung adenocarcinomas. Typically, histology is taken into consideration when choosing the treatment dose, along with size and location. In these patients, however, the dose used for the sellar metastases was chosen primarily for visual safety. This was typically lower than the dose for brain metastases in other locations.

Conclusion: SRS provides an alternative treatment approach for sellar/suprasellar metastases with excellent local control, symptom improvement and maintenance of systemic therapy as desired. As such, CNS failure is rarely the proximate cause of demise in pituitary metastases provided that endocrinopathies are recognized and managed appropriately.
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http://dx.doi.org/10.1007/s11102-020-01074-8DOI Listing
December 2020

evidence for glioblastoma cell death in temperatures found in the penumbra of laser-ablated tumors.

Int J Hyperthermia 2020 07;37(2):20-26

Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY, USA.

The concept of thermal therapy toward the treatment of brain tumors has gained traction in recent years. Traditionally, thermal therapy has been subdivided into hyperthermia, with mild elevation of temperature in treated tissue above the physiologic baseline; and thermal ablation, where even higher temperatures are achieved. The recent surge in interest has been driven by the use of novel thermal ablation technologies, including laser interstitial thermal therapy (LITT), that are implemented in brain tumor treatment. Here, we review previous scientific literature on the biologic effects of thermal therapy on brain tumors, with an emphasis on glioblastoma (GBM), an aggressive brain malignancy. In addition, we present evidence from our laboratory that even moderate elevations in temperature achieved in the penumbra around laser-ablated coagulum may also produce GBM cell death. While much remains to be elucidated in terms of the biology of thermal therapy, we propose that it is a welcome addition to the neuro-oncology armamentarium, in particular with regard to GBM, which is generally resistant to current chemoradiotherapeutic regimens.
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http://dx.doi.org/10.1080/02656736.2020.1774082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725000PMC
July 2020

Expression profiling of the adhesion G protein-coupled receptor GPR133 (ADGRD1) in glioma subtypes.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa053. Epub 2020 Apr 28.

Departments of Neurosurgery, New York, New York, USA.

Background: Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown.

Methods: We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas.

Results: We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors.

Conclusion: The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.
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http://dx.doi.org/10.1093/noajnl/vdaa053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262742PMC
April 2020

Resolution of Tonsillar Herniation and Syringomyelia Following Resection of a Large Anterior Frontal Parasagittal Meningioma.

Cureus 2020 Apr 11;12(4):e7636. Epub 2020 Apr 11.

Neurosurgery, New York University (NYU) School of Medicine, New York, USA.

Chiari I malformation is the herniation of cerebellar tonsils below the level of the foramen magnum due to congenital or acquired pathologies. Acquired Chiari I malformation (ACM) may occur secondary to space-occupying lesions (SOLs), such as intracranial tumors due to elevated intracranial pressure (ICP), and can be accompanied by syringomyelia. ACM and syringomyelia have been shown to resolve after resection of the SOL, without the need for adjuvant posterior fossa decompression. The vast majority of SOLs leading to ACM have been reported in the posterior fossa, thus exerting a direct mass effect on the cerebellum. Supratentorial SOLs leading to ACM are much less frequent but, when present, are most commonly parieto-occipital. We report a rare case of a large anterior left frontal, parasagittal meningioma causing ACM and syringomyelia. These findings resolved following the resection of the meningioma, with no further surgical intervention. Our case demonstrates that ACM can occur secondary to an anterior supratentorial mass and further supports the idea that decompression of the posterior fossa is not required for the resolution of intracranial tumor-associated ACM and syringomyelia.
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http://dx.doi.org/10.7759/cureus.7636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213766PMC
April 2020

Dissecting the default mode network: direct structural evidence on the morphology and axonal connectivity of the fifth component of the cingulum bundle.

J Neurosurg 2020 Apr 24;134(3):1334-1345. Epub 2020 Apr 24.

1Athens Microneurosurgery Laboratory, Evangelismos Hospital, Athens.

Objective: Although a growing body of data support the functional connectivity between the precuneus and the medial temporal lobe during states of resting consciousness as well as during a diverse array of higher-order functions, direct structural evidence on this subcortical circuitry is scarce. Here, the authors investigate the very existence, anatomical consistency, morphology, and spatial relationships of the cingulum bundle V (CB-V), a fiber tract that has been reported to reside close to the inferior arm of the cingulum (CingI).

Methods: Fifteen normal, formalin-fixed cerebral hemispheres from adults were treated with Klingler's method and subsequently investigated through the fiber microdissection technique in a medial to lateral direction.

Results: A distinct group of fibers is invariably identified in the subcortical territory of the posteromedial cortex, connecting the precuneus and the medial temporal lobe. This tract follows the trajectory of the parietooccipital sulcus in a close spatial relationship with the CingI and the sledge runner fasciculus. It extends inferiorly to the parahippocampal place area and retrosplenial complex area, followed by a lateral curve to terminate toward the fusiform face area (Brodmann area [BA] 37) and lateral piriform area (BA35). Taking into account the aforementioned subcortical architecture, the CB-V allegedly participates as a major subcortical stream within the default mode network, possibly subserving the transfer of multimodal cues relevant to visuospatial, facial, and mnemonic information to the precuneal hub. Although robust clinical evidence on the functional role of this stream is lacking, the modern neurosurgeon should be aware of this tract when manipulating cerebral areas en route to lesions residing in or around the ventricular trigone.

Conclusions: Through the fiber microdissection technique, the authors were able to provide original, direct structural evidence on the existence, morphology, axonal connectivity, and correlative anatomy of what proved to be a discrete white matter pathway, previously described as the CB-V, connecting the precuneus and medial temporal lobe.
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http://dx.doi.org/10.3171/2020.2.JNS193177DOI Listing
April 2020

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics.

Front Oncol 2019 17;9:417. Epub 2019 May 17.

Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.

The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.
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http://dx.doi.org/10.3389/fonc.2019.00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534082PMC
May 2019

Polysomy is associated with poor outcome in 1p/19q codeleted oligodendroglial tumors.

Neuro Oncol 2019 09;21(9):1164-1174

Department of Pathology, NYU Langone Health, New York, New York.

Background: Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status.

Methods: We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS).

Results: In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance.

Conclusions: The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors.
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http://dx.doi.org/10.1093/neuonc/noz098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571489PMC
September 2019

MR imaging phenotype correlates with extent of genome-wide copy number abundance in IDH mutant gliomas.

Neuroradiology 2019 Sep 27;61(9):1023-1031. Epub 2019 May 27.

Department of Pathology, NYU School of Medicine, New York, NY, USA.

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.
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http://dx.doi.org/10.1007/s00234-019-02219-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587301PMC
September 2019

Fingerprinting Orientation Distribution Functions in diffusion MRI detects smaller crossing angles.

Neuroimage 2019 09 16;198:231-241. Epub 2019 May 16.

Center for Advanced Imaging Innovation and Research (CAI(2)R), NYU School of Medicine, New York, NY, USA; Center for Biomedical Imaging, Dept. of Radiology, NYU School of Medicine, New York, NY, USA.

Diffusion tractography is routinely used to study white matter architecture and brain connectivity in vivo. A key step for successful tractography of neuronal tracts is the correct identification of tract directions in each voxel. Here we propose a fingerprinting-based methodology to identify these fiber directions in Orientation Distribution Functions, dubbed ODF-Fingerprinting (ODF-FP). In ODF-FP, fiber configurations are selected based on the similarity between measured ODFs and elements in a pre-computed library. In noisy ODFs, the library matching algorithm penalizes the more complex fiber configurations. ODF simulations and analysis of bootstrapped partial and whole-brain in vivo datasets show that the ODF-FP approach improves the detection of fiber pairs with small crossing angles while maintaining fiber direction precision, which leads to better tractography results. Rather than focusing on the ODF maxima, the ODF-FP approach uses the whole ODF shape to infer fiber directions to improve the detection of fiber bundles with small crossing angle. The resulting fiber directions aid tractography algorithms in accurately displaying neuronal tracts and calculating brain connectivity.
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http://dx.doi.org/10.1016/j.neuroimage.2019.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336899PMC
September 2019

Sequencing and curation strategies for identifying candidate glioblastoma treatments.

BMC Med Genomics 2019 04 25;12(1):56. Epub 2019 Apr 25.

Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians.

Methods: A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions.

Results: WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time.

Conclusion: These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.
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http://dx.doi.org/10.1186/s12920-019-0500-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485090PMC
April 2019

Direct RNA sequencing on nanopore arrays redefines the transcriptional complexity of a viral pathogen.

Nat Commun 2019 02 14;10(1):754. Epub 2019 Feb 14.

Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.

Characterizing complex viral transcriptomes by conventional RNA sequencing approaches is complicated by high gene density, overlapping reading frames, and complex splicing patterns. Direct RNA sequencing (direct RNA-seq) using nanopore arrays offers an exciting alternative whereby individual polyadenylated RNAs are sequenced directly, without the recoding and amplification biases inherent to other sequencing methodologies. Here we use direct RNA-seq to profile the herpes simplex virus type 1 (HSV-1) transcriptome during productive infection of primary cells. We show how direct RNA-seq data can be used to define transcription initiation and RNA cleavage sites associated with all polyadenylated viral RNAs and demonstrate that low level read-through transcription produces a novel class of chimeric HSV-1 transcripts, including a functional mRNA encoding a fusion of the viral E3 ubiquitin ligase ICP0 and viral membrane glycoprotein L. Thus, direct RNA-seq offers a powerful method to characterize the changing transcriptional landscape of viruses with complex genomes.
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http://dx.doi.org/10.1038/s41467-019-08734-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376126PMC
February 2019

Molecular Pathogenesis of Low-Grade Glioma.

Neurosurg Clin N Am 2019 Jan;30(1):17-25

Department of Neurosurgery, Kimmel Center for Stem Cell Biology, Laura and Isaac Perlmutter Cancer Center, Neuroscience Institute, Brain Tumor Center, NYU School of Medicine, 530 First Avenue, Skirball 8R, New York, NY 10016, USA. Electronic address:

Advances in genome sequencing have elucidated the genetics of low-grade glioma. Available evidence indicates a neomorphic mutation in isocitrate dehydrogenase (IDH) initiates gliomagenesis. Mutant IDH produces the oncometabolite 2-hydroxyglutarate, which inhibits enzymes that demethylate genomic DNA and histones. Recent findings by the authors and others suggest the ensuing hypermethylation alters chromatin conformation and the transcription factor landscape in brain progenitor cells, leading to a block in differentiation and tumor initiation. Work in preclinical models has identified selective metabolic and molecular vulnerabilities of low-grade glioma. These new concepts will trigger a wave of innovative clinical trials in the near future.
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http://dx.doi.org/10.1016/j.nec.2018.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260953PMC
January 2019

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma.

Sci Adv 2018 10 31;4(10):eaau5935. Epub 2018 Oct 31.

Department of Biochemistry and Molecular Pharmacology, NYUSoM, New York, NY, USA.

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
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http://dx.doi.org/10.1126/sciadv.aau5935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209383PMC
October 2018

Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma.

Clin Cancer Res 2019 02 5;25(4):1261-1271. Epub 2018 Nov 5.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York.

Purpose: Isocitrate dehydrogenase ()-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90% -mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in -mutant glioma.

Experimental Design: We evaluated expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous -mutant glioma tumorspheres was determined by cell viability assay.

Results: Compared to wild-type glioblastoma, -mutant gliomas have significantly higher RNA ( < 1 × 10) and protein by IHC ( = 0.0014 and < 4.3 × 10 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in -mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived -mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.

Conclusions: DLL3 is selectively and homogeneously expressed in -mutant gliomas and can be targeted with Rova-T in patient-derived -mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365589PMC
February 2019
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