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

Karajannis, Matthias A; Mauguen, Audrey; Maloku, Ekrem; Xu, Qingwen; Dunbar, Erin M; Plotkin, Scott R; Yaffee, Anna; Wang, Shiyang; Roland, J Thomas; Sen, Chandranath; Placantonakis, Dimitris G; Golfinos, John G; Allen, Jeffrey C; Vitanza, Nicholas A; Chiriboga, Luis A; Schneider, Robert J; Deng, Jingjing; Neubert, Thomas A; Goldberg, Judith D; Zagzag, David; Giancotti, Filippo G; Blakeley, Jaishri O
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 NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative 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 to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
PMID: 34224367
ISSN: 1538-8514
CID: 4932142

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study

Shepard, Matthew J; Xu, Zhiyuan; Kearns, Kathryn; Li, Chelsea; Chatrath, Ajay; Sheehan, Kimball; Sheehan, Darrah; Faramand, Andrew; Niranjan, Ajay; Kano, Hideyuki; Gurewitz, Jason; Bernstein, Kenneth; Liscak, Roman; Guseynova, Khumar; Grills, Inga S; Parzen, Jacob S; Cifarelli, Christopher P; Rehman, Azeem A; Atik, Ahmet; Bakhsheshian, Joshua; Zada, Gabriel; Chang, Eric; Giannotta, Steven; Speckter, Herwin; Wu, Hsiu-Mei; Kondziolka, Douglas; Golfinos, John G; Mathieu, David; Lee, Cheng-Chia; Warnick, Ronald E; Lunsford, L Dade; Sheehan, Jason P
BACKGROUND:Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE:To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS:An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS:A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION/CONCLUSIONS:AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.
PMID: 33469655
ISSN: 1524-4040
CID: 4861842

Functional connectivity of the default mode, dorsal attention and fronto-parietal executive control networks in glial tumor patients

Tordjman, Mickael; Madelin, Guillaume; Gupta, Pradeep Kumar; Cordova, Christine; Kurz, Sylvia C; Orringer, Daniel; Golfinos, John; Kondziolka, Douglas; Ge, Yulin; Wang, Ruoyu Luie; Lazar, Mariana; Jain, Rajan
PURPOSE/OBJECTIVE:Resting state functional magnetic resonance imaging (rsfMRI) is an emerging tool to explore the functional connectivity of different brain regions. We aimed to assess the disruption of functional connectivity of the Default Mode Network (DMN), Dorsal Attention Network(DAN) and Fronto-Parietal Network (FPN) in patients with glial tumors. METHODS:rsfMRI data acquired on 3T-MR of treatment-naive glioma patients prospectively recruited (2015-2019) and matched controls from the 1000 functional-connectomes-project were analyzed using the CONN functional toolbox. Seed-Based Connectivity Analysis (SBCA) and Independent Component Analysis (ICA, with 10 to 100 components) were performed to study reliably the three networks of interest. RESULTS:). For the FPN, increased connectivity was noted in the precuneus, posterior cingulate gyrus, and frontal cortex. No difference in the connectivity of the networks of interest was demonstrated between low- and high-grade gliomas, as well as when stratified by their IDH1-R132H (isocitrate dehydrogenase) mutation status. CONCLUSION/CONCLUSIONS:Altered functional connectivity is reliably found with SBCA and ICA in the DMN, DAN, and FPN in glioma patients, possibly explained by decreased connectivity between the cerebral hemispheres across the corpus callosum due to disruption of the connections.
PMID: 33528739
ISSN: 1573-7373
CID: 4789692

Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy

Vasudevaraja, Varshini; Rodriguez, Javier Hernaez; Pelorosso, Cristiana; Zhu, Kaicen; Buccoliero, Anna Maria; Onozato, Maristela; Mohamed, Hussein; Serrano, Jonathan; Tredwin, Lily; Garonzi, Marianna; Forcato, Claudio; Zeck, Briana; Ramaswami, Sitharam; Stafford, James; Faustin, Arline; Friedman, Daniel; Hidalgo, Eveline Teresa; Zagzag, David; Skok, Jane; Heguy, Adriana; Chiriboga, Luis; Conti, Valerio; Guerrini, Renzo; Iafrate, A John; Devinsky, Orrin; Tsirigos, Aristotelis; Golfinos, John G; Snuderl, Matija
Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.
PMID: 33274363
ISSN: 1554-6578
CID: 4694512

Skull Base Aerosol Generating Cases Amidst the COVID-19 Pandemic: An Experience from the Epicenter

Dastagirzada, Yosef; Klauberg, Olga; Sheerin, Kathleen; Lieberman, Seth; Lebowitz, Richard; McMenomey, Sean; Sen, Chandranath; Roland, J. Thomas; Golfinos, John G.; Pacione, Donato
Soon after the World Health Organization declared the severe acute respiratory syndrome coronavirus 2 a global health emergency on January 30, 2020, New York City was plagued by the virus and its health system and economy pushed to their limits. The majority of the limited neurosurgical data in relation to COVID-19 is anecdotal and the higher theoretical risk of transmission of the virus among skull base aerosol generating (SBAG) cases has not been investigated or discussed in a neurosurgical population. We discuss a series of 13 patients who underwent 15 SBAG surgical procedures during the peak of COVID-19 in our hospital system and the protocols use perioperatively for their procedures. Our data support that with proper preoperative testing, a well-delineated surgical algorithm, and appropriate personal protective equipment, emergent/urgent cases can be done safely in hospitals that are currently experiencing high volumes of COVID-19 cases as we did in March to May of 2020.
ISSN: 2193-634x
CID: 4832592

Improved Task-based Functional MRI Language Mapping in Patients with Brain Tumors through Marchenko-Pastur Principal Component Analysis Denoising

Ades-Aron, Benjamin; Lemberskiy, Gregory; Veraart, Jelle; Golfinos, John; Fieremans, Els; Novikov, Dmitry S; Shepherd, Timothy
Background Functional MRI improves preoperative planning in patients with brain tumors, but task-correlated signal intensity changes are only 2%-3% above baseline. This makes accurate functional mapping challenging. Marchenko-Pastur principal component analysis (MP-PCA) provides a novel strategy to separate functional MRI signal from noise without requiring user input or prior data representation. Purpose To determine whether MP-PCA denoising improves activation magnitude for task-based functional MRI language mapping in patients with brain tumors. Materials and Methods In this Health Insurance Portability and Accountability Act-compliant study, MP-PCA performance was first evaluated by using simulated functional MRI data with a known ground truth. Right-handed, left-language-dominant patients with brain tumors who successfully performed verb generation, sentence completion, and finger tapping functional MRI tasks were retrospectively identified between January 2017 and August 2018. On the group level, for each task, histograms of z scores for original and MP-PCA denoised data were extracted from relevant regions and contralateral homologs were seeded by a neuroradiologist blinded to functional MRI findings. Z scores were compared with paired two-sided t tests, and distributions were compared with effect size measurements and the Kolmogorov-Smirnov test. The number of voxels with a z score greater than 3 was used to measure task sensitivity relative to task duration. Results Twenty-three patients (mean age ± standard deviation, 43 years ± 18; 13 women) were evaluated. MP-PCA denoising led to a higher median z score of task-based functional MRI voxel activation in left hemisphere cortical regions for verb generation (from 3.8 ± 1.0 to 4.5 ± 1.4; P < .001), sentence completion (from 3.7 ± 1.0 to 4.3 ± 1.4; P < .001), and finger tapping (from 6.9 ± 2.4 to 7.9 ± 2.9; P < .001). Median z scores did not improve in contralateral homolog regions for verb generation (from -2.7 ± 0.54 to -2.5 ± 0.40; P = .90), sentence completion (from -2.3 ± 0.21 to -2.4 ± 0.37; P = .39), or finger tapping (from -2.3 ± 1.20 to -2.7 ± 1.40; P = .07). Individual functional MRI task durations could be truncated by at least 40% after MP-PCA without degradation of clinically relevant correlations between functional cortex and functional MRI tasks. Conclusion Denoising with Marchenko-Pastur principal component analysis led to higher task correlations in relevant cortical regions during functional MRI language mapping in patients with brain tumors. © RSNA, 2020 Online supplemental material is available for this article.
PMID: 33289611
ISSN: 1527-1315
CID: 4708782

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

Benjamin, Carolina; Ashayeri, Kimberly; Golfinos, John G; Placantonakis, Dimitris G; Silverman, Joshua; Kondziolka, Douglas
PURPOSE/OBJECTIVE: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/CONCLUSIONS: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.
PMID: 32860552
ISSN: 1573-7403
CID: 4587032

Introduction. COVID-19 and neurosurgery

Servadei, Franco; Arráez, Miguel A; Chen, Jincao; Golfinos, John G; Qureshi, Mahmood M
PMID: 33260136
ISSN: 1092-0684
CID: 4725562

Working Toward Consensus on Sporadic Vestibular Schwannoma Care: A Modified Delphi Study

Carlson, Matthew L; Link, Michael J; Driscoll, Colin L W; Haynes, David S; Billings, Heather A; Lohse, Christine M; Hall, Elissa R; Agazzi, Siviero; Barker, Frederick G; Brackmann, Derald E; Cueva, Roberto A; Golfinos, John G; Gurgel, Richard K; Kondziolka, Douglas; Kutz, J Walter; Neff, Brian A; Sheehan, Jason P; Van Gompel, Jamie J; Yu, Chung Ping
OBJECTIVE:To address variance in clinical care surrounding sporadic vestibular schwannoma, a modified Delphi study was performed to establish a general framework to approach vestibular schwannoma care. A multidisciplinary panel of experts was established with deliberate representation from key stakeholder societies. External validity of the final statements was assessed through an online survey of registered attendees of the 8th Quadrennial International Conference on Vestibular Schwannoma. STUDY DESIGN/METHODS:Modified Delphi method. METHODS:The panel consisted of 16 vestibular schwannoma experts (8 neurotology and 8 neurosurgery) and included delegates representing the AAOHNSF, AANS/CNS tumor section, ISRS, and NASBS. The modified Delphi method encompassed a four-step process, comprised of one prevoting round to establish a list of focus areas and three subsequent voting rounds to successively refine individual statements and establish levels of consensus. Thresholds for achieving moderate consensus, at ≥67% agreement, and strong consensus, at ≥80% agreement, were determined a priori. All voting was performed anonymously via the Qualtrics online survey tool and full participation from all panel members was required before procession to the next voting round. RESULTS:Through the Delphi process, 103 items were developed encompassing hearing preservation (N = 49), tumor control and imaging surveillance (N = 20), preferred treatment (N = 24), operative considerations (N = 4), and complications (N = 6). As a result of item refinement, moderate (4%) or strong (96%) consensus was achieved in all 103 final statements. Seventy-nine conference registrants participated in the online survey to assess external validity. Among these survey respondents, moderate (N = 21, 20%) or strong (N = 73, 71%) consensus was achieved in 94 of 103 (91%) statements, and no consensus was reached in 9 (9%). Of the four items with moderate consensus by the expert panel, one had moderate consensus by the conference participants and three had no consensus. CONCLUSION/CONCLUSIONS:This modified Delphi study on sporadic vestibular schwannoma codifies 100% consensus within a multidisciplinary expert panel and is further supported by 91% consensus among an external group of clinicians who regularly provide care for patients with vestibular schwannoma. These final 103 statements address clinically pragmatic items that have direct application to everyday patient care. This document is not intended to define standard of care or drive insurance reimbursement, but rather to provide a general framework to approach vestibular schwannoma care for providers and patients.
PMID: 33492814
ISSN: 1537-4505
CID: 4798842

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

Skandalakis, Georgios P; Komaitis, Spyridon; Kalyvas, Aristotelis; Lani, Evgenia; Kontrafouri, Chrysoula; Drosos, Evangelos; Liakos, Faidon; Piagkou, Maria; Placantonakis, Dimitris G; Golfinos, John G; Fountas, Kostas N; Kapsalaki, Eftychia Z; Hadjipanayis, Constantinos G; Stranjalis, George; Koutsarnakis, Christos
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.
PMID: 32330886
ISSN: 1933-0693
CID: 4402472