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Cochlear Implantation of a Patient with Definitive Neurosarcoidosis
Svrakic, Maja; Golfinos, John G; Zagzag, David; Roland, J Thomas
PMID: 30480198
ISSN: 2473-974x
CID: 3500552
LOW-GRADE ASTROCYTOMA CORE MUTATIONS IN IDH1, P53 AND ATRX COOPERATE TO BLOCK DIFFERENTIATION OF HUMAN NEURAL STEM CELLS VIA EPIGENETIC REPRESSION OF SOX2 [Meeting Abstract]
Modrek, Aram; Golub, Danielle; Khan, Themasap; Prado, Jod; Bowman, Christopher; Deng, Jingjing; Zhang, Guoan; Rocha, Pedro; Raviram, Ramya; Lazaris, Harris; Kader, Michael; Dhaliwal, Joravar; Chi, Andrew; Golfinos, John; Tsirigos, Aristotelis; Zagzag, David; Snuderl, Matija; Skok, Jane; Neubert, Thomas; Placantonakis, Dimitris
ISI:000402766800146
ISSN: 1523-5866
CID: 2591472
Role of High-Resolution Dynamic Contrast-Enhanced MRI with Golden-Angle Radial Sparse Parallel Reconstruction to Identify the Normal Pituitary Gland in Patients with Macroadenomas
Sen, R; Sen, C; Pack, J; Block, K T; Golfinos, J G; Prabhu, V; Boada, F; Gonen, O; Kondziolka, D; Fatterpekar, G
BACKGROUND AND PURPOSE: Preoperative localization of the pituitary gland with imaging in patients with macroadenomas has been inadequately explored. The pituitary gland enhancing more avidly than a macroadenoma has been described in the literature. Taking advantage of this differential enhancement pattern, our aim was to evaluate the role of high-resolution dynamic MR imaging with golden-angle radial sparse parallel reconstruction in localizing the pituitary gland in patients undergoing trans-sphenoidal resection of a macroadenoma. MATERIALS AND METHODS: A retrospective study was performed in 17 patients who underwent trans-sphenoidal surgery for pituitary macroadenoma. Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were obtained. Using an ROI-based method to obtain signal-time curves and permeability measures, 3 separate readers identified the normal pituitary gland distinct from the macroadenoma. The readers' localizations were then compared with the intraoperative location of the gland. Statistical analyses were performed to assess the interobserver agreement and correlation with operative findings. RESULTS: The normal pituitary gland was found to have steeper enhancement-time curves as well as higher peak enhancement values compared with the macroadenoma (P < .001). Interobserver agreement was almost perfect in all 3 planes (kappa = 0.89). In the 14 cases in which the gland was clearly identified intraoperatively, the correlation between the readers' localization and the true location derived from surgery was also nearly perfect (kappa = 0.95). CONCLUSIONS: This study confirms our ability to consistently and accurately identify the normal pituitary gland in patients with macroadenomas with the golden-angle radial sparse parallel technique with quantitative permeability measurements and enhancement-time curves.
PMCID:6080601
PMID: 28495945
ISSN: 1936-959x
CID: 2548692
Mutant IDH1 and seizures in patients with glioma
Chen, Hao; Judkins, Jonathon; Thomas, Cheddhi; Wu, Meijing; Khoury, Laith; Benjamin, Carolina G; Pacione, Donato; Golfinos, John G; Kumthekar, Priya; Ghamsari, Farhad; Chen, Li; Lein, Pamela; Chetkovich, Dane M; Snuderl, Matija; Horbinski, Craig
OBJECTIVE: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. METHODS: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. RESULTS: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1wt) patients and in 59%-74% of IDH1mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. CONCLUSIONS: The D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.
PMCID:5419985
PMID: 28404805
ISSN: 1526-632x
CID: 2528312
Tumoral Presentation of Homonymous Hemianopia and Prosopagnosia in Cerebral Amyloid Angiopathy-Related Inflammation
Hainline, Clotilde; Rucker, Janet C; Zagzag, David; Golfinos, John G; Lui, Yvonne W; Liechty, Benjamin; Warren, Floyd A; Balcer, Laura J; Galetta, Steven L
While cerebral amyloid angiopathy is a common cause of lobar hemorrhage, rarely it may be associated with an inflammatory response, thought to be incited by amyloid deposits. We report a 73-year-old woman with an extensive cancer history who presented with tumor-like lesions and symptoms of homonymous hemianopia and prosopagnosia. Found to have cerebral amyloid angiopathy-related inflammation proven by brain biopsy, she was treated successfully with immunosuppression.
PMID: 28187081
ISSN: 1536-5166
CID: 2437622
A matched cohort comparison of clinical outcomes following microsurgical resection or stereotactic radiosurgery for patients with small- and medium-sized vestibular schwannomas
Golfinos, John G; Hill, Travis C; Rokosh, Rae; Choudhry, Osamah; Shinseki, Matthew; Mansouri, Alireza; Friedmann, David R; Thomas Roland, J Jr; Kondziolka, Douglas
OBJECTIVE A randomized trial that compares clinical outcomes following microsurgery (MS) or stereotactic radiosurgery (SRS) for patients with small- and medium-sized vestibular schwannomas (VSs) is impractical, but would have important implications for clinical decision making. A matched cohort analysis was conducted to evaluate clinical outcomes in patients treated with MS or SRS. METHODS The records of 399 VS patients who were cared for by 2 neurosurgeons and 1 neurotologist between 2001 and 2014 were evaluated. From this data set, 3 retrospective matched cohorts were created to compare hearing preservation (21 matched pairs), facial nerve preservation (83 matched pairs), intervention-free survival, and complication rates (85 matched pairs) between cases managed with SRS and patients managed with MS. Cases were matched for age at surgery (+/- 10 years) and lesion size (+/- 0.1 cm). To compare hearing outcomes, cases were additionally matched for preoperative Class A hearing according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines. To compare facial nerve (i.e., cranial nerve [CN] VII) outcomes, cases were additionally matched for preoperative House-Brackmann (HB) score. Investigators who were not involved with patient care reviewed the clinical and imaging records. The reported outcomes were as assessed at the time of the last follow-up, unless otherwise stated. RESULTS The preservation of preoperative Class A hearing status was achieved in 14.3% of MS cases compared with 42.9% of SRS cases (OR 4.5; p < 0.05) after an average follow-up interval of 43.7 months and 30.3 months, respectively. Serviceable hearing was preserved in 42.8% of MS cases compared with 85.7% of SRS cases (OR 8.0; p < 0.01). The rates of postoperative CN VII dysfunction were low for both groups, although significantly higher in the MS group (HB III-IV 11% vs 0% for SRS; OR 21.3; p < 0.01) at a median follow-up interval of 35.7 and 19.0 months for MS and SRS, respectively. There was no difference in the need for subsequent intervention (2 MS patients and 2 SRS patients). CONCLUSIONS At this high-volume center, VS resection or radiosurgery for tumors = 2.8 cm in diameter was associated with low overall morbidity. The need for subsequent intervention was the same in both groups. SRS was associated with improved hearing and facial preservation rates and reduced morbidity, but with a shorter average follow-up period. Facial function was excellent in both groups. Since patients were not randomly selected for surgery, different clinical outcomes may be of different value to individual patients. Both anticipated medical outcomes and patient goals remain the drivers of treatment decisions.
PMID: 27035174
ISSN: 1933-0693
CID: 2059352
Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-beta Small Molecule Inhibitor
Bayin, N Sumru; Ma, Lin; Thomas, Cheddhi; Baitalmal, Rabaa; Sure, Akhila; Fansiwala, Kush; Bustoros, Mark; Golfinos, John G; Pacione, Donato; Snuderl, Matija; Zagzag, David; Barcellos-Hoff, Mary Helen; Placantonakis, Dimitris
High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
PMCID:5156509
PMID: 27978994
ISSN: 1476-5586
CID: 2363642
Mutant IDH1 and thrombosis in gliomas
Unruh, Dusten; Schwarze, Steven R; Khoury, Laith; Thomas, Cheddhi; Wu, Meijing; Chen, Li; Chen, Rui; Liu, Yinxing; Schwartz, Margaret A; Amidei, Christina; Kumthekar, Priya; Benjamin, Carolina G; Song, Kristine; Dawson, Caleb; Rispoli, Joanne M; Fatterpekar, Girish; Golfinos, John G; Kondziolka, Douglas; Karajannis, Matthias; Pacione, Donato; Zagzag, David; McIntyre, Thomas; Snuderl, Matija; Horbinski, Craig
Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.
PMCID:5640980
PMID: 27664011
ISSN: 1432-0533
CID: 2374852
THE PROGNOSTIC VALUE OF POLYSOMY IN OLIGODENDROGLIAL TUMORS [Meeting Abstract]
Chen, Hui; Thomas, Cheddhi; Munoz, Felipe Andres; Alexandrescu, Sanda; Horbinskis, Craig; Olar, Adriana; McGuone, Declan; Camelo-Piragua, Sandra; Wang, Lu; Pentsova, Elena; Phillips, Joanna; Aldape, Ken; Iafrate, AJohn; Golfinos, John; Chi, Andress; Zagzag, David; Rosenblum, Marc; Ohman-Strickland, Pamela; Hameed, Meera; Snuderl, Matija
ISI:000398604102197
ISSN: 1523-5866
CID: 2545132
GPR133 PROMOTES HYPOXIA-DRIVEN TUMOR PROGRESSION IN GLIOBLASTOMA [Meeting Abstract]
Frenster, Joshua; Bayin, NSumru; Kane, Josh Robert; Rubenstein, Jordan; Modrek, Aram; Baitamal, Rabaa; Dolgalev, Igor; Rudzenski, Katie; Snuderl, Matija; Golfinos, John; Doyle, Werner; Pacione, Donato; Chi, Andrew; Heguy, Adriana; Shohdy, Nadim; MacNeil, Douglas; Huang, Xinyan; Parker, Erik; Zagzag, David; Placantonakis, Dimitris
ISI:000398604104099
ISSN: 1523-5866
CID: 2545192