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Intravoxel Incoherent Motion Metrics as Potential Biomarkers for Survival in Glioblastoma

Puig, Josep; Sanchez-Gonzalez, Javier; Blasco, Gerard; Daunis-I-Estadella, Pepus; Federau, Christian; Alberich-Bayarri, Angel; Biarnes, Carles; Nael, Kambiz; Essig, Marco; Jain, Rajan; Wintermark, Max; Pedraza, Salvador
OBJECTIVE: Intravoxel incoherent motion (IVIM) is an MRI technique with potential applications in measuring brain tumor perfusion, but its clinical impact remains to be determined. We assessed the usefulness of IVIM-metrics in predicting survival in newly diagnosed glioblastoma. METHODS: Fifteen patients with glioblastoma underwent MRI including spin-echo echo-planar DWI using 13 b-values ranging from 0 to 1000 s/mm2. Parametric maps for diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were generated for contrast-enhancing regions (CER) and non-enhancing regions (NCER). Regions of interest were manually drawn in regions of maximum f and on the corresponding dynamic susceptibility contrast images. Prognostic factors were evaluated by Kaplan-Meier survival and Cox proportional hazards analyses. RESULTS: We found that fCER and D*CER correlated with rCBFCER. The best cutoffs for 6-month survival were fCER>9.86% and D*CER>21.712 x10-3mm2/s (100% sensitivity, 71.4% specificity, 100% and 80% positive predictive values, and 80% and 100% negative predictive values; AUC:0.893 and 0.857, respectively). Treatment yielded the highest hazard ratio (5.484; 95% CI: 1.162-25.88; AUC: 0.723; P = 0.031); fCER combined with treatment predicted survival with 100% accuracy. CONCLUSIONS: The IVIM-metrics fCER and D*CER are promising biomarkers of 6-month survival in newly diagnosed glioblastoma.
PMCID:4936699
PMID: 27387822
ISSN: 1932-6203
CID: 2179042

Neuroimaging of cerebrovascular complications in cancer patients

Chapter by: Nagpal, Prashant; Ellika, Shehanaz; Jain, Rajan
in: Handbook of neuro-oncology neuroimaging by Newton, Herbert B [Eds]
San Diego, CA, US: Elsevier Academic Press, 2016
pp. 797-810
ISBN: 978-0-12-800945-1
CID: 2259692

Assessing the Effects of Software Platforms on Volumetric Segmentation of Glioblastoma

Dunn, William D; Aerts, Hugo J W L; Cooper, Lee A; Holder, Chad A; Hwang, Scott N; Jaffe, Carle C; Brat, Daniel J; Jain, Rajan; Flanders, Adam E; Zinn, Pascal O; Colen, Rivka R; Gutman, David A
Background/UNASSIGNED:Radiological assessments of biologically relevant regions in glioblastoma have been associated with genotypic characteristics, implying a potential role in personalized medicine. Here, we assess the reproducibility and association with survival of two volumetric segmentation platforms and explore how methodology could impact subsequent interpretation and analysis. Methods/UNASSIGNED:Post-contrast T1- and T2-weighted FLAIR MR images of 67 TCGA patients were segmented into five distinct compartments (necrosis, contrast-enhancement, FLAIR, post contrast abnormal, and total abnormal tumor volumes) by two quantitative image segmentation platforms - 3D Slicer and a method based on Velocity AI and FSL. We investigated the internal consistency of each platform by correlation statistics, association with survival, and concordance with consensus neuroradiologist ratings using ordinal logistic regression. Results/UNASSIGNED:We found high correlations between the two platforms for FLAIR, post contrast abnormal, and total abnormal tumor volumes (spearman's r(67) = 0.952, 0.959, and 0.969 respectively). Only modest agreement was observed for necrosis and contrast-enhancement volumes (r(67) = 0.693 and 0.773 respectively), likely arising from differences in manual and automated segmentation methods of these regions by 3D Slicer and Velocity AI/FSL, respectively. Survival analysis based on AUC revealed significant predictive power of both platforms for the following volumes: contrast-enhancement, post contrast abnormal, and total abnormal tumor volumes. Finally, ordinal logistic regression demonstrated correspondence to manual ratings for several features. Conclusion/UNASSIGNED:Tumor volume measurements from both volumetric platforms produced highly concordant and reproducible estimates across platforms for general features. As automated or semi-automated volumetric measurements replace manual linear or area measurements, it will become increasingly important to keep in mind that measurement differences between segmentation platforms for more detailed features could influence downstream survival or radio genomic analyses.
PMCID:5870135
PMID: 29600296
ISSN: 2474-0713
CID: 3011032

Glioma Angiogenesis and Perfusion Imaging: Understanding the Relationship between Tumor Blood Volume and Leakiness with Increasing Glioma Grade

Jain, R; Griffithy, B; Alotaibi, F; Zagzag, D; Fine, H; Golfinos, J; Schultz, L
BACKGROUND AND PURPOSE: The purpose of this study was to investigate imaging correlates to the changes occurring during angiogenesis in gliomas. This was accomplished through in vivo assessment of vascular parameters (relative CBV and permeability surface-area product) and their changing relationship with increasing glioma grade. MATERIALS AND METHODS: Seventy-six patients with gliomas underwent preoperative perfusion CT and assessment of relative CBV and permeability surface-area product. Regression analyses were performed to assess the rate of change between relative CBV and permeability surface-area product and to test whether these differed for distinct glioma grades. The ratio of relative CBV to permeability surface-area product was also computed and compared among glioma grades by using analysis of variance methods. RESULTS: The rate of change in relative CBV with respect to permeability surface-area product was highest for grade II gliomas followed by grade III and then grade IV (1.64 versus 0.91 versus 0.27, respectively). The difference in the rate of change was significant between grade III and IV (P = .003) and showed a trend for grades II and IV (P = .098). Relative CBV/permeability surface-area product ratios were the highest for grade II and lowest for grade IV. The pair-wise difference among all 3 groups was significant (P < .001). CONCLUSIONS: There is an increase in relative CBV more than permeability surface-area product in lower grade gliomas, whereas in grade III and especially grade IV gliomas, permeability surface-area product increases much more than relative CBV. The rate of change of relative CBV with respect to permeability surface-area product and relative CBV/permeability surface-area product ratio can serve as an imaging correlate to changes occurring at the tumor microvasculature level.
PMID: 26206809
ISSN: 1936-959x
CID: 1684132

Idiopathic spinal cord herniation: an imaging diagnosis with a significant delay

Carter, Britton J; Griffith, Brent D; Schultz, Lonni R; Abdulhak, Muwaffak M; Newman, Daniel S; Jain, Rajan
BACKGROUND CONTEXT: Idiopathic spinal cord herniation (ISCH) is an underrecognized entity that is often underappreciated by the neurosurgery and neuroradiologic communities. This leads to delayed diagnosis, multiple imaging studies, other diagnostic tests, inappropriate surgeries, and repeat office visits. PURPOSE: To evaluate common associations between ISCH and patient demographics/clinical presentation and to analyze the potential for delayed diagnosis. PATIENT SAMPLE: Patient sample included those diagnosed with ISCH on imaging at our institution from June 20, 2005 to December 3, 2012. OUTCOME MEASURES: These were based on the patient improvement/stability/decline based on the patients' most recent clinic/office visit when compared with initial presentation. METHODS: A retrospective search of radiology reports was performed using Illuminate software from June 20, 2005 to December 3, 2012, using the search term "idiopathic spinal cord herniation." Clinical data were reviewed including patient's age, sex, presenting clinical symptoms, number and type of imaging studies performed as part of the workup, other diagnostic tests, pain procedures, surgeries, and time between original presentation and diagnosis of ISCH on imaging. RESULTS: A total of 55 patients had the search term "idiopathic spinal cord herniation" included in their radiology report, of which 37 patients were found to meet the imaging and clinical diagnosis of ISCH. The median time from presentation to imaging diagnosis was 20 months in patients younger than 60 years and 5 months in those 60 years or older (p=.02). Of the 37 patients evaluated, 27 (73%) had no change in symptoms, 5 patients (14%) experienced worsening of symptoms, and 5 (14%) experienced symptom improvement from original presentation to most recent office visit. Among all patients evaluated, three underwent repair of the ventral dural defect in ISCH, resulting in clinical improvement. There was a median of nine outpatient office visits, three magnetic resonance images (MRIs), and one electromyography (EMG) per patient presenting with ISCH. The most frequent complaints were neck/upper back pain in 70%, upper/lower extremity numbness/paresthesias/weakness in 49%, hyperreflexia in 22%, and burning chest pain in 22%. CONCLUSIONS: Prolonged time to diagnosis and subsequent treatment of ISCH protracts patient symptoms and is associated with redundant diagnostic tests and patient visits. Earlier use of MRI in younger patients (younger than 60 years) may be warranted in those with a clinical presentation suggestive of Brown-Sequard symptomatology. Increasing recognition of ISCH in imaging and surgical communities would lead to improved patient care.
PMID: 25857588
ISSN: 1878-1632
CID: 1685662

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Brat, Daniel J; Verhaak, Roel G W; Aldape, Kenneth D; Yung, W K Alfred; Salama, Sofie R; Cooper, Lee A D; Rheinbay, Esther; Miller, C Ryan; Vitucci, Mark; Morozova, Olena; Robertson, A Gordon; Noushmehr, Houtan; Laird, Peter W; Cherniack, Andrew D; Akbani, Rehan; Huse, Jason T; Ciriello, Giovanni; Poisson, Laila M; Barnholtz-Sloan, Jill S; Berger, Mitchel S; Brennan, Cameron; Colen, Rivka R; Colman, Howard; Flanders, Adam E; Giannini, Caterina; Grifford, Mia; Iavarone, Antonio; Jain, Rajan; Joseph, Isaac; Kim, Jaegil; Kasaian, Katayoon; Mikkelsen, Tom; Murray, Bradley A; O'Neill, Brian Patrick; Pachter, Lior; Parsons, Donald W; Sougnez, Carrie; Sulman, Erik P; Vandenberg, Scott R; Van Meir, Erwin G; von Deimling, Andreas; Zhang, Hailei; Crain, Daniel; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron; Bowen, Jay; Dicostanzo, Katie; Gastier-Foster, Julie; Leraas, Kristen M; Lichtenberg, Tara M; Pierson, Christopher R; Ramirez, Nilsa C; Taylor, Cynthia; Weaver, Stephanie; Wise, Lisa; Zmuda, Erik; Davidsen, Tanja; Demchok, John A; Eley, Greg; Ferguson, Martin L; Hutter, Carolyn M; Mills Shaw, Kenna R; Ozenberger, Bradley A; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Jensen, Mark A; Liu, Jia; Pihl, Todd; Raman, Rohini; Wan, Yunhu; Wu, Ye; Ally, Adrian; Auman, J Todd; Balasundaram, Miruna; Balu, Saianand; Baylin, Stephen B; Beroukhim, Rameen; Bootwalla, Moiz S; Bowlby, Reanne; Bristow, Christopher A; Brooks, Denise; Butterfield, Yaron; Carlsen, Rebecca; Carter, Scott; Chin, Lynda; Chu, Andy; Chuah, Eric; Cibulskis, Kristian; Clarke, Amanda; Coetzee, Simon G; Dhalla, Noreen; Fennell, Tim; Fisher, Sheila; Gabriel, Stacey; Getz, Gad; Gibbs, Richard; Guin, Ranabir; Hadjipanayis, Angela; Hayes, D Neil; Hinoue, Toshinori; Hoadley, Katherine; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven; Jones, Corbin D; Kucherlapati, Raju; Lai, Phillip H; Lander, Eric; Lee, Semin; Lichtenstein, Lee; Ma, Yussanne; Maglinte, Dennis T; Mahadeshwar, Harshad S; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew L; Mieczkowski, Piotr A; Moore, Richard A; Mose, Lisle E; Mungall, Andrew J; Pantazi, Angeliki; Parfenov, Michael; Park, Peter J; Parker, Joel S; Perou, Charles M; Protopopov, Alexei; Ren, Xiaojia; Roach, Jeffrey; Sabedot, Thais S; Schein, Jacqueline; Schumacher, Steven E; Seidman, Jonathan G; Seth, Sahil; Shen, Hui; Simons, Janae V; Sipahimalani, Payal; Soloway, Matthew G; Song, Xingzhi; Sun, Huandong; Tabak, Barbara; Tam, Angela; Tan, Donghui; Tang, Jiabin; Thiessen, Nina; Triche, Timothy Jr; Van Den Berg, David J; Veluvolu, Umadevi; Waring, Scot; Weisenberger, Daniel J; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Xu, Andrew W; Yang, Lixing; Zack, Travis I; Zhang, Jianhua; Aksoy, B Arman; Arachchi, Harindra; Benz, Chris; Bernard, Brady; Carlin, Daniel; Cho, Juok; DiCara, Daniel; Frazer, Scott; Fuller, Gregory N; Gao, JianJiong; Gehlenborg, Nils; Haussler, David; Heiman, David I; Iype, Lisa; Jacobsen, Anders; Ju, Zhenlin; Katzman, Sol; Kim, Hoon; Knijnenburg, Theo; Kreisberg, Richard Bailey; Lawrence, Michael S; Lee, William; Leinonen, Kalle; Lin, Pei; Ling, Shiyun; Liu, Wenbin; Liu, Yingchun; Liu, Yuexin; Lu, Yiling; Mills, Gordon; Ng, Sam; Noble, Michael S; Paull, Evan; Rao, Arvind; Reynolds, Sheila; Saksena, Gordon; Sanborn, Zack; Sander, Chris; Schultz, Nikolaus; Senbabaoglu, Yasin; Shen, Ronglai; Shmulevich, Ilya; Sinha, Rileen; Stuart, Josh; Sumer, S Onur; Sun, Yichao; Tasman, Natalie; Taylor, Barry S; Voet, Doug; Weinhold, Nils; Weinstein, John N; Yang, Da; Yoshihara, Kosuke; Zheng, Siyuan; Zhang, Wei; Zou, Lihua; Abel, Ty; Sadeghi, Sara; Cohen, Mark L; Eschbacher, Jenny; Hattab, Eyas M; Raghunathan, Aditya; Schniederjan, Matthew J; Aziz, Dina; Barnett, Gene; Barrett, Wendi; Bigner, Darell D; Boice, Lori; Brewer, Cathy; Calatozzolo, Chiara; Campos, Benito; Carlotti, Carlos Gilberto Jr; Chan, Timothy A; Cuppini, Lucia; Curley, Erin; Cuzzubbo, Stefania; Devine, Karen; DiMeco, Francesco; Duell, Rebecca; Elder, J Bradley; Fehrenbach, Ashley; Finocchiaro, Gaetano; Friedman, William; Fulop, Jordonna; Gardner, Johanna; Hermes, Beth; Herold-Mende, Christel; Jungk, Christine; Kendler, Ady; Lehman, Norman L; Lipp, Eric; Liu, Ouida; Mandt, Randy; McGraw, Mary; Mclendon, Roger; McPherson, Christopher; Neder, Luciano; Nguyen, Phuong; Noss, Ardene; Nunziata, Raffaele; Ostrom, Quinn T; Palmer, Cheryl; Perin, Alessandro; Pollo, Bianca; Potapov, Alexander; Potapova, Olga; Rathmell, W Kimryn; Rotin, Daniil; Scarpace, Lisa; Schilero, Cathy; Senecal, Kelly; Shimmel, Kristen; Shurkhay, Vsevolod; Sifri, Suzanne; Singh, Rosy; Sloan, Andrew E; Smolenski, Kathy; Staugaitis, Susan M; Steele, Ruth; Thorne, Leigh; Tirapelli, Daniela P C; Unterberg, Andreas; Vallurupalli, Mahitha; Wang, Yun; Warnick, Ronald; Williams, Felicia; Wolinsky, Yingli; Bell, Sue; Rosenberg, Mara; Stewart, Chip; Huang, Franklin; Grimsby, Jonna L; Radenbaugh, Amie J; Zhang, Jianan
BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
PMCID:4530011
PMID: 26061751
ISSN: 1533-4406
CID: 1685142

Clinical predictors of abnormal magnetic resonance imaging findings in patients with asymmetric sensorineural hearing loss

Ahsan, Syed F; Standring, Robert; Osborn, Daniel A; Peterson, Ed; Seidman, Michael; Jain, Rajan
IMPORTANCE: Asymmetric sensorineural hearing loss (ASNHL) is commonly encountered in an otolaryngologic clinical practice. Determining what factors are associated with abnormal magnetic resonance imaging (MRI) findings will help with diagnostic workup. OBJECTIVE: To evaluate the association between clinical and audiometric factors and abnormal MRI findings in patients with ASNHL. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review from an urban, tertiary referral center of 451 patients with ASNHL who underwent MRI testing between January 2005 and December 2011. MAIN OUTCOMES AND MEASURES: Medical records were reviewed for audiometric parameters as well as clinical presentation and compared with MRI results, which were categorized as abnormal, normal, or incidental. Data analysis included chi2 tests, logistic regression analysis, and multivariate analysis. RESULTS: A total of 48 patients (10.6%) had abnormal MRI findings. Only 21 patients (4.7%) had a mass of the cerebellopontine angle/internal auditory canal on MRI, making up 40% of all abnormal MRI findings. The next most common MRI finding was labyrinthitis (n = 13; 25%). Vertigo/dizziness (n = 20; P = .01), tinnitus (n = 18; P = .02), sudden hearing loss (n = 15; P = .054), and 15-dB asymmetry at 3 kHz (n = 39; P = .01) were associated with abnormal MRI findings. Loud noise exposure was associated with normal MRI findings. Logistic regression analysis showed that vertigo/dizziness (odds ratio [OR], 2.14; 95% CI, 1.15-3.96; P = .02), unilateral tinnitus (OR, 2.15; 95% CI, 1.14-4.03; P = .02), and 15-dB asymmetry at 3 kHz (OR, 2.62; 95% CI, 1.24-5.57; P = .01) were significantly associated with abnormal MRI findings. Multivariate analysis showed that only 15-dB asymmetry at 3 kHz (OR, 2.42; 95% CI, 1.07-5.50; P = .03) was significantly associated with an abnormal MRI finding. CONCLUSIONS AND RELEVANCE: This study found that asymmetry of 15 dB at 3 kHz on audiometry was associated with higher positive yield on use of MRI in evaluating patients with ASNHL. We recommend that patients who present with ASNHL with this audiometric characteristic undergo MRI as part of their diagnostic workup.
PMID: 25719460
ISSN: 2168-619x
CID: 1602512

Diffusion MRI quality control and functional diffusion map results in ACRIN 6677/RTOG 0625: A multicenter, randomized, phase II trial of bevacizumab and chemotherapy in recurrent glioblastoma

Ellingson, Benjamin M; Kim, Eunhee; Woodworth, Davis C; Marques, Helga; Boxerman, Jerrold L; Safriel, Yair; McKinstry, Robert C; Bokstein, Felix; Jain, Rajan; Chi, T Linda; Sorensen, A Gregory; Gilbert, Mark R; Barboriak, Daniel P
Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.
PMCID:4383029
PMID: 25672376
ISSN: 1791-2423
CID: 1522932

Perfusion Imaging in Neuro-Oncology: Basic Techniques and Clinical Applications

Griffith, Brent; Jain, Rajan
Perfusion imaging is a method for assessing the flow of blood occurring at the tissue level and can be accomplished by both CT and MR perfusion techniques. The use of perfusion imaging has increased substantially in the past decade, particularly in neuro-oncologic imaging, where it is has been used for brain tumor grading and directing biopsies or targeted therapy, as well as for the evaluation of treatment response and disease progression. This article discusses the basic principles and techniques of perfusion imaging, as well as its applications in neuro-oncology.
PMID: 25953286
ISSN: 1557-8275
CID: 1639742

Perfusion Imaging: Perfusion CT

Chapter by: Griffith, Brent; Jain, Rajan
in: Brain tumor imaging by Jain, Rajan; Essig, Marco [Eds]
New York : Thieme, [2015]
pp. ?-?
ISBN: 9781604068306
CID: 2560302