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EE-40: Prediction of Glioma Grade Based on Preoperative Imaging, Intraoperative ContrastEnhanced Ultrasound Compared to Perfusion Magnetic Resonance Imaging Noah Brauner, Mittul Gulati, Mark S. Shiroishi, Edward G. Grant, Ki-Eun Chang, Joshua Bakhsheshian, Eisha Christian, Gabriel Zada and Ilya Lekht Keck School of Medicine of the University of Southern California Los Angeles, CA Disclosures - Off-Label Use: - This presentation describes the off-label use of an FDA-approved microbubble ultrasound contrast agent (UCA) for the evaluation of gliomatous brain tumors. - Grant Support: - M.S.S. is supported in part by SC CTSI (NIH/NCRR/NCATS) Grant # KL2TR000131 and Toshiba American Medical Systems. Purpose - Histopathologic grading of gliomas has important implications on patient prognosis1. - Currently, preoperative imaging with contrast-enhanced MRI and perfusion MRI can be helpful to determine glioma grade prior to resection. - Intraoperative contrast enhanced ultrasound (iCEUS) offers an adjunct to MRI and may be more accurate at assessing glioma grade allowing for more precise tumor sampling and accurate patient prognosis2,3. Case Report - BE, a 71 year old female with history of prior resection of a right frontal atypical meningioma presents for a routine follow up MRI. Imaging Findings: Initial Follow-up MRI Axial T2-weighted (A) and FLAIR (B) images at the level of the third ventricle show enlargement of the right medial temporo-occipital gyrus with corresponding increased T2/FLAIR signal (arrows) and mild mass effect on the right lateral ventricle. No significant enhancement was noted on post contrast images (not pictured). A B Imaging Findings: Perfusion MRI Relative cerebral blood flow (rCBV) color map (A) with region of interest (ROI) signal intesnitytime curves (B) show increased rCBV in the anterior portion of the right temporo-occipital mass with 1.6x rCBV compared to the contralateral normal white matter, suggestive of low grade glioma4. B A Imaging Findings: iCEUS -How We Do It Schematic of Intraoperative Contrast Enhanced Ultrasound (iCEUS) UCA structure: Lipid shell with internal gas Ultrasound Contrast Agent (UCA): -45 sec agitation -0.3 ml IV bolus -followed by 10 ml NS flush Lungs Venous system Heart Pulmonary artery UCA lipid shell breaks -Shell metabolized -Inner gas released into bloodstream and exhaled Lungs Venous system Ultrasound Machine Brain: Lesion of Interest Pulmonary vein UCA particle size: 1-5 um t1/2 = ~1.3 min Pulmonary capillary size: ~5.5 um Pulse Inversion Imaging Mechanical index < 0.8 Cine images obtained Arterial system Heart Imaging Findings: Intraoperative Contrast Enhanced Ultrasound (iCEUS) - Based on prior work by Prada et al, different histopathologic grades of gliomas demonstrate distinct contrast enhancement patterns2. Arterial Phase * Time to CEUS Peak (TTP)* Venous Phase* Contrast Enhancement Low Grade Glioma 15 sec 20 sec 30 sec Mild Anaplastic Glioma 10 sec 15 sec 20-25 sec Mild-High Glioblastoma Multiforme 2-3 sec 5 sec 10 sec High *time measured from ultrasound contrast seen in the main adjacent parenchymal arteries. Imaging Findings: iCEUS iCEUS cine clip and corresponding Time-Intensity Curve (TIC) of the tumor (blue square/curve) compared to normal brain parenchyma (orange square/curve) show fast time-to-peak (TTP) of 12 sec, steep wash-in slope (WIS) and venous phase wash-out of the tumor, suggestive of high grade anaplastic glioma2 and discordant with perfusion MRI. Final Pathologic Diagnosis Anaplastic Astrocytoma (WHO grade III) Imaging findings: Companion Case - MRI 52 year old male with history of prior GBM status post resection and radiation therapy. Axial FLAIR (A) and T1-weighted post contrast (B) sequences show an enhancing mass in the right fronto-temporal lobe with surrounding edema-like signal. MRI perfusion scan with rCBV color map (C) and ROI perfusion curves (D) show a rCBV 2.5x higher than the contralateral normal parenchyma. Differential considerations include recurrent tumor versus radiation necrosis5. A C B D Imaging Findings: iCEUS - Recurrence vs. Radiation Necrosis - Evaluation of radiation necrosis with iCEUS by Mattei and Prada et al 3,6 showed no significant contrast enhancement on iCEUS versus gliomas which had characteristic enhancement patterns. Arterial Phase * Time to CEUS Peak (TTP)* Venous Phase* Contrast Enhancement Low Grade Glioma 15 sec 20 sec 30 sec Mild Anaplastic Glioma 10 sec 15 sec 20-25 sec Mild-High Glioblastoma Multiforme 2-3 sec 5 sec 10 sec High Radiation Necrosis none none none none *time measured from ultrasound contrast seen in the main adjacent parenchymal arteries. Imaging Findings: Companion case - iCEUS Side-by-side gray scale and iCEUS in the same patient shows contrast first entering the feeding artery (arrow-A) five seconds after injection (A). Peak enhancement occurs in the tumor at ten seconds (B). A representative image taken in the middle of the venous phase at 27 seconds (C) shows draining veins (arrow-C). Contrast enhancement pattern is compatible with recurrent GBM which was confirmed on pathology. Radiation necrosis would be expected to lack any significant enhancement. A B C Discussion Advantages of iCEUS - Visualization of dynamic tumor enhancement patterns. - More accurate evaluation of vascular perfusion (UCAs are purely intravascular agents and do not diffuse into interstitium). - Differentiation of radiation necrosis from recurrent tumor - UCAs are safe in renal failure and have extremely low adverse event rates7. Discussion Disadvantages of iCEUS - Sonographic window limited by size/shape of cranial defect. - Operator dependent. - No current fusion imaging between iCEUS and CT/MRI - Limited but growing amount of high quality evidence on the efficacy and utility of this emerging modality Discussion Future Directions - Differentiation of normal brain parenchyma from infiltrating gliomatous tissue during and after resection to improve patient outcomes. - Improved extent of resection = improved patient survival8 - Decreased normal parenchyma excision = decreased neurologic morbidity - Guidance of tumor tissue sampling to highest grade areas (prevention of inappropriate downgrading.) - iCEUS guided ablative therapy for small intracranial lesions. Summary - Gliomatous tumors represent a wide spectrum of neoplasms and delineation of these tumor’s histopathologic grade has important prognostic implications. - MRI, and particularly MRI perfusion, is a useful tool in evaluation of glioma grade pre-operatively but has its limitations. - The development of iCEUS as a modality may offer an additional and potentially more accurate way to evaluate glioma grade prior to resection. - iCEUS has many other potential advantages which may further help in the diagnosis and treatment of these devastating tumors. - Future prospective studies are needed to determine iCEUS utility in predicting tumor grade and how its predictive value compares to that of MRI perfusion examinations. References 1. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16 (Suppl 4):iv1–iv63, 2014 2.Prada F, Mattei L, Del Bene M, Aiani L, Saini M, Casali C, et al: Intraoperative cerebral glioma characterization with contrast enhanced ultrasound. BioMed Res Int 2014:484261, 2014 3. Prada F, Perin A, Martegani A, Aiani L, Solbiati L, Lamperti M, et al: Intraoperative contrast-enhanced ultrasound for brain tumor surgery. Neurosurgery 74:542–552, 2014 4. Law M, Yang S, Wang H, et al. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. AJNR Am J Neuroradiol 2003;24:1989–98. 5. Shah R, Vattoth S, Jacob R, et al. Radiation Necrosis in the Brain: Imaging Features and Differentiation from Tumor Recurrence. Radiographics 32: 1343-1359, 2012 6. Mattei L, Prada F, Legnani F, et al. Differentiating brain radionecrosis from tumor recurrence: A role for contrast enhanced ultrasound (CEUS)? Case report. Neuro Oncol. 16 (Suppl 2): ii84. 2014 (Abstract) 7. Piscaglia F, Bolondi L: The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 32:1369–1375, 2006 8. Sanai N, Berger MS: Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–764, 264–266, 2008