Abstracts to the resection cavity. The average patient age was 54.9 years. Nine patients had had a primary diagnosis of melanoma, eight had had non-small cell lung cancer (NSCLC), five had had renal cell carcinoma (RCC), two had had breast cancer, two had had cervical cancer, two had had colorectal cancer (CRC), and five had had other primary tumors. Twenty-one patients had received gamma knife, three patients had received synergy, and eight patients had received fractionated radiosurgery (FRS). The primary outcome measured was time to progression within the resection cavity. RESULTS: Long-term control was achieved in 88% of patients. The average time to recurrence for tumors that were not controlled was 381 days. CONCLUSION: High rates of local tumor control can be achieved with surgical resection in selected patients followed by stereotactic radiosurgery to the resection cavity. Further analysis is required, however, to identify factors correlated with increased tumor control. These findings suggest that adjuvant radiosurgery is a viable option for achieving local control within the resection cavity in patients with cerebral metastases. RADIOBIOLOGY RB-01. IN VITRO AND IN VIVO RADIOSENSITIZATION BY FGFR-1 INHIBITION USING THE ANTAGONIST SSR128129E IN HUMAN GLIOBLASTOMA MODELS Isabelle Ader 1, Caroline Delmas 2, Nicolas Skuli 1, Florence Darlot 1, Gilles Favre 1, Françoise Bono 3, Christine Toulas 1, and Elizabeth L. Cohen-Jonathan Moyal 1; 1INSERM, Institut Claudius Regaud; 2Institut Claudius Regaud, INSERM; 3Sanofi Aventis PURPOSE: Resistance of glioblastoma to radiotherapy is mainly due to tumor cell radioresistance, which is partially controlled by growth factors such as fibroblast growth factor (FGF). Because we have previously shown the role of FGF-2 through RhoB in tumor cell radioresistance, here we investigated whether FGF receptor (FGFR) inhibition may represent a new strategy to optimize the efficiency of radiotherapy in glioblastomas. METHODS: We first treated prior to irradiation four different human glioblastoma cell lines in vitro with the specific FGFR inhibitor, SSR12819E, and studied the radiosensitizer effect of this compound. We then investigated the effect of SSR12819E on the downstream pathway. We generated orthotopic xenografts in nude mice to study the in vivo radiosensitizer effect of SSR128129E. We studied the survival of the animals without any neurological signs. RESULTS: Treating glioma cells with SSR12819E increases the radiosensitivity of radioresistant glioma cell lines by activating radiation-induced mitotic cell death. This in vitro radiosensitizer effect of SSR128129E is a consequence of an SSR12819E-induced FGFR-1 internalization and ubiquitination and of an inhibition of radiation-induced RhoB activation. Treating hypoxic U87 cells with SSR128129E 1 mM led to the activation of the proteasome-dependant degradation of the hypoxia-inducible factor, HIF1alpha, suggesting a role of SSR128129E and thus of FGFR-1 inhibition in the regulation of hypoxia. Moreover, treating orthotopically U87 xenografted mice with SSR128129 before submitting the animals to two subsequent 2.5 Gy fractions significantly increased their survival compared with the other treatment groups. This in vivo radiosensitizer effect was not associated in our experimental conditions with the regulation of angiogenesis, demonstrating that controlling the intrinsic tumor cells’ radioresistance by inhibiting FGFR-1 pathways is sufficient to radiosensitize these tumors. CONCLUSION: Inhibiting FGFR-1 pathways with SSR128129E, the first-in-class compound able to inhibit FGF-2 binding to FGFR-1, may represent an interesting strategy to conceive new radiosensitizer agents. RB-03. ADJUVANT STEREOTACTIC RADIOSURGERY INCREASES TUMOR CONTROL RATES IN PATIENTS WITH CEREBRAL METASTASES AFTER SURGICAL RESECTION Christopher M. Jackson , Anubav Amin , Pokmeng See , Gustavo Pradilla , Eric Tryggestad , and Michael Lim ; Johns Hopkins University BACKGROUND: Cerebral metastases occur in 15% 2 20% of all cancer patients and are generally associated with dismal prognosis and considerable morbidity. Historically, the standard of care for patients with cerebral metastasis has been resection for solitary or symptomatic lesions followed by whole brain radiation therapy (WBRT). While WBRT has been associated with improved survival, the associated neurotoxicity can significantly affect cognitive function and quality of life. Stereotactic radiosurgery allows for local radiation delivery while minimizing exposure to healthy tissue and is therefore of considerable interest as a method of increasing control rates within the tumor bed while avoiding the neurotoxicity associated with WBRT. METHODS: This study is a retrospective analysis of a series of 32 patients with intracranial metastases who had undergone surgical resection followed by gamma knife, synergy, or fractionated radiosurgery iv112 NEURO-ONCOLOGY † NOVEMBER 2010 RB-04. WHOLE-BRAIN RADIATION OF ADULT MICE DEPLETES OLIGODENDROGLIAL PROGENITOR CELLS Celina Crisman , Peter Canoll , and Jeffrey Bruce ; Columbia University BACKGROUND: Radiation therapy confers an established survival advantage in glioblastoma multiforme patients and forms an integral component of treatment paradigms. Radiation damages dividing cells and thus primarily targets tumor cells; however, radiation’s effects may extend to any dividing cell within the field. Radiation’s detrimental effects on neural progenitors in areas such as the SVZ and hippocampus have been demonstrated; however, less is known regarding the in vivo effects of radiation on oligodendrocyte progenitor cells (OPCs), particularly at levels of radiation similar to those utilized in patients. This information is important, given the presence of OPCs throughout the brain, their role in maintaining myelinating glia, and their possible contributions to tumorigenesis. This study uses whole-brain radiation in mice at levels similar to those given in human treatment protocols and follows its effect on OPCs. METHODS: Adult mice received 60 Gy of radiation in 10 fractionated doses via a Cesium-137 irradiator. A 1.4-cm lead barrier with a cranial window limited exposure to the head. Irradiated mice and nonirradiated control mice were killed and perfused 2 weeks following the last dose of radiation. Immunohistochemistry for OPC markers, including Olig2 and PDGFRalpha, was performed. RESULTS: All mice survived radiation but demonstrated a marked reduction in OPCs in the cortex and subcortical white matter. CONCLUSION: These findings demonstrate that whole-brain radiation at doses comparable to those given to glioma patients has profound effects on OPCs. The depletion of OPCs likely contributes to white matter damage seen after radiation therapy. In addition, given the recent evidence that gliomas recruit OPCs, the depletion of OPCs could affect the dynamic of tumor recurrence after radiation. Further studies are needed to determine the consequences of radiation-induced depletion of OPCs in the setting of glioma therapy. RADIOLOGY RA-01. CELLULAR INVASION, MOTILITY, AND PROLIFERATION LEVEL ESTIMATES (CIMPLE MAPS): APPLICATION TO TEMOZOLOMIDE- AND BEVACIZUMAB-TREATED PATIENTS Benjamin M. Ellingson 1, Whitney B. Pope 1, Albert Lai 2, Phioanh L. Nghiemphu 2, and Timothy F. Cloughesy 2; 1Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles; 2Department of Neurology, David Geffen School of Medicine, University of California Los Angeles INTRODUCTION: Microscopic invasion of tumor cells and undetected tumor proliferation are the primary reasons for the dismal prognosis of glioblastoma. Identifying and quantifying spatially localized brain regions undergoing high rates of cell migration and proliferation is critical for improving patient survival; however, no noninvasive imaging biomarkers for estimating proliferation and migration rates of human gliomas in vivo are currently available. A mathematical model of macroscopic glioma growth has been developed based on the proliferation potential of gliomas and their ability to invade. On the basis of the strong correlation between tumor cell density and the apparent diffusion coefficient (ADC) estimated from diffusion magnetic resonance imaging, we hypothesized that this equation could be solved analytically and displayed on a voxel-wise basis for use in characterizing microscopic tumor growth and invasion. The resulting cell invasion, motility, and proliferation level estimates (CIMPLE) image maps represent a new method of quantifying the level of aggressive Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 inform the patient-specific model simulations, we have found that radiation response in these patients, quantified by both clinical and model-generated measures, could have been predicted prior to treatment with high accuracy. This result relies on a simplifying assumption of a homogeneous spherical geometry; however, we have previously used the mathematical model to illustrate the complex and essential role of the neuroanatomy in tumor morphology. Using the full three-dimensional RT dose prescribed clinically, we apply our model to the patients previously studied and present a detailed spatial analysis of the radiation model predictions to individual glioblastoma patients and highlight the model’s ability to predict disease response or progression on the full 3D architecture of the brain. These results and tools suggest that a mathematical model can create a virtual in silico tumor with the same growth kinetics as a particular patient and can not only predict treatment response in individual patients in vivo but also provide a basis for evaluation of response or progression of disease in each patient to any given therapy. Abstracts RA-03. ACCURATE IDENTIFICATION OF RECURRENT GLIOMAS BY KINETIC ANALYSIS OF a-METHYL-L-TRYPTOPHAN UNIDIRECTIONAL UPTAKE ON PET Csaba Juhasz , Sandeep Mittal , Otto Muzik , Diane C. Chugani , Pulak K. Chakraborty , Gautam Bahl , and Geoffrey R. Barger ; Wayne State University BACKGROUND: Most grade II-IV gliomas show increased alpha-[C-11]methyl-L-tryptophan (AMT) uptake on positron emission tomography (PET) before treatment. We analyzed the sensitivity and specificity of AMT kinetic variables derived from dynamic PET images to differentiate recurrent infiltrating gliomas from post-treatment changes. METHODS: Twenty-three adults (mean age, 49 years), with previously resected WHO grade II-IV gliomas and possible tumor recurrence underwent dynamic AMT PET scanning with blood input function 8 months to 8 years (mean, 3.4 years) after initial surgery. Previous postsurgical treatment included chemotherapy and/or radiation (21 patients) or no further therapy (2 patients). Kinetic AMT parameters, including the unidirectional uptake rate constant (K) and the transport rate (estimated by the volume of distribution, VD) were measured in magnetic resonance imaging (MRI)-detected lesions, and lesion/normal cortex ratios were also calculated. Tumor recurrence was determined by subsequent histology (11 patients) or based on at least 1-year follow-up with serial clinical and MRI evaluations. RESULTS: Fourteen patients had true tumor recurrence, and 9 patients showed no evidence of tumor on histopathology or long-term follow-up. MRI showed contrast-enhancing lesions suspicious for tumor recurrence in 19 patients, providing good sensitivity (86%) but low specificity (22%) for tumor recurrence. Both kinetic AMT PET variables (K and VD) and also lesion/cortex K and VD ratios were higher in recurrent tumors than in non-tumorous lesions, with the best group-separation provided by AMT K lesion/cortex ratios (2.2 + 0.6 vs. 1.1 + 0.2, respectively; P , 0.001). Using a cut-off value of 1.35 (i.e., a 35% increase) for maximal K ratios, recurrent tumors were detected with 100% sensitivity and 89% specificity; the only falsely classified lesion was a previous glioblastoma with no evidence of recurrence on subsequent histology following reoperation. CONCLUSIONS: Increased unidirectional uptake rate of AMT on dynamic PET can provide a highly sensitive and specific identification of recurrent low- and high-grade gliomas after surgery and chemoradiation. RA-04. NON-CONTRAST ENHANCEMENT IN GLIOBLASTOMA IS ASSOCIATED WITH IDH-1 MUTATION AND MULTIFOCALITY Jose A. Carrillo , Albert Lai , Phioanh (Leia) Nghiemphu , Anh Tran , Parham Moftakhar , Timothy F. Cloughesy , and Whitney B. Pope ; UCLA INTRODUCTION: It has previously been reported that the presence of non –contrast enhancing tumor (nCET) component in glioblastoma is associated with a favorable outcome. The IDH-1 mutation and MGMT promoter methylation also are associated with improved survival. We performed a retrospective analysis in a large set of patients to evaluate the contribution of IDH-1 genotype and MGMT to the benefit of nCET. METHODS: We identified 200 newly diagnosed glioblastoma multiforme (GBM) patients who were treated with upfront radiation and temozolomide at UCLA who had available preoperative MRI scans for evaluation and extensive clinical annotation. Scans were scored by a neuroradiologist for multiple imaging features, including the presence and amount of nCET+ tumor. MGMT methylation and IDH-1 mutation were determined by methylation-specific polymerase chain reaction and DNA sequencing. Overall and progressionfree survival (OS and PFS, respectively) were recorded. Differences in outcomes were assessed using Kaplan-Meier survival analysis and Fisher exact tests. RESULTS: nCET+ characteristics differed for multifocality and mutation of IDH-1 but not for age, gender, subtotal resection, presence of satellites, bevacizumab treatment, or MGMT methylation. For nCET+ tumors with IDH-1 mutation and nCET+ tumors with wild-type IDH-1, the median PFSs were 22.7 months and 8.3 months, respectively (P ¼0.003), and the median OSs were 35.2 months and 15.6 months, respectively (P ¼ 0.0007). The presence of nCET was associated with worse PFS and OS in patients with IDH-1 wild-type tumors, possibly because of increased multifocality. MGMT methylation was found in 37.9% of 182 GBMs. For unmethylated GBM, the presence or absence of nCET did not appear to affect PFS or OS. CONCLUSION: Preliminary data suggest that nCET+ GBMs are associated with the IDH-1 mutation and multifocality. More detailed survival analyses are being performed to evaluate the prognostic role of nCET. RA-05. MAGNETIC RESONANCE IMAGING SPECTROSCOPY IN PEDIATRIC ATYPICAL TERATOID/RHABDOID TUMORS Carol Bruggers , Kevin Moore , and Soumen Khatua ; University of Utah INTRODUCTION: Central nervous system (CNS) atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive malignancies diagnosed in very young children. Despite having initial chemosensitivity, most patients die of progressive disease, although long-term survival has occurred. AT/RTs shows distinctive histology, characteristic immunohistochemistry, and SMARCB1 gene mutations [1]. No distinguishing radiographic imaging findings exist. Brain computed tomography shows heterogeneous aggressive, hyper-dense tumors with occasional cysts, calcifications, necrosis, and hemorrhage. On magnetic resonance imaging, AT/RTs show isointensity on T1-weighted images and heterogeneous T2 shortening with gadolinium enhancement. Diffusion-weighted imaging demonstrates diffusion restriction, reflecting tumor cellularity [2]. However, these findings are common in aggressive pediatric brain tumors. Magnetic resonance spectroscopy (MRS) provides functional information regarding cell membrane metabolism, neuronal integrity, and energy metabolism. MRS has helped in differentiating gliomas, ependymomas, medulloblastomas, and choroid plexus tumors. However, scarce information regarding MRS utility for AT/RTs exists. OBJECTIVE: To determine childhood CNS AT/RT MRS patterns. MATERIALS AND METHODS: We performed an institutional retrospective review of MRS in children diagnosed with CNS AT/RT between 2007 and 2010. RESULTS: On short TE-MRS, 6 of 6 patients had elevated choline and lipid/lactate. No patients showed significant detectable NAA peaks. On long TE-MRS, all patients showed markedly elevated choline. Only 1 patient showed mild lactate elevation. CONCLUSIONS: MRS revealed AT/RT features characteristic of aggressive cellular malignant neoplasms. However, all patients also demonstrated marked lipid peak elevation, which is unusual in PNET-MB and may permit preoperative discrimination. Quantitative MRS analysis of larger PNET-MB and AT/RT series may aid in achieving more definitive diagnoses in the future. ([1] Packer RJ et al. Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 2002;24:337-42; [2] Cheng YC, et al. Neuroradiological findings in atypical teratoid/rhabdoid tumor of the central nervous system. Acta Radiol. 205 Feb 46: 89-96.) RA-06. IMAGING OF CNS METASTATIC LESIONS USING 18F-FLUOROTHYMIDINE PET Mary K.Gumerlock 1, EthanStolzenberg 1, Kar-MingFung 1, Mary L.Smith 1, Katarzyna Kedzierska 1, George Chacko 2, Robert B. Epstein 1, and Jennifer Holter 1; 1University of Oklahoma Health Sciences Center; 2 Midwest Medical Isotopes Magnetic resonance imaging (MRI) is the gold standard for diagnosing metastatic disease in the central nervous system (CNS). However, once treatment has been initiated, MRI becomes less specific in differentiating the effects of treatment from recurrent disease. While positron emission tomography (PET) with 2-deoxy-2-[F18]-fluoro-D-glucose (FDG) has become a mainstay of oncologic imaging for systemic malignancies, it has significant drawbacks in imaging CNS tumors because of high glucose uptake in normal brain tissue. Because of low cell turnover in normal brain, radiotracers selective to cell proliferation such as 3′ -deoxy-3′ -[F18]-fluorothymidine (FLT) may offer improved sensitivity and specificity in diagnosing CNS tumors. FLT is trapped in the cytosol of dividing cells after phosphorylation by thymidine kinase in DNA synthesis, thus affording a means to delineate tissue with a high proliferative index. Such an agent is therefore useful for both initial diagnosis and follow-up. We describe 5 patients with CNS metastases who underwent resection and postoperative follow-up. Patients had FLT-PET scanning 1 –12 days before surgery. Tumors identified on MRI NEURO-ONCOLOGY † NOVEMBER 2010 iv113 Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 malignant behavior. In the current study, we demonstrated the utility of CIMPLE maps to predict progression-free survival (PFS) and overall survival (OS) in patients with recurrent glioblastoma treated with either bevacizumab and temozolomide or temozolomide alone. METHODS: Seventeen patients with recurrent glioblastoma from our Neuro-Oncology database were included in this study. Ten patients were treated with bevacizumab and temozolomide, and 7 patients were given salvage temozolomide. Three sequential ADC maps were obtained at the beginning of treatment for use in calculating CIMPLE maps. RESULTS: Estimates of cell motility rate, cell proliferation rate, and invasion velocity were significantly higher in patients treated with bevacizumab and temozolomide than in patients treated with temozolomide alone. Stratification of patients based on levels of cell motility, proliferation, or invasion velocity could be used to predict PFS and OS. CONCLUSION: CIMPLE maps are a novel method of determining the level of aggressive malignant behavior and quantifying the effects of treatment. Abstracts RA-07. FINDING EARLY PROGNOSTIC MARKERS FROM METABOLIC AND PHYSIOLOGIC MR IMAGING PARAMETERS, FOR NEWLY DIAGNOSED GBM PATIENTS RECEIVING RADIATION, TEMOZOLOMIDE AND A PKC INHIBITOR Rupa Parvataneni 1, Achuta Kadambi 1, Ilwoo Park 1, Adam Elkhaled 1, Emma Essock-Burns 1, Inas Khayal 1, Nicolas Butowski 2, Kathleen Lamborn 2, Susan Chang 2, and Sarah Nelson 1; 1Surbeck Laboratory of Advanced Imaging, Department of Radiology and Biomedical Imaging; 2Department of Neurological Surgery, University of California INTRODUCTION: The purpose of this study was to use metabolic and physiologic magnetic resonance imaging parameters to identify prognostic markers in glioblastoma multiforme (GBM) patients receiving radiation (RT), temozolomide (TMZ), and a protein kinase C (PKC) inhibitor. METHODS: We identified 43 newly diagnosed GBM patients, with KPS . ¼ 60 and age . ¼ 18 yrs. Within 5 weeks of surgery patients received standard RT plus TMZ and a PKC inhibitor. A 3-T magnetic resonance scanner was used to image patients before RT and at 1 and 2 months into treatment. Parameters analyzed within the entire T2 abnormality included excess choline and creatine (median and summation) and lactate (maximum and summation). Parameters analyzed within contrast-enhancing lesions included choline-to-NAA index (average, standard deviation, and maximum) and apparent diffusion coefficient. Variables collected at that time point that were significant at P ≤0.15 in a univariate Cox proportional model (assessing progression-free survival from their respective time points) were included in a bootstrap analysis (B ¼ 500) in conjunction with a forward stepwise procedure based on Akaike criteria. Age was forced in the model, and the extent of resection was included with significant imaging variables. The same analysis was performed for overall survival. RESULTS: At baseline (max)lactate, (sum)choline, and (ave)CNI were selected in 72%, 70%, and 75% of the 500 bootstrap samples, respectively. Incorporating these parameters in a multivariable Cox proportional model yielded (max)lactate (HR, 1.06E5; P , .001), (sum)choline (HR, 0.87; P , .001), (ave)CNI (HR,1.56; P ¼ .01), and age (HR, 1.01; P ¼ .73). At month 1, (med)choline and (ave)CNI were selected in 74% and 88% of the samples, respectively, yielding (med)exCho (HR, 3.77; P ¼ .064), (ave)CNI (HR,1.98; P ¼ .005), and age (HR,1.09; P , .001) . CONCLUSION: The bootstrap resampling procedure suggests that the following parameters are potential predictors of PFS from their respective time points: baseline: maximum lactate, summation excess choline, and average CNI; month 1: median excess choline and average CNI. RA-08. MENINGIOMAS: CORRELATION OF APPARENT DIFFUSION COEFFICIENT VALUES AND HISTOPATHOLOGICAL SUBTYPE Eser Sanverdi 1, BurceOzgen 1, Kader Karli Oguz 1, FigenSoylemezoglu 2, and Melike Mut 3; 1Hacettepe University Department of Radiology; 2Hacettepe University Department of Pathology; 3Hacettepe University Department of Neurosurgery, Institute of Nerurological Sciences and Psychiatry Meningiomas are mainly benign lesions. However, atypical or malignant subtypes have more aggressive clinical courses with higher recurrence rates. The purpose of this study was to preoperatively assess the different histopathological subtypes of meningiomas using apparent diffusion coefficient (ADC) values. Magnetic resonance images of 109 patients (40 men and 69 women; mean age, 48.5 years; age range, 21 –82 years) treated from 2002 to 2008 were retrospectively evaluated. Mean tumor size and the degree of associated edema were noted. The TRACE signal intensity of the lesions was evaluated and graded. ADC values were recorded as the mean of 3 measurements from different areas of the lesion. ADC value of contralateral normal-appearing subcortical parietal white matter (WM) was measured; an ADC ratio of meningioma/WM was calculated for the purpose of iv114 NEURO-ONCOLOGY † NOVEMBER 2010 normalization. Twenty-nine patients had histopathological diagnosis of atypical or malignant meningioma. The measured mean ADC values were 0.84 + 0.1 × 1023 mm2/s for meningiomas; 0.82 + 0.1 × 1023 mm2/s for atypical or malignant tumors, 0.85 + 0.12 × 1023 mm2/s for benign tumors, and 0.75 + 0.8 × 1023 mm2/s for WM. The calculated ADC ratios were 1.02 + 0.15 for atypical/malignant tumors and 1.17 + 0.07 for benign ones. The ADC ratios of malignant and benign lesions were statistically different (P , 0.001). By the ROC analysis, an ADC value of 1.08 + 0.04 × 1023 mm2/s was found as a cut-off value (P , 0.001), with a sensitivity of 72% and a specificity of 87%. Sex, age, and tumor size showed no statistically significant difference. For the subtypes of benign meningiomas, ADC values were not a distinguishing feature. The mitotic activity rates and proliferation indexes of atypical or malignant meningiomas were statistically significant from the ones in the benign subgroup. ADC ratios were found to be useful in distinguishing malignant meningiomas from benign meningiomas and could be used to predict this aggressive subtype preoperatively to better guide patient management. RA-09. POSTMORTEM PATHOLOGICAL CORRELATION OF INCREASING MRI T2/FLAIR HYPERINTENSITY CHANGES IN GLIOBLASTOMA PATIENTS AFTER TREATMENT WITH BEVACIZUMAB Jay-Jiguang Zhu , Rolf Pfannl , Daniel Do-Dai , Kevin Yao , John Mignano , Julian K. Wu , and Nadine Linendoll ; Tufts Medical Center Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with a median overall survival of 14.5 months despite aggressive therapy including surgical resection, radiation, and adjuvant chemotherapy with temozolomide. Bevacizumab, an antiangiogenic agent, has emerged as an effective treatment option for patients with progressive GBM. Historically, magnetic resonance imaging (MRI) has been the primary imaging modality used to monitor GBM tumor burden and treatment response. Before the bevacizumab era, tumor progression was usually associated with increasing enhancement on post-contrast T1-weight images and worsening T2-prolongation on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. However, with bevacizumab treatment, a discordant finding between post-contrast T1 and FLAIR images is frequently observed in many GBM patients. Although lesion(s) apparently improve or are stable on post-contrast T1 images, there are progressively increasing areas of hyperintense FLAIR signal in the surrounding and distant white matter. The speculated causes for the FLAIR changes include direct tumor infiltration, radiation changes, vasogenic edema, or a combination of the above. To determine the anatomic and physiologic correlates of these bevacizumabspecific changes, we collected 5 brains postmortem from GBM patients who received bevacizumab treatment. Coregistration of MRI abnormalities, radiation fields, and detailed pathological examination of 3 brains revealed the progressive reduction of tumor burden with increasing distance from the original tumor mass or surgical site. However, in areas with FLAIR hyperintensities on MRI, which were far away from tumor masses or cavities and also outside radiation fields and included the contralateral hemisphere, we could not identify tumor cells. This finding supports the hypothesis that these changes are not directly related to tumor infiltration. At the meeting, we will present the pathological examination results of all 5 postmortem brains as well as the immunohistochemistry studies with angiogenesis factors and GBM tumor markers. RA-10. USING ADVANCED MR IMAGING TO DETERMINE HIGH-RISK REGIONS IN PATIENTS WITH HIGH-GRADE GLIOMAS AND POTENTIAL CHANGES IN RADIATION PLANS Kathryn Beal , Tim Chan , Yoshiya Yamamda , Andrei Holodny , Philip H. Gutin , Zhigang Zhang , and Robert J. Young ; MSKCC PURPOSE: To assess advanced magnetic resonance imaging (MRI) before and after radiation therapy (RT) for high-grade gliomas (HGGs) to determine whether high-risk regions for recurrence can be identified. MATERIALS AND METHODS: Sixteen patients were enrolled in a prospective, IRB-approved study of advanced MRI before and after RT for HGGs. Eligibility criteria included histologically confirmed HGG and age ≥ 18 years. Patients received RT on the basis of standard MRI findings. Eight patients were treated with hypofractionated RT (36 Gy in 6 fractions) with concurrent temozolomide (TMZ) and bevacizumab; 7 patients with standard RT (60 Gy in 30 fractions) with concurrent TMZ; and 1 patient with abbreviated RT (40 Gy in 15 fractions) with concurrent TMZ. All patients underwent advanced MRI (perfusion, spectroscopy, and diffusion tensor) before and after RT. RESULTS: Median follow-up after pre-RT MRI was 8.4 months (range, 3.2– 12.1 months). Three patients had radiographic progression; the median progression-free survival was 6.7 months (range, Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 were correlated with FLT-PET uptake. Semiquantitative analysis using standard uptake values (SUVs) was performed. Tumor tissue was submitted for histopathology that included Ki-67 indices. Correlation coefficients and standard regression analyses were performed. Diagnoses included mucinsecreting adenocarcinoma, squamous cell carcinoma, adenocarcinomas of lung and breast origin, and diffuse large B-cell lymphoma. MRI showed tumor volumes of 9.1–55.9 cm3 (mean, 24.6 cm3; median,17.3 cm3); FLT tumor volumes of 1.2 –97.3 cm3 (mean, 32.9 cm3; median, 22.7 cm3); SUVs of 0.58 –21.5 (mean, 6.6; median, 3.8); and Ki-67 of 34 –47 (mean, 43.2; median, 46). High signal-to-noise ratios enabled the ready determination of FLT tumor volume. As expected, SUVs and Ki-67 indices were elevated. We conclude that FLT-PET is more sensitive than MRI in delineating the extent of metastatic disease in the CNS. Documentation of treatment response and survival prediction await further patient follow-up. Abstracts RA-11. USING SUSCEPTIBILITY-WEIGHTED IMAGING TO PREDICT RESPONSE TO COMBINED ANTI-ANGIOGENIC, CYTOTOXIC, AND RADIATION THERAPY IN GBM PATIENTS Janine M. Lupo 1, Emma Essock-Burns 2, Soonmee Cha 2, Susan M. Chang 2, Nicholas Butowski 2, and Sarah J. Nelson 2; 1University of California; 2 University of California, San Francisco Susceptibility-weighted imaging (SWI) is a powerful tool for highresolution imaging of the vasculature that has been shown to improve the diagnosis of brain neoplasms. The goal of this study was to investigate whether the amount of SWI hypointensity (SWI-h) within the postgadolinium contrast-enhancing lesion (CEL) on the postsurgical pretreatment scan could predict response in patients with newly diagnosed glioblastoma multiforme (GBM) who received concomitant antiangiogenic, cytotoxic, and radiation therapy. After GBM resection, 25 patients were imaged before therapy and then scanned serially every 2 months while on therapy until progression. In addition to standard clinical magnetic resonance imaging, high-resolution T2*-weighted SWI was performed on a 3-T scanner. The SWI images were thresholded within the contrast-enhancing lesion to calculate the volume of SWI-h within the enhancement for each patient’s pretreatment scan. Progression-free survival (PFS), calculated from the baseline pre-therapy scan to radiologic progression, and overall survival (OS) were used to assign patients to 1 of 3 response groups: 1) nonresponders (PFS , 6 months, OS , 12 months); 2) intermediate responders (PFS 6– 12 months, OS 12 –18 months); and 3) sustained responders (PFS . 12 months, OS . 18 months). For OS- and PFS-based response categories, the percent of SWI-h within the CEL was significantly higher in sustained responders than in non-responders, suggesting that tumors with a larger extent of damaged vasculature initially are more likely to benefit from a treatment regimen containing an antiangiogenic agent. Spearman rank correlation coefficients showed good association between the percent of SWI-h within the CEL and PFS and OS (P , 0.001), with a greater amount of SWI-h indicating a more favorable prognosis. Adjusting for baseline KPS, age, and extent of resection, multivariate Cox regression analysis showed that the percent of SWI-h within the CEL was predictive of both PFS and OS (HR, 0.961 and 0.935, respectively; P , 0.005). These early differences suggest that SWI is especially advantageous for determining which patients would benefit most from a given therapy and provide clinicians with a tool for identifying the best candidates for diverse therapeutic strategies. RA-12. UNIDIMENSIONAL VERSUS VOLUMETRIC ASSESSMENT IN GLIOMA PATIENTS TREATED WITH TEMOZOLOMIDE (TMZ): RESCUE TRIAL RESULTS Normand Laperriere 1, James Perry 2, David Macdonald 3, Warren Mason 1, Jay Easaw 4, Rolando Del Maestro 5, Walter Kucharczyk 6, Douglas Hussey 1, Kim Greaves 7, Steven Moore 7, and Jean-Francois Pouliot 7; 1Princess Margaret Hospital; 2Sunnybrook Health Sciences Centre; 3London Regional Cancer Centre; 4Tom Baker Cancer Centre; 5Montreal Neurological Institute and Hospital; 6University Health Network; 7Merck INTRODUCTION: Several methods to standardize the assessment of tumor response in cancer trials have been introduced. The Response Evaluation Criteria in Solid Tumors (RECIST, 2000; revised 2009) measure the longest tumor diameter (1-dimensional assessment). The World Health Organization criteria (WHO, 1979; revised 1981) multiply the longest tumor diameter with the longest perpendicular diameter (2-dimensional assessment). Both methods are limited in that the criteria were developed to standardize reporting rather than as precise measures of tumor changes; results vary with slice angle, and insensitivity to asymmetric tumor changes is common. Advances in imaging software now enable 3dimensional volumetric assessments of actual tumor size. METHODS: The primary objective of this retrospective analysis was to compare the response and progression evaluation as assessed by RECIST, WHO criteria, and volumetric analysis in glioma patients treated with continuous dose-intense temozolomide (TMZ) in the phase II RESCUE trial. Secondary objectives included comparing automated RECIST (MERGE I-Response) to center evaluations. RESULTS: A total of 111 patients had 2 or more data points and were considered evaluable. Automated evaluation led to a median increase of 0.64 cm in the longest tumor diameter. Perfect correlation of the 3 methods occurred in 66% of patients; sensitivity differences were noted in 24% of patients; and no correlation was observed in 10% of patients. Using the 3 methods, a correlation between response or disease stabilization and median time to progression and overall survival could be obtained. CONCLUSIONS: Volumetric assessment appeared to be a more sensitive measure of early treatment response or tumor progression. Standard conversion factors may be inaccurate and do not allow exact interchangeability between methods. Volumetric assessment, as a more sensitive method of detecting clinical changes, may provide important advantages in clinical studies by increasing the number of patients evaluable for response and providing better correlation of radiological and clinical outcomes. RA-13. PRE-CONTRAST MRI T1 HYPERINTENSITIES IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED WITH BEVACIZUMAB Paula K. Rauschkolb , Scott D. Smith , Clifford J. Belden , Enrico C. Lallana , and Camilo E. Fadul ; Dartmouth-Hitchcock Medical Center BACKGROUND: Bevacizumab alone or in combination with other agents is frequently used as second-line therapy for recurrent glioblastoma (GBM). The response rate is between 30% and 60% with improvement in 6-month progression-free survival. However, most patients will have progression, and there are no biomarkers that correlate with outcome. We observed precontrast T1 hyperintensities in the region of the tumor bed in many of these patients; this study examined patient and imaging characteristics that correlate with this finding and its implications with respect to clinical outcome. METHODS: We reviewed data from patients with primary GBM who received bevacizumab upon recurrence. Magnetic resonance imaging (MRI) studies performed before and after treatment were reviewed, and volumetric analysis was performed using semi-automated segmentation. RESULTS: Twenty-one patients met the inclusion criteria. Of the 16 patients who had no evidence of pre-contrast T1 hyperintensity on MRI prior to receiving bevacizumab, 12 developed T1 hyperintensity on MRI after receiving bevacizumab. Three of the 5 patients whose scans revealed pre-contrast T1 hyperintensities prior to receiving bevacizumab had an increase in volume after treatment. There were no differences in patient characteristics between groups. The correlation between MRI findings and progression free survival and overall survival is being analyzed. CONCLUSIONS: Approximately 75% of patients included in this study developed new pre-contrast T1 hyperintensities on MRI or an increase in the volume from that measured prior to treatment. The correlation between clinical outcomes and the presence or volume change of these pre-contrast T1 findings is being analyzed. RA-14. INTER-OBSERVER AGREEMENT OF PRE- AND POSTOPERATIVE MRI VOLUMETRIC MEASUREMENTS OF MENINGIOMAS AND THEIR DURAL TAIL LisetteBosscher , MariamSlot , E.Sanchez , B M.Uitdehaag , W P.Vandertop , and S. M. Peerdeman ; VU University Medical Center INTRODUCTION: The extent of resection of meningioma and dural tail are correlated with clinical outcome after surgery. Our aim was to establish the interobserver variability of magnetic resonance imaging (MRI) volumetric measurements of tumor and dural tail. The extent of resection can influence clinical decisions adjuvant therapy and follow-up imaging. METHODS: We studied pre- and postoperative MRI scans of prospectively collected patients. Scans were performed before surgery, ,72 hours after surgery, and 3 months after surgery. T1-weighted MP-rage series for 3-dimensional reconstruction were used. All scans were performed on a 1.5-T MRI system. Meningioma volumes were measured using Brainlab iPlan. Measurements were made by a neurosurgeon and a neuroradiologist. Tumor volume, dural tail volume, and total volume (tumor including tail) were measured. Dural tail was defined as thickening of the meninges of twice the normal thickness of the dura, tapering away from the tumor, with contrast enhancement on 2 successive slices. RESULTS: Thirty-three patients (35 meningiomas) were included. Tumor volumes ranged from 1.627 to 113.426 cm3. Dural tail volumes ranged from 0 to 10.931 cm3. The correlation of preoperative measurement of total volume was 0.991 (P , 0.01). Following surgery, the correlation was 0.630 (P , 0.01) for postoperative measurement , 72 hours and 0.518 (P , 0.01) for 3 months postoperatively. Correlation coefficients for dural NEURO-ONCOLOGY † NOVEMBER 2010 iv115 Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 2.5 –11.2 months). Two patients, one of whom had progressive disease, died. A comparison of immediate pre- and post-treatment MRI revealed no change in spectroscopy findings, with mean Cho/NAA ratios ranging from 3.3 to 3.6; no change in diffusion tensor metrics; and decreased perfusion, with mean rCBV values ranging from 2.8 to 1.9. The 3 patients with progressive disease showed persistently low rCBV values (mean, 1.0). Progression occurred along the major tracts extending from the treatment site, as predicted by diffusion tractography. CONCLUSION: In the limited number of recurrences in this study, quantitative spectroscopy, perfusion, and diffusion tensor abnormalities were not useful for predicting the location of recurrence. Diffusion tractography may have predictive value and may potentially modify RT plans, as progression developed along white matter tracts close to but not within the high-dose region of RT. Further analysis of the recurrence patterns with respect to these sequences, particularly tractography, is warranted. Abstracts tail and tumor volume separately show a similar decrease of correlation after operation. CONCLUSIONS: On preoperative MRI, interobserver correlation was high. Interobserver correlation deteriorated on postoperative MRI, which suggests that postoperative changes influence interobserver variability for residual tumor volume. There was no difference in interobserver variability between MRI , 72 hours after surgery MRI at 3 months after surgery. Correlation for dural tail measurement was low for all time points. Follow-up data after 1 year are not yet complete. Further study will establish the importance of these findings with regard to meningioma growth and recurrence. result of a learning effect since the observers had already assessed the first postoperative MRI. Although one would expect the surgeon to overestimate the amount of tumor resection, we found the opposite to be true. Further follow-up with MRI 1 year postoperatively will be performed. RA-15. LONGITUDINAL CHANGES IN WHITE MATTER FOLLOWING RADIATION AND BEVACIZUMAB THERAPY: A DIFFUSION TENSOR IMAGING STUDY Deborah T. Blumenthal , Felix Bokstein , Moran Artzi , Mika Palmon , Orna Aizenstein , Razi Sitt , Karen Gurevich , Andy Kanner , Zvi Ram , Benjamin Corn , and Dafna Ben Bashat ; Tel Aviv Sourasky Medical Center INTRODUCTION: Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor. The objective responses found in the treatment of recurrent malignant glioma are attributable to the normalization of tumor vasculature and may not represent a direct antitumor effect. Magnetic resonance diffusion-weighted imaging (DWI) has been suggested as a potential marker of antitumor effect. Specific radiographic findings associated with outcome have not been fully elucidated. METHODS: We performed a retrospective analysis of 80 patients with relapsed malignant glioma who started bevacizumab therapy between January 2008 and September 2009. MRI was performed before treatment (baseline), every 6 to 8 weeks during treatment, and at the time of disease progression. Objective response, median progression-free survival (PFS), median overall survival (OS), and infiltrative tumor progression were evaluated in reference to the presence or absence of restricted diffusion (RD) on DWI. RESULTS: Fifty-nine patients (39 men and 20 women) were eligible for review. Twenty-one patients were excluded because of insufficient imaging or clinical information. The median age was 52 years (range, 22 – 76 years). Forty-six patients had glioblastoma, and 13 patients had anaplastic gliomas. The development and subsequent progression of RD was associated with a trend toward reduced PFS (15 vs 26 weeks) and OS (27 weeks vs 37.5 weeks). The presence of RD on baseline MRI was associated with reduced PFS (15.5 vs 22.5 weeks) but not OS (32 vs 37.5 weeks). The development of RD associated with focal neurological symptoms was associated with a trend toward reduced PFS (15 vs 25 weeks) and OS (27 vs 37.5 weeks). CONCLUSION: The correlation of changes on DWI with clinical and standard radiographic findings may be useful in predicting outcome in patients undergoing therapy with bevacizumab, as the presence of either restricted diffusion pre-treatment or the development of symptomatic or progressive areas of restricted diffusion. RA-16. CORRELATION BETWEEN THE SIMPSON GRADING SYSTEM AND POSTOPERATIVE MRI-FINDINGS AFTER SURGICAL TREATMENT OF MENINGIOMAS Mariam Slot , L. Bosscher , E. Sanchez , B. M. Uitdehaag , W. P. Vandertop , and S. M. Peerdeman ; VU University Medical Center The Simpson Grading System, introduced in 1957, is a subjective measure of the extent of meningioma resection. We studied the correlation of this subjective measure with postoperative magnetic resonance imaging (MRI) findings. METHODS: Data were prospectively collected. Simpson grade was given by the surgeon immediately after surgery and before imaging. MRI was performed , 72 hours after surgery and 3 months after surgery. Scans were scored independently by a neurosurgeon and a neuroradiologist. Both were blinded to the Simpson grade. Interobserver agreement on MRI assessment and agreement on extent of resection between the surgeon and MRI assessors were evaluated using weighted kappa statistics. RESULTS: Thirty-four patients (36 meningiomas) were included. Interobserver agreement on MRI assessment was good for early postoperative MRI (kappa ¼ 0.625) and for MRI after 3 months (kappa ¼ 0.658). Agreement on the extent of tumor resection between the surgeon’s opinion of the Simpson grade and the MRI grading system according to the MRI assessors was poor for early postoperative MRI (kappa ¼ 0.328 and 0.433 for neurosurgeon and radiologist, respectively) and for MRI after 3 months (k ¼ 0.328 and 0.474, respectively). We also evaluated the difference in grading of the radiologist and the neurosurgeon on the early postoperative MRI and for MRI after 3 months. This interobserver agreement was found to be very good (kappa ¼ 0.963 and 1.0, respectively) CONCLUSIONS: These data suggest that surgical assessment correlates with MRI findings, but this agreement is rather limited. We question whether the Simpson grade is a reliable measure of the extent of meningioma resection. High kappa values for interobserver agreement on the postoperative and the 3-month MRI might be the iv116 NEURO-ONCOLOGY † NOVEMBER 2010 RA-18. MAGNETIC RESONANCE IMAGING OF VIRAL SPREAD AND INTRATUMORAL INFLAMMATION DURING ONCOLYTIC VIROTHERAPY Anne Kleijn 1, John W. Chen 2, Phillip Z. Sun 2, Jason Buhrman 2, Samuel D. Rabkin 2, Ralph Weissleder 2, Robert L. Martuza 2, Martine L. Lamfers 1, and Giulia Fulci 2; 1Erasmus Medical Center; 2Massachusetts General Hospital, Harvard Medical School One of the major drawbacks in treating gliomas is the poor efficiency of drug delivery. Oncolytic viruses (OVs) that can selectively replicate in tumor cells and potentially reach the infiltrating margins of the tumor represent a promising tool to overcome the problem. However, host factors limit the in vivo therapeutic efficacy of OVs. We recently demonstrated that the intratumoral infiltration of phagocytic microglia or macrophages inhibits the capacity of OVs to spread through the tumor. Combining OVs with immunosuppressant drugs can therefore increase the spread and efficacy of OVs. However, the lack of a noninvasive imaging technique to detect intratumoral OV spread and phagocytic infiltration constitutes an important limitation in evaluating the results of new therapeutic strategies. We tested 2 magnetic resonance imaging (MRI) techniques. The first technique uses a gadolinium-based contrast agent to detect the activity of myeloperoxidase (MPO), an enzyme present in phagocytic cells. MRI shows increased MPO activity after OV delivery. In animal studies, pretreatment with cyclophosphamide reduces this enzymatic activity. The MRI data correlated with immunohistochemistry and MPO mRNA levels and activity measured ex vivo. We also found that this technique presents a unique spatial resolution, whereby the inflammation process at the border and in the center of the tumor can be distinguished and provides us with information on tumor size and shape. The second technique allows imaging of the spatio-temporal distribution of OVs through the use of artificial peptides presenting magnetic contrast through chemical exchange saturation transfer (CEST). We generated an OV armed with a CEST-reporter gene to be tested in brain tumor oncolytic virotherapy. Because these technologies can be combined, together they will provide a powerful diagnostic tool to monitor the efficacy of OVs and glioma response to virotherapy, thus leading to the design of efficient strategies that overcome the influence of host factors. Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 Localized changes in white matter areas distant from primary brain tumor lesions following radiation therapy (RT) and chemotherapy have been reported. These changes have been attributed to disease deterioration as well as acute-, early-, and late-delayed post-therapy effects and have been associated with functional and cognitive impairments. Recently, bevacizumab, an antiangiogenic biologic agent, was approved by the FDA as a second-line therapy for recurrent or progressive malignant glioma. However, the effect of bevacizumab on the normal-appearing white matter (NAWM) is unclear. In this work, we scanned 16 patients with primary intracranial tumors before and after RT and during bevacizumab therapy and 31 age-matched healthy controls. One additional patient with breast cancer who was treated with bevacizumab for her systemic disease was scanned before and 2.5 months after beginning biologic therapy. Diffusion tensor imaging was used to evaluate NAWM changes in patients with tumors treated with radiation and bevacizumab compared to healthy controls. Volumes of interest were defined in the corticospinal tracts and in the major white matter fibers, calculated from both hemispheres for the control group and from the hemisphere contralateral to the lesion-containing hemisphere in patients with tumors. Following RT, changes in diffusivity values were detected, even in low radiation fields. Changes were also detected during or following bevacizumab therapy in 4 patients who had large tumors (16 –62 cm3) at baseline. In all other patients, including the breast cancer patient, no changes in diffusivity values were detected. These results support the hypothesis that post-radiation changes occur without evidence for additional white matter toxicity from bevacizumab therapy in normal brain tissue. These results may have important clinical implications regarding the use of bevacizumab-related therapies. RA-17. DIFFUSION-WEIGHTED MRI FOR THE EVALUATION OF RESPONSE TO THERAPY AND PROGNOSIS IN PATIENTS TREATED WITH BEVACIZUMAB Nina Martinez , Richard Gorniak , Lisa Tartaglino , Michael Scanlan , and Jon Glass ; Thomas Jefferson University Abstracts RA-21. UNUSUAL TREATMENT-RELATED INTRA- AND PERI-VENTRICULAR DIFFUSION HYPERSIGNAL MRI ABNORMALITIES MIMICKING DISEASE PROGRESSION IN A PATIENT RECEIVING INTRA-VENTRICULAR LIPOSOMAL CYTARABINE Elena Pentsova , Marc Rosenblum , Andrei Holodny , Lia Palomba , and Antonio Omuro ; MSKCC BACKGROUND: Although contrast-enhanced magnetic resonance imaging (MRI) has been the modality of choice in monitoring therapy, it appears insufficient to monitor patients receiving anti– vascular endothelial growth factor (VEGF) therapy. In this study, a rodent anti-VEGF antibody, B20-4.1.1, was used to mimic clinical bevacizumab treatment in an orthotopic rat 9L glioma, and multimodal MRI and 1H MRS were used to sequentially monitor tumor status during treatment. METHODS: Male Fisher rats were inoculated with 9L glioma cells in the left cerebral hemisphere. Tumor-bearing rats (n ¼ 5) were treated with B20-4.1.1 (10 mg/kg 3 times a week) with or without (n ¼ 3) irinotecan (50 mg/kg fortnightly) starting 15 days after inoculation. A 7T Varian Inova system was used to acquire MR images. These were analyzed for Dav, tumor volume, and gadolinium signal enhancement using Aedes (aedes.uku.fi) under Matlab platform. TARQUIN was used for spectral data analyses. RESULTS: Overall survival in untreated and treated rats was 22.3 and 31.2 days, respectively. Dav and rate of T2-volume expansion did not differ between the 2 groups. B20-4.1.1 markedly inhibited the time course of T1 signal in the tumor following gadolinium bolus. The time to maximum was prolonged nearly 3-fold in B20-4.1.1–treated rats during the first week of treatment. MRS revealed a strong increase in peaks centered at 1.3 and 0.9 ppm in treated tumors as early as day 3. TARQUIN analysis of in vivo spectra revealed substantial elevations in Lac/Cr, 1.3Lip/Cr, and 0.9Lip/Cr ratios that paralleled the observed slowdown of T1 signal kinetics following gadolinium bolus. CONCLUSION: B20-4.1.1 slows down gadolinium leakage into the tumor, suggesting reduced perfusion and vascular leakiness. 1H MRS revealed large increases in saturated lipids and lactate during early B20-4.1.1 treatment, indicating severe hypoxia associated with cell growth arrest. 1H MRS with MRI techniques probing diffusion and vascular functions provide a fuller picture of the effects of antiangiogenic treatment and helps detect favorable responses early in therapy. INTRODUCTION: The development of new restricted diffusion on magnetic resonance imaging (MRI) (diffusion-weighted imaging [DWI] hyperintensity) in patients with brain tumors is usually suspicious for early disease progression. We report autopsy findings in a patient undergoing treatment with intra-ventricular liposomal cytarabine who developed unusual intraand peri-ventricular bilateral DWI hyperintensities affecting both lateral ventricle occipital horns with a liquid-liquid level appearance, mimicking disease progression. CASE REPORT: A 69-year-old man with Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma complicated by leptomeningeal metastasis and biopsy-proven neurolymphomatosis was treated with intra-Ommaya liposomal cytarabine in combination with rituximab, highdose methotrexate, and bendamustine. The clinical course was complicated by periods of altered mental status in the absence of seizures, intracranial hypertension, or meningitis. Ventricular cerebrospinal fluid analysis was unremarkable except for protein level (30 mg/dl); cytology and flow cytometry studies were negative. MRI of the brain revealed new DWI hyperintensity within both lateral ventricle occipital horns, with a fluid-fluid level, and without contrast enhancement. Follow-up MRI revealed periventricular DWI hyperintensities surrounding the occipital horns bilaterally accompanied by fluid-attenuated inversion recovery hyperintensity in the corresponding area; the radiology interpretation favored progression of leptomeningeal disease and parenchymal tumor invasion. The patient died shortly afterwards of infection complications. Autopsy showed no evidence of lymphoma in the brain, leptomeninges, spinal cord, nerve roots, or sciatic nerves. Analysis of the periventricular white matter in the area corresponding to the MRI abnormalities showed degenerative changes represented by swollen axons and astrogliosis, possibly of a toxic etiology. DISCUSSION: In spite of MRI-restricted diffusion lesions, autopsy confirmed the patient remained in complete remission and that the lesions were likely treatment-related. The diffusion-positive intraventricular material may have corresponded to lipid deposits from the intraventricular liposomal cytarabine and adjacent inflammatory reaction. Recognizing such unusual radiographic abnormalities as possible complications of liposomal cytarabine rather than disease progression is important for optimal disease management. RA-20. INSULAR ANATOMY AND SURGICAL TREATMENT OF BRAIN TUMOR: TRACTOGRAPHY OF INSULAR GYRI AND SELECTION OF THE IDEAL INSULAR INCISION Kelvin Mok 1, Marcelo M. Valença 2, Ehsan Sherafat 1, and André Olivier 1; 1 Montreal Neurological Institute and Hospital; 2Federal University of Pernambuco INTRODUCTION: Many reports have suggested that small insular brain tumors can be safely removed without any neurological deficit or transient incapacities. In contrast, lesions localized in the insula may be associated with neglect syndrome, aphasia, oral apraxia, mutism, epilepsy, dysphagia, and cardiac abnormalities. Individually identifying the white matter tracts that are related to each of the 5 main insular gyri may be of great value to presurgical planning and in understanding neoplastic disease propagation. In the present study, we evaluated the anatomic relationship of tracts in each of the gyri as well as the possible damage caused by a virtual incision. METHODS: We acquired diffusion tensor imaging of 4 healthy volunteers on a 3-T magnetic resonance scanner. In addition, we performed hypothetical 2-cm insular incisions (central sulcus [CS], transverse incision in the middle CS, small sulcus between the anterior and medium small gyri, and the anterior-inferior limiting sulcus) to identify the tracts that could be damaged by the respective incision. Tractography was performed in a 22-year-old woman using the right insula. RESULTS: The total volume of insular cortex varied from 7,084 mm3 to 9,391 mm3. The volume of cortex and cortex + white matter for each gyrus was, respectively: anterior small gyrus (ASG; 2,488 mm3, 3,268 mm3), middle small gyrus (664 mm3, 749 mm3), posterior small gyrus (870 mm3, 1,080 mm3), anterior long gyrus (ALG; 1,640 mm3, 2,237 mm3), and posterior long gyrus (595 mm3, 924 mm3). Fibers were observed between the amygdala and ASG/ALG. A central insular incision using the CS as reference caused disruption to several tracts, particularly damaging fibers traveling through the inferior fronto-occipital and uncinate fasciculi. The transverse incision did not interrupt any temporal, occipital, or frontal fibers, while injury to parietal fibers were limited. CONCLUSION: Several important fibers cross the insular extreme capsule, and presurgical evaluation to determine incision placement is of major relevance in the management insular brain tumors. RA-22. ATPYICAL PRESENTATION AND MORBIDITY WITH RITUXIMAB IN DIFFUSE LARGE B-CELL LYMPHOMA INFILTRATING THE SPINE Gregory J. Murad , Anthony T. Yachnis , and Erin M. Dunbar ; University of Florida INTRODUCTION: With newer regimens involving chemotherapy and immunomodulating agents such as rituximab, B-cell lymphoma patients have experienced improved response rates, treatment response, and overall survival. However, these treatments are not without morbidity, especially when disease progression is less than typical. REPORT: We present the case of a 71-year-old immunocompetent patient diagnosed with localized gastric diffuse large B-cell lymphoma (DBCL). Initial systemic staging and infectious serologies were negative, with the exception of locoregional nodes. Complete radiographic and clinical response was achieved with 6 cycles of R-CHOP, and the patient was placed on maintenance rituximab. Immediately following the sixth cycle, the patient developed acute ascending lower extremity paraparesis that worsened over several weeks. An expansile intradural, intramedullary, T1-weighted contrast enhancement throughout the thoracic spinal cord, which was worst at T7-8, was observed. Systemic restaging with positron emission tomography/computed tomography and exhaustive radiographic, cerebrospinal fluid, and blood work-up failed to identify a potential etiology. Empiric steroids and IGG therapy were unhelpful. The patient underwent T7-8 laminectomy and spinal cord biopsy for diagnosis. Pathology revealed necrotizing myelopathy with a large number of atypical, necrotic B cells infiltrating the spinal cord. Abundant CD68-immunoreactive macrophages, vacuolar-like changes, and axons undergoing Wallerian degeneration were also seen. No evidence of infection, ischemia, or other etiologies was identified. This necrosis was most consistent with treatment effect. DISCUSSION: This case illustrates a less-than-typical clinical and radiographic pattern of progression for locoregional gastric DBCL in a patient with an otherwise excellent response to R-CHOP. We hypothesize that the patient developed occult intradural, intramedullary spinal cord involvement that responded dramatically to rituximab, leading to the acute presentation. This case also illustrates the added benefit of dedicated spine imaging for occult brain and spinal cord involvement of lymphoma. NEURO-ONCOLOGY † NOVEMBER 2010 iv117 Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 RA-19. 1H MRS WITH MRI TECHNIQUES PROBING DIFFUSION AND VASCULAR FUNCTIONS PROVIDES A FULLER PICTURE OF ANTI-VEGF TREATMENT EFFECTS ON RAT 9L GLIOMA Enrico C. Lallana 1, Kyle A. Brong 2, Khan Hekmatyar 3, Neil Jerome 3, MartinWilson 4, Camilo E.Fadul 1, and Risto A.Kauppinen 3; 1Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center; 2Dartmouth College; 3 Dartmouth Medical School; 4University of Birmingham Abstracts RA-23. COMPARISON OF DSC-DERIVED PERFUSION PARAMETERS IN PATIENTS NEWLY DIAGNOSED WITH GBM TREATED WITH EITHER RT 1 TMZ OR RT 1 TMZ 1 ANTI-ANGIOGENIC THERAPY Emma Essock-Burns , Yan Li , Janine Lupo , Mei-Yin Polley , Nicholas Butowski , Soonme Cha , Susan Chang , and Sarah Nelson ; University of California, San Francisco RA-24. SENSITIVITIES AND ARTIFACTS WITH MRI IN PCNSL IMPACTING PATIENT CARE NathanKohler , RonaldQuisling , and Erin M.Dunbar ; University of Florida A 54-year-old patient with biopsy-proven primary central nervous system lymphoma (PCNSL) diffusely involving the basal ganglia, centrum semi ovale, brain stem, and bilateral temporal lobes achieved a complete radiographic and clinical response with 6 bi-weekly cycles of high-dose methotrexate monotherapy. Prior to the last planned maintenance cycle, routine imaging with 3-T magnetic resonance imaging (MRI) demonstrated interval development of T1-weighted enhancement in the bilateral orbital-frontal region that was interpreted as being highly concerning for radiographic progression at our institution and by outside review. The T2-weighted signal was normal in this region. The patient declined biopsy in favor of immediate initiation of non-protocol therapy with temozolomide and rituximab while the diagnosis was being confirmed. After 1 cycle, the previous MRI findings had resolved on 1.5-T MRI, thus raising the concern for artifact on prior MRI. This was confirmed the following month when back-to-back 3T and then1.5-T MRIs were performed within 10 minutes. The 3-T MRI showed the same changes, yet the 1.5-T MRI findings were unremarkable. The findings on the previous 3-T MRI were confirmed to represent volumetric susceptibility artifact created by partial volume averaging from the air within the paranasal sinuses and the brain parenchyma, with a possible contribution from the nearby vascular flow. The patient has had no clinical or radiographic (1.5-T MRI) disease progression for more than 14 months. This case led to the standard use of 1.5-T MRI for PCNSL at our institution. Although this artifact has been reported in the neuro-radiology literature, it is not as frequently discussed throughout the wider neuro-oncology community. Therefore, this presentation will include a literature review of the sensitivities and artifacts encountered with 3-T and 1.5-T MRI, with special attention given to the radiographic challenges further imposed by lymphoma and other lesions occurring in locations of particular vulnerability to volumetric susceptibility artifact. iv118 NEURO-ONCOLOGY † NOVEMBER 2010 Gliomas are primary brain neoplasms known to aggressively invade the surrounding issue. Angiogenesis is a key mechanism by which tumor cells sustain and continue their aggressive growth. Hypoxia is a hallmark of aggressive tumor growth and can be assessed clinically through [18F]-Fluoromisonidazole (FMISO)-labeled positron emission tomography (PET). We developed a biomathematical model characterizing gliomas into distinct cellular phenotypes including normoxic, hypoxic, and necrotic cells that interact with themselves and the microenvironment through the secretion of tumor angiogenic factors and underlying vascularity. Applying this model to specific glioma patients, we simulated spatial maps of tumor hypoxia to allow direct comparisons with FMISO-PET images. We applied a pharmacokinetic model to the hypoxic maps at each brain voxel to capture the FMISO tracer activity curve for each voxel. We applied an analytical simulator for the PET image acquisition and reconstruction methods. Quantitative spatial comparisons between the patient and simulated images for our case study suggests that virtual PET closely aligns with corresponding clinical PET relative to magnetic resonance imaging (MRI) abnormality. The distribution of pixel intensities in the virtual and real FMISO-PET were not statistically different (Kolmogorov-Smirnov test, 97.5% certainty,). The maximum hypoxic activity in both the simulated and real PET was within the T1 gadolinium tumor abnormality. This work establishes a direct link between anatomical (MRI) and molecular (PET) imaging and provides a potential tool for predicting the hypoxic distribution on a patient-specific level and addresses otherwise untenable questions in molecular imaging and neuro-oncology. This unique tool provides a quantitative dynamic understanding of the biological connection between anatomical changes seen on MRI and biochemical activity seen on PET of gliomas in vivo and may be utilized to investigate the degree to which PET imaging can detect clinically relevant changes in tumor metabolic activity in vivo. RA-26. PRE-TREATMENT GLIOBLASTOMA PROLIFERATION AND INVASION KINETICS: A MECHANISM TO PREDICT PSEUDOPROGRESSION Addie E. Boone , Russell C. Rockne , Maciej M. Mrugala , and Kristin R. Swanson ; University of Washington Published data estimate that 20-50% of progressive enhancement on magnetic resonance imaging (MRI) occurring within 12 weeks after chemoradiotherapy is the result of pseudoprogression (Psp) and does not indicate true progression (TP) of disease. Although novel methods and modalities to distinguish Psp from TP are being evaluated, no widely accepted noninvasive mechanism for predicting Psp in individual patients is currently available. The proliferation-invasion (P-I) model, when applied to pretreatment MRI data, effectively quantifies the net migration (D) and net proliferation (rho) rate of untreated glioma growth and invasion. Furthermore, the P-I model has been extended to predict individual glioma response to radiation therapy. We investigated the application of the P-I model as a mechanism to predict which patents would be more likely to experience Psp and TP. Twelve patients’ MRI studies, taken before and after chemoradiotherapy, were reviewed retrospectively. Nine patients were clinically confirmed to exhibit Psp, and 3 patients were confirmed to exhibit TP. The patients were then evaluated based on model-generated parameters of the net migration (D) and proliferation rates (rho) of their gliomas. Of the 9 Psp patients, 7 (77%) had pretreatment D/rho , 1 mm2, and of the 3 TP patients, 2 (66%) had pretreatment D/rho . 1 mm2. A pretreatment D/rho , 1 mm2 indicated a more focal, less invasive tumor that was more likely to be highly vascularized and hypoxic. Thus, after chemotherapy, such tumors may be more prone to enhanced edema due to the increased permeability of the tumor vasculature and more likely to exhibit enhancement on radiographic imaging. Though additional investigation is necessary to determine if this relationship persists, preliminary results suggest the application of the P-I model to patient-specific pre-chemoradiotherapy MRI data provides model-derived parameters that offer a quantitative mechanism to help predict which patients are more likely to experience Psp. Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 INTRODUCTION: The therapy paradigm for glioblastoma multiforme (GBM), a highly malignant and vascularized brain tumor, is shifting from a purely cytotoxic approach to incorporating targeted, cytostatic therapy. The standard of care for GBM patients includes combined radio- and cytotoxic (i.e. temozolomide) therapy. Cytostatic antiangiogenic therapy, thought to normalize the tumor vasculature, has shown improved disease management in patients with recurrent disease. Dynamic susceptibility contrast imaging (DSCI) can detect vascular changes following antiangiogenic therapy. METHODS: Seventy-one patients newly diagnosed with GBM were imaged serially every 2 months on a 3-T scanner. Thirty-six patients received conventional therapy (radiotherapy plus temozolomide), and 35 patients received conventional and concurrent antiangiogenic therapy (radiotherapy plus temozolomide and a protein kinase C inhibitor). DSCI was acquired with a gradient-echo, echo-planar sequence (TE/TR, 54/ 1500 ms; flip angle, 358; FOV, 24 × 24 cm2; matrix, 128 × 128) during gadolinium injection. Perfusion parameters, peak height (PH) and percent signal recovery (%REC), were calculated from the dynamic curves to assess blood volume and leakage, respectively. The putative tumor region included the contrast-enhancing lesion, fluid-attenuated inversion recovery hyperintensity, and elevated choline-to-NAA index. The extreme portion of abnormality within this region, defined as the 90th percentile for PH and 25th percentile for %REC, was identified serially. Cox regression analysis was used to determine whether early perfusion biomarkers were predictive of progression-free survival (PFS) and overall survival (OS). RESULTS: Within 2 months of starting therapy, PH decreased (Wilcoxon sign-rank, P ¼ .001) and %REC increased (Wilcoxon sign-rank, P ¼ .03) from baseline in patients receiving concurrent antiangiogenic therapy, while no significant changes in PH or %REC were observed in patients receiving conventional therapy. The %REC was predictive of both PFS (P , .009) and OS (P , .02) for patients receiving concurrent antiangiogenic therapy but was not predictive for patients receiving conventional therapy. CONCLUSION: This study highlights the utility of perfusion imaging in assessing response to antiangiogenic therapy, since predictive changes in underlying vasculature were observed prior to evidence of clinical progression. Future validation studies will include other antiangiogenic therapies. RA-25. IN SILICO PET IMAGING: FROM ANATOMIC GLIOMA GROWTH DYNAMICS TO METABOLIC TUMOR ACTIVITY VIA BIO-MATHEMATICAL MODELING Kristin R. Swanson 1, Stanley Gu 1, Gargi Chakraborty 1, Adam Alessio 1, Jonathan Claridge 1, Russell C. Rockne 1, Mark Muzi 1, Kenneth A. Krohn 1, Alexander M. Spence 1, Ellsworth C. Alvord 1, Alexander R. Anderson 2, and Paul Kinahan 1; 1University of Washington; 2Integrative Mathematical Oncology, Moffitt Cancer Research Center Abstracts RA-27. REAL-TIME IN VIVO IMAGING OF NEURAL STEM CELLS FOR TARGETED THERAPY OF MEDULLOBLASTOMA Margarita Gutova 1, Vazgen Khankaldyyan 2, Kelsey A. Herrmann 1, Ira Harutyunyan 2, Yelena Abramyants 1, Alexander J. Annala 1, Joseph Najbauer 1, Rex A. Moats 2, Gregory M. Shackleford 3, Michael E.Barish 1, and Karen S.Aboody 14; 1Department of Neurosciences, Beckman Research Institute at City of Hope, Duarte, California 91010; 2Radiology MS 81; 3Division of Hematology-Oncology, USC Keck School of Medicine and The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, California 90027; 4Division of Neurosurgery at City of Hope, Duarte, CA 91010 SC-02. NOTCH PATHWAY BLOCKADE AFFECTS THE DIFFERENTIATING AND MIGRATORY CAPACITY OF BRAIN TUMOR INITIATING CELLS Karina Kristoffersen , Marie-Thérése Stockhausen , and Hans S. Poulsen ; Department of Radiation Biology, National University Hospital Brain tumor initiating cells (bTICs) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bTICs are hypothesized to be involved in tumor initiation, progression, treatment resistance and relapse. The Notch signaling pathway has been indicated to play a functional role in GBM cells, and considering its known importancy in normal NSC, this pathway might be an appropriate target for bTICs-directed GBM therapy. The aim of the present project was therefore to investigate the significance of Notch expression and activation in GBM-derived bTICs. Primary neurosphere cultures were established in serum-free media from xenografts originally derived from human primary GBM. All cultures were enriched in cells with NSC-like characteristics, and the majority of cultures exhibited high Notch expression and activation. Notch pathway blockade by the gamma-secretase inhibitor DAPT led to reduced primary neurosphere formation. Established neurosphere cultures treated with DAPT displayed reduced expression of the NSC marker Nestin and increased expression differentiation markers, suggesting increased differentiation upon Notch inhibition. When neurosphere cells were plated in serum-containing media in order to induce differentiation during concomitant DAPT treatment, they showed an altered differentiation pattern, in accordance with the established role of Notch during cell fate decisions. Finally, the Notch pathway was demonstrated to play a role in the malignant phenotype of the neurosphere cultures, as displayed by inhibition of cell migration and cell viability upon Notch blockade. The overall effect of DAPT was more pronounced in cultures exhibiting high Notch expression and activation than in cultures with low Notch expression and activation. These results suggest that Notch signaling contributes to the stem cell-like character and tumorigenic potential of bTICs when they harbor dysregulated Notch pathway activation and that it might be possible to target bTICs in human GBM through the Notch signaling pathway. STEM CELLS SC-01. INDUCED PHENOTYPIC DIFFERENTIATION OF GLIOBLASTOMA STEM CELLS REVISITED – DETECTION OF GLYCOMIC RESPONSE BASED ON METABOLIC LABELING Huan He 1, Mark R. Emmett 2, Alan G. Marshall 2, Yongjie Ji 3, Charles A. Conrad 3, Waldemar Priebe 3, Howard Colman 3, Frederick F. Lang 3, and Timothy L. Madden 3; 1NHMFL; 2NHMFL, Tallahassee; 3The University of Texas MD Anderson Cancer Center, Houston INTRODUCTION: Relapse of glioblastoma multiforme (GBM) may be due to cancer stem cells (CSCs), which account for only , 1% of total tumor cells. GSC11, one of the glioma CSC lines, shows different phenotypic differentiation when treated with signal transducer and activator of transcription 3 (STAT3) phosphorylation inhibitor (WP1193) or serum (J. Proteome Res. 2010, 9, 2098 –2108). Cell-surface carbohydrate patterns (present on glycosphingolipids and glycoproteins) play a key role in defining tumor malignancy. Differential analysis of the cellular glycomic response of GSC11 cells may provide insight into the underlying biologic processes. We have developed a true relative quantification method based on metabolic labeling of glycosphingolipids with isotope-labeled serine in the presence of a serine synthesis inhibitor. METHODS: GSC11 cells are grown in medium with isotopically labeled serine plus a serine synthesis inhibitor to produce “heavy” glycosphingolipids, whereas the treated (with STAT3 inhibitor or serum) GSC11 cells are grown with natural serine plus a serine synthesis inhibitor to produce “light” glycosphingolipids. The two cell cultures are then mixed, extracted, separated by NanoLC, and analyzed online by LTQ 14.5 T Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) (Anal. Chem., 2008. 80, 3985 –3990). Relative quantification of glycosphingolipids between the two cell cultures is based on the ratio of “heavy” vs “light” glycosphingolipids. RESULTS: As part of a complete systems biology study of CSC differentiation (J. Proteome SC-03. PODOCALYXIN EXPRESSION CORRELATES WITH ASTROCYTOMA TUMOR GRADE Zev A. Binder , Brent Orr , Michael Lim , Jon D. Weingart , Henry Brem , Alessandro Olivi , Gregory J. Riggins , and Gary L. Gallia ; Johns Hopkins School of Medicine Astrocytomas are a class of primary brain tumors that range from grade II astrocytomas, considered benign, to glioblastoma multiforme (GBM). The diagnosis of tumor grade is made based on histologic characteristics. Molecular characterization of astrocytomas could potentially improve the accuracy of diagnosis, lead to new therapeutic targets, and be helpful in determining prognosis. We demonstrate that expression of the cell surface anti-adhesin protein podocalyxin (PODXL) increases with astrocytoma grade. Furthermore, we observe that within the same tumor, low-grade portions have low PODXL expression while neighboring high-grade portions have elevated PODXL expression. Primary tumor samples were obtained and processed within 24 hours of collection. Samples were mechanically and enzymatically dissociated, underwent red blood cell lysis, and were centrifuged in a 30% sucrose solution (w/v). Cells were then stained with a PE-conjugated mouse monoclonal anti-podocalyxin and analyzed on a Beckman Coulter FACSanalyzer machine. Flow cytometry was performed on primary tumor samples to avoid any bias introduced by culturing the tumors. Eight grade II astrocytomas and 37 GBMs were analyzed for PODXL expression. The mean PODXL expression of GBMs was significantly higher than that of grade II astrocytomas (p ¼ 0.0065). Tissue samples from two patients with high- and low-grade portions of tumor (based on magnetic resonance imaging [MRI] with gadolinium) were also evaluated. In both cases, areas of apparent high-grade tumor correlated with elevated PODXL expression while areas of apparent low-grade tumor correlated with low PODXL expression. Our study demonstrates that NEURO-ONCOLOGY † NOVEMBER 2010 iv119 Downloaded from https://academic.oup.com/neuro-oncology/article-abstract/12/suppl_4/iv112/1522628 by guest on 21 May 2020 Medulloblastomas are heterogeneous cerebellar neoplasms, which are the most common malignant brain tumors of childhood. Despite recent advances in treatment, these tumors are associated with high morbidity and mortality. Neural stem cells (NSCs) have been investigated in preclinical animal models as delivery vehicles for therapeutic genes to treat tumors in the central nervous system. We hypothesize that NSCs genetically modified to express an activating carboxylesterase (CE), an enzyme that converts CPT-11 prodrug to SN-38 (a potent topoisomerase I inhibitor), will localize specifically to cerebellar tumor foci. We have examined the homing and distribution of CE-expressing NSCs (NSC.CE) in vitro and in clinically relevant transgenic and orthotopic experimental models of medulloblastoma: 1) murine medulloblastoma induced by activation of the Hedgehog pathway in granule neuronal precursors of the cerebellum and 2) human medulloblastoma (Daoy) cerebellar implants in nude mice. In vitro cell migration assays revealed robust migration of NSC.CE cells to murine and human tumorconditioned media. Exposure of these medulloblastoma cells to NSC.CE-conditioned medium in the presence of CPT-11 resulted in medullobastoma cell killing 1000-fold more efficient than with CPT-11 alone. These data support the rational for use of the CE/CPT-11 enzyme/ prodrug system for the treatment of medulloblastoma. We next injected NSC.CE cells labeled with FePro (ferumoxide-protamine sulfate) iron nanoparticles into the cerebellum of tumor-bearing mice. MRI was used for realtime in vivo monitoring of NSC.CE-FePro cell migration. NSC.CE cells were detected intratumorally in both medulloblastoma models and confirmed by histological methods. Three-dimensional reconstruction was used to analyze tumor volume and biodistribution of NSCs within tumors. This approach allowed us to determine at high resolution the locations of NSCs in relation to tumor, as well as the migration routes of NSC.CE cells in the tumor-bearing brain. Currently, we are evaluating the in vivo therapeutic efficacy of NSC-mediated enzyme/prodrug therapy in mice. These studies will lay the foundation for translation of NSC-mediated therapy into clinical trials for children and young adults with medulloblastoma. This novel therapy may improve the therapeutic index, while sparing neurons and preserve cognitive function, properties critical to achieving the most favorable outcomes for these patients. Res. 2010, 9, 430 –443), we previously reported cellular glycosphingolipid response to phenotypic differentiation in GSC11 cells based on our nLC-MS method (Anal. Chem. 2007, 79, 8423 –8430). Our current true relative quantification method is based on incorporation of heavy isotopes into glycosphingolipids by metabolic labeling. We applied this method to verify previously reported responses of glycosphingolipids in GSC11 to induced phenotypic differentiation (1) based on isotopic labeling. We were able to detect less than a 2-fold change in glycosphingolipids. Preliminary data demonstrate that glycosphingolipid labeling may also be used to trace specific biosynthetic pathways.