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Background: Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed. Objectives: The goal of this study was to demonstrate the feasibility of non-thermal focused-ultrasound (FUS) to induce tremor-suppression in an ET rat model. Methods: Harmaline-induced tremor rats were treated with FUS along the inferior olivary (IO) system. EMG was recorded continuously during treatment in order to quantify FUS-induced tremor suppression. T2-weighted MRI was performed immediately following treatment and periodically thereafter. Results: FUS treatment at an intensity of 27.2 W/cm2 (Isppa) induced significant reduction of tremor in 12 out of 13 ET rats. Tremor frequency was reduced from 6.2 ± 2.8 to 2 ± 1 Hz, p

Previous studies suggest that 14–30% of glioblastoma multiforme (GBM) patients and 5–24% of patients with brain metastases demonstrate imaging treatment-effects in the first few months after treatment [1], [2], [3]. These treatment-induced imaging changes, often termed pseudoprogression/radiation-necrosis, are depicted as increasing volumes of contrast-enhancing lesions on MRI, mimicking progression. Therefore, treatment decisions, such as whether to operate on a patient with radiographic deterioration, continue current treatment or change treatment is a daily unsolved struggle. In addition, radiation-based treatments may also induce vascular malformations such as radiation-induced Cavernous malformations (RICM) and capillary telangiectasias. Cavernous malformations are low-flow vascular malformations, characterized by the lack of mural elements of mature vascular structures and intervening parenchymal neural tissue [4]. Radiation induced capillary telangiectasias (RIT), thin-walled ectatic capillaries with intervening normal brain parenchyma, usually occur 3–9 months after irradiation. Cavernomas take a longer time to develop (1–35 years) after radiation [5]. RICMs mostly develop in the pediatric population [6], but are also observed in adults. In a literature search from 2006 by Nimjee et al [7], 76 cases of RICMs were found. A retrospective study conducted at Mayo clinic found 32 RICMs [5]. RICMs latency median was 12.0 years with only 3 diagnosed in the first two years post radiation (9.3%). Kleinschmidt-DeMasters and Lillehei [8] found 13 cases between 2000 and 2016 in their surgical neuropathology databases. The latency median was 18 years. Strenger et al calculated a cumulative index of 2.24%, 3.86%, 4.95%, and 6.74% at 5, 10, 15, and 20 years following radiotherapy of children, respectively [9]. Vinchon et al [10] identified cumulative indices for their cohort in children at 10 years of 8.9%. Although RICMs are rare in adults with astrocytoma, mainly due to poor survival, three cases of long term survivals were reported in the literature to develop RICMs 10, 19 and 26 years post radiotherapy [11]. Gaensler and colleagues reported a series of 20 patients with RITs (6 proven pathologically) for whom the latency was only 2.7 years [12]. 70% of the 20 patients were 1 h (60–105 min) after a conventional injection of contrast agent. Blue/tumor regions in the TRAMs represent efficient clearance of contrast from the tissue (delayed signal early signal). The TRAMs were validated histologically in 51 resected lesions from patients with primary and metastatic brain tumors reaching 92% positive predictive value (PPV) and 100% sensitivity to morphologically active tumor. When studying the histological samples, we found that the common vessels morphology in the blue regions was undamaged vessels lumens, while vessels in the red regions presented different stages of vessel necrosis. Therefore, one explanation for the difference between the two populations may be that vessels in blue/tumor regions provide efficient contrast clearance from the tissue, while the damaged lumens in the red/treatment-effects regions are unable to clear the accumulating contrast, resulting in contrast accumulation. Over 400 adult patients have been recruited thus far to our ongoing TRAMs-based studies in Israel since 2010. As the TRAMs cannot differentiate blood vessels from active tumor (both appearing blue), we studied here whether RCIMs/RITs may mimic tumors in the TRAMs.

When high pulsed electric fields (PEFs) are applied to the brain electroporation occurs. Depending on the electric fields strength, irreversible electroporation, inducing necrotic cell death or reversible electroporation, inducing BBB disruption may occur. We have developed a unique minimally-invasive setup for treating brain tumors employing a single insulated intracranial electrode with an exposed tip placed within the tumor and an external surface electrode. This unique setup, termed point-source electroporation, provides intratumoral irreversible-electroporation (inducing necrosis) with surrounding reversible BBB disruption, enabling efficient delivery of systemically administered drugs into the infiltrating zone. Treatment duration is 1–2 min. An efficacy study conducted with 120 glioma-bearing rats resulted in suppressed tumor growth rates in the electroporation+Cisplatin group (1.1±0.1) relative to growth rates in the control group (5.2±1.0), p< 0.047, and in the Cisplatin-only group p< 0.012 (3.92±1.0) (Welch’s F(2,12.73)=10.84; p< 0.002; ω2=0.28). Kaplan-Meir analysis revealed that electroporation+Cisplatin prolonged survival significantly (χ2=7.54; p< 0.006). Immunofluorescence analysis revealed significant infiltration of peripheral macrophages and CD8+ cells in the residual tumor. A finite elements simulation demonstrated the feasibility for obtaining clinically-relevant treatment volumes (~6cm diameter) using a single 3mm (diameter) intracranial catheter. Additionally, we discovered that low PEFs, an order of magnitude lower than electroporation threshold, can also transiently disrupt the BBB by a different mechanism, enabling penetration of both small (Gd/NaF) and large (Evans blue bound to serum albumin) molecules and immune cells, non-invasively. The extent of BBB disruption, measured in mice using delayed-contrast MRI, was found to be linearly dependent both on the electric field strength (r2=0.9,p< 0.03) and on the number of applied pulses (r2=0.94,p< 0.003). These results demonstrate the feasibly of applying combined systemic chemotherapy with point-source electroporation, a minimal-invasive/rapid treatment of PEFs, for obtaining significant antineoplastic effects. Furthermore, low PEFs may be applied non-invasively, rapidly and repeatedly for obtaining reversible BBB disruption.

// Amos Toren 1 , Tatyana Pismenyuk 1 , Michal Yalon 1 , Shani Freedman 1 , Amos J. Simon 1 , Tamar Fisher 1 , Itai Moshe 1 , Juergen K.V. Reichardt 2 , Shlomi Constantini 3 , Yael Mardor 4 , David Last 4 , David Guez 4 , Dianne Daniels 4 , Moria Assoulin 4 , Ruty Mehrian-Shai 1 1 Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 2 YachayTech University, Urcuqui, Ecuador 3 Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel-Aviv-Sourasky Medical Center, Israel 4 The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel Correspondence to: Ruty Mehrian-Shai, email: Ruty.Shai@sheba.health.gov.il Keywords: glioblastoma multiforme, temozolomide, chemosensitivity, proliferation, zinc Abbreviations: GBM: Glioblastoma multiforme; TMZ: Temozolomide; ZnCl 2 : Zinc chloride Received: May 30, 2016 Accepted: July 19, 2016 Published: August 19, 2016 ABSTRACT Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients positively respond to it. It has been shown that zinc metal reestablishes chemosensitivity but this effect has not been tested with TMZ. Using both in vitro and in vivo experimental approaches, we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and Caspase-3 expression and a decrease in growth fraction as manifested by low ki67 and lower colony formation. Analysis of GBM as intracranial xenografts in athymic mice and administration of concurrent TMZ and zinc yielded results consistent with those of the in vitro analyses. The co-treatment resulted in significant reduction in tumor volume in TMZ/zinc treated mice relative to treatment with TMZ alone. Our results suggest that zinc may serve as a potentiator of TMZ therapy in GBM patients.

High-grade gliomas constitute a group of aggressive CNS cancers that have high morbidity and mortality rates. Despite extensive research, current therapeutic approaches enable survival beyond 2 years in rare cases only. Thrombin and its main CNS target, protease-activated receptor-1, have been implicated in tumor progression and brain edema. Our aim was to study protease-activated receptor-1 (PAR-1) protein expression and thrombin-like activity levels in both in vitro and in vivo models of glioblastoma and correlate them with the volume of the surrounding edema. We measured the presence of PAR-1 protein using fluorescence immunohistochemistry and assessed thrombin activity in various glial and non-glial cell lines and in a CNS-1 glioma rat model using a thrombin-specific fluorescent assay. Thrombin activity was found to be highly elevated in various high-grade glioma cell lines as well as in non-glial malignant cell lines. In the CNS-1 glioma model, the level of PAR-1 fluorescence in the tumor was significantly elevated compared to adjacent regions of reactive gliosis or distant brain areas. The elevated level of thrombin activity observed in the high-grade glioma positively correlated with tumor-induced brain edema. In conclusion, thrombin is secreted from glioma cells and PAR-1 may be a new biological marker for high-grade gliomas.

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood–brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)–HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA–HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA–HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.

Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients.One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist.Histological validation confirmed that regions of contrast agent clearance in the TRAMs1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P.0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated.The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

BACKGROUND AND PURPOSE: The interpretation of the radiologic response of bevacizumab-treated patients with recurrent high-grade gliomas represents a unique challenge. Delayed-contrast MR imaging was recently introduced for calculating treatment-response-assessment maps in patients with brain tumors, providing clear separation between active tumor and treatment effects. We studied the application of standard and delayed-contrast MR imaging for assessing and predicting the response to bevacizumab. MATERIALS AND METHODS: Twenty-four patients with recurrent high-grade gliomas were scanned before and during bevacizumab treatment by standard and delayed-contrast MR imaging. The mean change in lesion volumes of responders (overall survival, ≥1 year) and nonresponders (overall survival

Conventional MRI is unable to differentiate progression from treatment effects (TEs) in brain tumor (BT) patients. We have applied a novel technique, based on MR images acquired with a delay of >1 hour, enabling high resolution complete separation between tumor (contrast clearance at the delayed time point) and TEs (contrast accumulation) with no overlap. 496 maps were calculated for 151 patients with primary/metastatic BTs recruited/followed on study. The maps were validated by comparing pre-surgical maps of 51 resected patients with histology, resulting in 100% sensitivity and 93% specificity to active tumor regions (ATRs). Following initial validation, the maps were used for making 232 clinical decisions. In 67 cases the decision was to continue follow-up and in 165 to change treatment (surgery, chemoradiation, radiation treatments, switch to Avastin, etc). The incidence of decisions to change treatment was significantly higher in primary BTs (83%) than in metastatic BTs (54%). The application to Avastin was studied in 20 recurrent GBM patients and 2 patients with breast cancer brain metastases scanned pre/during Avastin. 90% of the GBM patients demonstrated significant reduction in TEs 1 month (58 ± 16% of original volume, p < 0.03) and up to 3 months (55 ± 19%, p < 0.04) post treatment. 80% demonstrated a reduction in ATRs 1 month post treatment (56 ± 18% of original volume, p5 months post treatment. This data suggests that Avastin may induce antineoplastic effects (mostly short term), and not only reduction in TEs/edema, as previously suggested. In 10 GBM patients who reached progression, the change in ATRs 1 month post treatment was found to correlate significantly with patients' PFS. The correlation calculated from the maps (r2 = 0.9, p < 0.0001) was significantly higher than those calculated from T1-Gd (r2= 0.65, p < 0.009) and FLAIR (r2 = 0.55, p < 0.02), suggesting the maps provide additional information regarding response to Avastin. A subgroup of 6 patients underwent re-irradiation during Avastin. All showed significant radiological response in the maps (ATRs decreased to 62 ± 10% of original volume while TEs increased to 296 ± 72%), in agreement with clinical stabilization, while conventional MRI showed radiological deterioration (T1-Gd/FLAIR showed stable/increased enhancing volumes reaching 92 ± 21%/155 ± 18% of original volumes). 2 patients with 4 breast cancer metastases showed significant response as well (ATRs decreased to 10 ± 3% of original volumes). In summary, our high resolution, easy to interpret, model-independent maps provide clear differentiation between tumor/non-tumor tissues in BT patients undergoing conventional treatments. Initial experience with Avastin suggests that the maps may also be valuable in assessing response to antiangiogenic treatments.

In spite of aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme due to tumor infiltration into the surrounding brain as well as poor blood–brain barrier penetration of most therapeutic agents. In this paper we present a novel approach for a minimally invasive treatment and a non-invasive response assessment methodology consisting of applying intracranial point-source electroporation and assessing treatment effect volumes using magnetic resonance imaging. Using a unique setup of a single intracranial electrode and an external surface electrode we treated rats' brains with various electroporation protocols and applied magnetic resonance imaging to study the dependence of the physiological effects on electroporation treatment parameters. The extent of blood–brain barrier disruption and later volumes of permanent brain tissue damage were found to correlate significantly with the treatment voltages (r2 = 0.99, p < 0.001) and the number of treatment pulses (r2 = 0.94, p < 0.002). Blood–brain barrier disruption depicted 3.2 ± 0.3 times larger volumes than the final permanent damage volumes (p < 0.0001). These results indicate that it may be beneficial to use more than one modality of electroporation when planning a treatment for brain tumors.

The development of imaging methodologies for detecting blood-brain-barrier (BBB) disruption may help predict stroke patient's propensity to develop hemorrhagic complications following reperfusion. We have developed a delayed contrast extravasation MRI-based methodology enabling real-time depiction of subtle BBB abnormalities in humans with high sensitivity to BBB disruption and high spatial resolution. The increased sensitivity to subtle BBB disruption is obtained by acquiring T1-weighted MRI at relatively long delays (~15 minutes) after contrast injection and subtracting from them images acquired immediately after contrast administration. In addition, the relatively long delays allow for acquisition of high resolution images resulting in high resolution BBB disruption maps. The sensitivity is further increased by image preprocessing with corrections for intensity variations and with whole body (rigid+elastic) registration. Since only two separate time points are required, the time between the two acquisitions can be used for acquiring routine clinical data, keeping the total imaging time to a minimum. A proof of concept study was performed in 34 patients with ischemic stroke and 2 patients with brain metastases undergoing high resolution T1-weighted MRI acquired at 3 time points after contrast injection. The MR images were pre-processed and subtracted to produce BBB disruption maps. BBB maps of patients with brain metastases and ischemic stroke presented different patterns of BBB opening. The significant advantage of the long extravasation time was demonstrated by a dynamic-contrast-enhancement study performed continuously for 18 min. The high sensitivity of our methodology enabled depiction of clear BBB disruption in 27% of the stroke patients who did not have abnormalities on conventional contrast-enhanced MRI. In 36% of the patients, who had abnormalities detectable by conventional MRI, the BBB disruption volumes were significantly larger in the maps than in conventional MRI. These results demonstrate the advantages of delayed contrast extravasation in increasing the sensitivity to subtle BBB disruption in ischemic stroke patients. The calculated disruption maps provide clear depiction of significant volumes of BBB disruption unattainable by conventional contrast-enhanced MRI.

Background— Cell labeling with superparamagnetic iron oxide (SPIO) nanoparticles enables noninvasive MRI and tracking of transplanted stem cells. We sought to determine whether mesenchymal stem cell (MSC) outcome is affected by SPIO labeling in a rat model of myocardial infarction. Methods and Results— Rat MSCs were labeled with SPIO (ferumoxides; Endorem; Guerbet, Villepinte, France). By trypan-blue exclusion assay, almost 100% of the cells remained viable after labeling. Seven days after MI, rats were randomized to injections of 2×10 6 SPIO-labeled MSCs, 2×10 6 unlabeled MSCs, or saline. Labeled cells were visualized in the infarcted myocardium as large black spots by serial MRI studies throughout the 4-week follow-up. The presence of labeled cells was confirmed by iron staining and real-time polymerase chain reaction on postmortem specimens. At 4 weeks after transplantation, the site of cell injection was infiltrated by inflammatory cells. Costaining for iron and ED1 (resident macrophage marker) showed that the iron-positive cells were cardiac macrophages. By real-time polymerase chain reaction, the Y-chromosome-specific SRY DNA of MSCs from male donors was not detected in infarcted hearts of female recipients. Serial echocardiography studies at baseline and 4 weeks after cell transplantation showed that both unlabeled and labeled MSCs attenuated progressive left ventricular dilatation and dysfunction compared with controls. Conclusions— At 4 weeks after transplantation of SPIO-labeled MSCs, the transplanted cells are not present in the scar and the enhanced MRI signals arise from cardiac macrophages that engulfed the SPIO nanoparticles. However, both labeled and unlabeled cells attenuate left ventricular dilatation and dysfunction after myocardial infarction.

Background— Activated macrophages have a significant role in wound healing and damaged tissue repair. We sought to explore the ability of ex vivo activated macrophages to promote healing and repair of the infarcted myocardium. Methods and Results— Human activated macrophage suspension (AMS) was prepared from a whole blood unit obtained from young donors in a closed sterile system and was activated by a novel method of hypo-osmotic shock. The AMS (&4×10 5 cells) included up to 43% CD14-positive cells and was injected into the ischemic myocardium of rats (n=8) immediately after coronary artery ligation. The control group (n=9) was treated with saline injection. The human cells existed in the infarcted heart 4 to 7 days after injection, as indicated by histology, human growth hormone-specific polymerase chain reaction, and magnetic resonance imaging (MRI) tracking of iron oxide–nanoparticle-labeled cells. After 5 weeks, scar vessel density (±SE) (25±4 versus 10±1 per mm 2 ; P P P P Conclusions— Early after myocardial infarction, injection of AMS accelerates vascularization, tissue repair, and improves cardiac remodeling and function. Our work suggests a novel clinically relevant option to promote the repair of ischemic tissue.

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm2 to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced Ti-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, RD, reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and RD were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P < .002 and r = 0.77, P < .001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.

2063 Background: Conventional MRI is unable to differentiate tumor progression from treatment-induced effects (pseudoprogression/radiation-necrosis) in brain tumor patients, thus significantly impacting patients’ management with no current solution. Methods: We have applied a novel MRI-based methodology for high resolution depiction of tumor/non-tumor tissues. This unique model-independent technique is based on robust MRI sequences acquired with a delay, enabling complete separation between tumor (contrast clearance at the delayed time point) and treatment effects (contrast accumulation) with no overlap. 498 treatment response assessment maps were calculated for 149 patients with primary/metastatic brain tumors and 9 with AVM recruited/followed on study. Results: The maps were validated by comparing pre-surgical maps of 51 patients with primary/metastatic brain tumors who underwent surgery with histology, resulting in 100% sensitivity and 94% specificity to active tumor. This validation confirms that cont...

e13002 Background: We have recently demonstrated delayed contrast extravasation MRI for calculating maps providing clear, high resolution depiction of tumor/non-tumor tissues. >100 brain tumor patients have been recruited in 3 clinical studies. In all cases increased tumor volumes (TVs) on our maps were followed by progression while stable/decreased TVs did not require treatment changes. Following histological validation the maps are being used for clinical decisions. Methods: Our maps were applied for improved patient management in 23 patients post treatment in which consensus regarding tumor progression vs. treatment effects (TEs) has not been reached. In all cases increased enhancement was shown on T1-MRI and rCBV was low/inconclusive. Results: In 5 GBM patients 1-3 months post surgery our maps showed significant TVs, therefore 2 were started on Avastin and 3 were re-operated. One of the latter showed increased enhancement on T1-MRI after the second operation. The maps showed no TV consistent with later clinical improvement. Two GBM patients 3-4.5 months post chemoRT showed increased TEs and stable TVs consistent with pseudoprogression. Adjuvant TMZ was continued followed by decreased lesion volumes. 2 patients (GBM/AA) showed increased TVs 5 months/years post chemoRT and were referred to Avastin/surgery. One patient was scanned 2 wks post chemoRT with clinical deterioration and rescanned 3 wks later when stabilized showing significantly increased TVs with no change on standard MRI. The patient was re-operated. Brain mets patients were recruited 1-21 months post SRS. Four showed significant TVs and were referred to treatment (surgery, WBRT, Xeloda). Two were followed for 3-6 months and upon increase in TV were referred to surgery. In 6 patients 73-100% of the enhancing lesion consisted of TEs thus are currently stable under FU. In 3 the lesion has resolved within 2-4 months. Active tumor was confirmed histologically in all above resected lesions. Conclusions: Following validation of our easily interpreted color code maps patients are now referred from 4 major Israeli hospitals with a question of progression vs TEs. Our data suggests that the maps may be used for improved patient management when standard MRI is inconclusive.

The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases.

2078 Background: Changes in enhancement seen in post treatment brain MRIs in primary and secondary brain malignancies often mimic tumor progression (pseudoprogression, radiation necrosis). Conventional MRI cannot differentiate tumor progression from treatment related effects resulting in suboptimal patient management. Methods: The application of delayed contrast extravasation MRI for depicting unique vessels characteristics with high resolution and high sensitivity to subtle BBB disruption is demonstrated in 17 GBM and 15 brain metastases patients undergoing standard chemoradiation and radiosurgery respectively. Results: 2 primary vessel function populations were defined: a slow population where contrast clearance from the tissue was slower than accumulation, and a fast population where clearance was faster than accumulation. Ten stereotactic biopsies acquired from GBM patients showed complete correlation with the maps, confirming the discrimination between fast population regions, reflecting morphological active tumor and slow regions reflecting necrosis/treatment-induced changes. Typical fast population vessel morphology consisted of proliferating endothelial cells, dilated lumen, peri vascular fibrosis and glumeroloid vessels, while slow regions consisted of necrotic vessels, in agreement with the observed MRI vessel function. The fast component volume 3 weeks post treatment was significantly correlated with the fast volume 4 (r2=0.84, p2=0.84, p