Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Radiographic Response Assessment Strategies for Early-Phase Brain Trials in Complex Tumor Types and Drug Combinations: from Digital "Flipbooks" to Control Systems Theory.

There is an urgent need for drug development in brain tumors. While current radiographic response assessment provides instructions for identifying large treatment effects in simple high- and low-grade gliomas, there remains a void of strategies to evaluate complex or difficult to measure tumors or tumors of mixed grade with enhancing and non-enhancing components. Furthermore, most patients exhibit some period of alteration in tumor growth after starting a new therapy, but simple response categorization (e.g., stable disease, progressive disease) fails to provide any meaningful insight into the depth or degree of potential "subclinical" therapeutic response. We propose a creative solution to these issues based on a tiered strategy meant to increase confidence in identifying therapeutic effects even in the most challenging tumor types, while also providing a framework for complex evaluation of combination and sequential treatment schemes. Specifically, we demonstrate the utility of digital "flipbooks" to quickly identify subtle changes in complex tumors. We show how a modified Levin criteria can be used to quantify the degree of visual changes, while establishing estimates of the association between tumor volume and visual inspection. Lastly, we introduce the concept of quantifying therapeutic response using control systems theory. We propose measuring changes in volume (proportional), the area under the volume vs. time curve (integral) and changes in growth rates (derivative) to utilize a "PID" controller model of single or combination therapeutic activity.

Therapeutic Response Assessment of High-Grade Gliomas During Early-Phase Drug Development in the Era of Molecular and Immunotherapies.

ABSTRACT: Several new therapeutic strategies have emerged over the past decades to address unmet clinical needs in high-grade gliomas, including targeted molecular agents and various forms of immunotherapy. Each of these strategies requires addressing fundamental questions, depending on the stage of drug development, including ensuring drug penetration into the brain, engagement of the drug with the desired target, biologic effects downstream from the target including metabolic and/or physiologic changes, and identifying evidence of clinical activity that could be expanded upon to increase the likelihood of a meaningful survival benefit. The current review article highlights these strategies and outlines how imaging technology can be used for therapeutic response evaluation in both targeted and immunotherapies in early phases of drug development in high-grade gliomas.

[99mTc]-Bis-Methionine-DTPA Single-Photon Emission Computed Tomography Impacting Glioma Management: A Sensitive Indicator for Postsurgical/Chemoradiotherapy Response Assessment.

Background: The present study evaluated the prognostic value of [99mTc]MDM (bis-methionine-DTPA) follow-up single-photon emission computed tomography (SPECT) imaging for response assessment to chemoradiotherapy in glioma postoperatively. Materials and Methods: One hundred fourteen glioma patients (80 M:34 F) were followed postoperatively by sequential [99mTc]MDM SPECT, dynamic susceptibility contrast-enhanced (DSCE)-MRI, and magnetic resonance spectroscopy (MRS) at baseline, 6, 12, and 22.5 months postchemoradiotherapy. The quantitative imaging results and the clinical outcome were used for response assessment and for the final diagnosis. The quantitative parameter of [99mTc]MDM SPECT were also used for survival analysis. Results: A significantly (p = 0.001) lower target to nontarget (T/NT) ratio was observed in responders than in nonresponders. The sensitivity and specificity of [99mTc]MDM-SPECT for identifying tumor recurrence from radiation necrosis at a cutoff ratio of 1.90 were estimated at 97.9% and 92%. Whereas, the sensitivity and specificity of DSCE-MRI with the normalized cerebral blood volume (nCBV) cutoff of 3.32 for this differentiation was found to be 84.6% and 93.0%. MRS intensity ratios of Cho/NAA and Cho/Cr provided comparatively lower sensitivity of 81.0% and 85.3% and specificity of 73.0% and 73.7%. T/NT ratios correlated with nCBV (r = 0.775, p < 0.001) and to a moderate extent with Cho/NAA ratios (r = 0.467, p = 0.001). [99mTc]MDM SPECT and DSCE-MRI provided comparable results for predicting response assessment to chemoradiotherapy. There was a final diagnosis in 72 patients, of which 47 cases were tumor recurrence and 25 were radiation necrosis. The Kaplan-Meier analysis indicated that patients with T/NT ratio <1.9 showed prolonged survival (53.8 months) as compared (37.2 months) with those who demonstrated T/NT ratio >1.9 (p = 0.0001). Conclusion: Thus, this low-cost SPECT technique in combination with DSCE-MRI can be used accurately for mapping the disease activity, response assessment, and survival in glioma. [99mTc]MDM SPECT and DSCE-MRI had the same diagnostic efficacy to detect recurrent/residual tumor and radiation necrosis while MRS was inferior to both the techniques.

Genomic Biomarker Assessment in Gliomas: Impacts of Molecular Testing on Clinical Practice and Trial Design.

Recent discoveries elucidating the genetic underpinnings of glial neoplasms have revealed myriad recurrent alterations that have clinical value by improving accuracy of diagnosis and prognosis. Furthermore, this wealth of genomic information provides the basis for targeted therapies and the subsequent design of biomarker-based clinical trials. This review summarizes the current landscape of clinically relevant molecular alterations in gliomas and describes the role of routine molecular testing in context of treatment planning for standards of care and clinical trials.

Evidence for improved survival with bevacizumab treatment in recurrent high-grade gliomas: a retrospective study with ("pseudo-randomized") treatment allocation by the health insurance provider.

INTRODUCTION: Despite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider's approval of reimbursement. METHODS: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider. RESULTS: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant. CONCLUSION: Our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation.

PURPOSE: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator. METHODS: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls. RESULTS: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat's head and in a digital model of a rat's head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant. CONCLUSIONS: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.

Endogenous Chemical Exchange Saturation Transfer MRI for the Diagnosis and Therapy Response Assessment of Brain Tumors: A Systematic Review.

Purpose: To generate a narrative synthesis of published data on the use of endogenous chemical exchange saturation transfer (CEST) MRI in brain tumors. Materials and Methods: A systematic database search (PubMed, Ovid Embase, Cochrane Library) was used to collate eligible studies. Two researchers independently screened publications according to predefined exclusion and inclusion criteria, followed by comprehensive data extraction. All included studies were subjected to a bias risk assessment using the Quality Assessment of Diagnostic Accuracy Studies tool. Results: The electronic database search identified 430 studies, of which 36 fulfilled the inclusion criteria. The final selection of included studies was categorized into five groups as follows: grading gliomas, 19 studies (area under the receiver operating characteristic curve [AUC], 0.500-1.000); predicting molecular subtypes of gliomas, five studies (AUC, 0.610-0.920); distinction of different brain tumor types, seven studies (AUC, 0.707-0.905); therapy response assessment, three studies (AUC not given); and differentiating recurrence from treatment-related changes, five studies (AUC, 0.880-0.980). A high bias risk was observed in a substantial proportion of studies. Conclusion: Endogenous CEST MRI offers valuable, potentially unique information in brain tumors, but its diagnostic accuracy remains incompletely known. Further research is required to assess the method's role in support of molecular genetic diagnosis, to investigate its use in the posttreatment phase, and to compare techniques with a view to standardization.Keywords: Brain/Brain Stem, MR-Imaging, Neuro-OncologySupplemental material is available for this article.© RSNA, 2020.

Development and in vitro assessment of an anti-tumor nano-formulation.

This study aims to develop a new anti-cancer formulation based on the chelator Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone). Dp44mT has outstanding anti-tumor activity and the unique ability to overcome multidrug-resistance in cancer cells. This highly toxic compound has thus far only been applied in free form, limiting its therapeutic effectiveness. To reach its full therapeutic potential, however, Dp44mT should be encapsulated in a nano-carrier that would enable its selective and controlled delivery to malignant cells. As the first step towards this goal, here we encapsulate Dp44mT in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA), characterize this nano-formulation, and evaluate its therapeutic potential against cancer cells in vitro. Our results showed that the Dp44mT-loaded NPs were homogenous in shape and size, and had good colloidal stability. These PLGA NPs also showed high encapsulation efficiency and loading capacity for Dp44mT and enabled the sustained and tunable release of this chelator. Dp44mT-NPs were uptaken by cancer cells, showed a strong and dose-dependent cytotoxicity towards these cells, and significantly increased apoptotic cell death, in both monolayer and spheroid tumor models. This formulation had a low-level of toxicity towards healthy control cells, indicating an inherent selectivity towards malignant cells. These results demonstrate the great potential of this novel Dp44mT-based nano-formulation for the use in cancer therapy.

Bevacizumab Use and the Risk of Arterial and Venous Thromboembolism in Patients with High-Grade Gliomas: A Nested Case-Control Study.

STUDY OBJECTIVE: Bevacizumab is used in the treatment of recurrent glioblastoma, but evidence is limited on the incidence of thromboembolic complications regarding the use of this drug in real-world settings. We evaluated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) associated with the use of bevacizumab among adults diagnosed with high-grade gliomas in a commercially insured U.S. DESIGN: Nested case-control study. DATA SOURCE: Truven Health MarketScan Commercial and Medicare Supplemental health claims databases (2009-2015). PATIENTS: A total of 2157 patients with high-grade gliomas who underwent incident (first-time) craniotomy, radiation, and concurrent temozolomide treatment between 2009 and 2015 were identified. Overall, 25 cases of ATE and 99 cases of VTE were each identified in this cohort, and each case was matched to up to 10 controls (170 for ATE and 819 for VTE) based on sex, age, quarter year of index time, and follow-up duration by using incidence density sampling without replacement from the overall cohort. Controls were at risk for the outcome of interest (ATE or VTE) at the time of case occurrence and survived at least as long as their referent case. MEASUREMENTS AND MAIN RESULTS: Exposure to bevacizumab was determined during inpatient or outpatient encounters between the index date (date of the incident craniotomy) and the ATE or VTE event or corresponding matched control date. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of ATE and VTE separately. A higher proportion of patients with ATE received bevacizumab compared with controls (28% vs 17%; adjusted OR 1.51, 95% CI 0.54-4.24), but this excess in odds was not statistically significant. Similarly, bevacizumab was not significantly associated with VTE (13% vs 9%; adjusted OR 1.40, 95% CI 0.71-2.75). CONCLUSION: We found no significant association between the use of bevacizumab and the occurrence of thromboembolic events in patients with high-grade gliomas, although our study was limited by the small number of ATE events. Because the potential for complications from arterial thrombosis cannot be completely ruled out, further research is needed to confirm the thromboembolic safety of bevacizumab in a larger sample of patients with high-grade gliomas.

Assessment of 213Bi-anti-EGFR MAb treatment efficacy in malignant cancer cells with [1-13C]pyruvate and [18F]FDG.

Evaluation of response to therapy is among the key objectives of oncology. A new method to evaluate this response includes magnetic resonance spectroscopy (MRS) with hyperpolarized 13C-labelled metabolites, which holds promise to provide new insights in terms of both therapeutic efficacy and tumor cell metabolism. Human EJ28Luc urothelial carcinoma and LN18 glioma cells were treated with lethal activity concentrations of a 213Bi-anti-EGFR immunoconjugate. Treatment efficacy was controlled via analysis of DNA double-strand breaks (immunofluorescence γH2AX staining) and clonogenic survival of cells. To investigate changes in metabolism of treated cells vs controls we analyzed conversion of hyperpolarized [1-13C]pyruvate to [1-13C]lactate via MRS as well as viability of cells, lactate formation and lactate dehydrogenase activity in the cellular supernatants and [18F]FDG uptake in treated cells vs controls, respectively. Treatment of malignant cancer cells with 213Bi-anti-EGFR-MAb induced intense DNA double-strand breaks, resulting in cell death as monitored via clonogenic survival. Moreover, treatment of EJ28Luc bladder cancer cells resulted in decreased cell viability, [18F]FDG-uptake and an increased lactate export. In both EJ28Luc and LN18 carcinoma cells treatment with 213Bi-anti-EGFR-MAb triggered a significant increase in lactate/pyruvate ratios, as measured with hyperpolarized [1-13C]pyruvate. Treatment with 213Bi-anti-EGFR-MAb resulted in an effective induction of cell death in EJ28Luc and LN18 cells. Lactate/pyruvate ratios of hyperpolarized [1-13C]pyruvate proved to detect early treatment response effects, holding promise for future clinical applications in early therapy monitoring.

Assessment of Early Therapeutic Response to Nitroxoline in Temozolomide-Resistant Glioblastoma by Amide Proton Transfer Imaging: A Preliminary Comparative Study with Diffusion-weighted Imaging.

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. In this preliminary study, the purpose was to evaluate the feasibility of APT imaging in monitoring the early therapeutic response to nitroxoline (NTX) in a temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) mouse model, which was compared with diffusion-weighted imaging (DWI). Here, we prepared TMZ-resistant GBM mouse model (n = 12), which were treated with 100 mg/kg/day of NTX (n = 4) or TMZ (n = 4), or saline (n = 4) for 7 days for the evaluation of short-term treatment by using APT imaging and DWI sequentially. The APT signal intensities and apparent diffusion coefficient (ADC) values were calculated and compared before and after treatment. Moreover, immunohistological analysis was also employed for the correlation between APT imaging and histopathology. The association between the APT value and Ki-67 labeling index was evaluated by using simple linear regression analysis. The short-term NTX treatment resulted in significant decrease in APT value as compared to untreated and TMZ group, in which APT signals were increased. However, we did not observe significantly increased mean ADC value following short-term NTX treatment. The Ki-67 labeling index shows a correlation with APT value. APT imaging could show the earlier response to NTX treatment as compared to ADC values in a TMZ-resistant mouse model. We believe that APT imaging can be a useful imaging biomarker for the early therapeutic evaluation in GBM patients.

Early response assessment of glioma patients to definitive chemoradiotherapy using chemical exchange saturation transfer imaging at 7 T.

BACKGROUND: Patients with newly diagnosed inoperable glioma receive chemoradiotherapy (CRT). Standard Response Assessment in Neuro-Oncology (RANO) takes a minimum of 4 weeks after the end of treatment. PURPOSE/HYPOTHESIS: To investigate whether chemical exchange saturation transfer (CEST) MRI enables earlier assessment of response to CRT in glioma patients. STUDY TYPE: Longitudinal prospective study. POPULATION: Twelve brain tumor patients who underwent definitive CRT were included in this study. Three longitudinal CEST MRI measurements were performed for each patient at 7T: first before, second immediately after completion of CRT, and a third measurement as a 6-week follow-up. FIELD STRENGTH/SEQUENCE: Conventional MRI (contrast-enhanced, T2 w and diffusion-weighted imaging) at 3T and T2 w and CEST MRI at 7T was performed for all patients. ASSESSMENT: The mean relaxation-compensated relayed nuclear-Overhauser-effect CEST signal (rNOE) and the mean downfield-rNOE-suppressed amide proton transfer (dns-APT) CEST signal were investigated. Additionally, choline-to-N-acetyl-aspartate ratios (Cho/NAA) were evaluated using single-voxel 1 H-MRS in six of these patients. Performance of obtained contrasts was analyzed in assessing treatment response as classified according to the updated RANO criteria. STATISTICAL TEST: Unpaired Student's t-test. RESULTS: The rNOE signal significantly separated stable and progressive disease directly after the end of therapy (post-treatment normalized to pre-treatment mean ± SD: rNOEresponder = 1.090 ± 0.110, rNOEnon-responder = 0.808 ± 0.155, P = 0.015). In contrast, no significant difference was observed between either group when assessing the normalized dns-APT (dns-APTresponder = 0.953 ± 0.384, dns-APTnon-responder = 0.972 ± 0.477, P = 0.95). In the smaller MRS subcohort, normalized Cho/NAA decreased in therapy responders (Cho/NAAresponder = 0.632 ± 0.007, Cho/NAAnon-responder = 0.946 ± 0.124, P = 0.070). DATA CONCLUSION: rNOE mediated CEST imaging at 7T allowed for discrimination of responders and non-responders immediately after the end of CRT, additionally supported by 1 H-MRS data. This is at least 4 weeks earlier than the standard clinical evaluation according to RANO. Therefore, CEST MRI may enable early response assessment in glioma patients. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:1268-1277.

Volumetric assessment of tumor size changes in pediatric low-grade gliomas: feasibility and comparison with linear measurements.

PURPOSE: We report a retrospective comparison between bi-dimensional RANO criteria and manual volumetric segmentation (MVS) in pediatric low-grade gliomas. METHODS: MRI FLAIR or T1 post contrast images were used for assessment of tumor response. Seventy patients were included in this single center study, for each patient two scans were assessed ("time 0" and "end of therapy") and response to therapy was evaluated for both methods. Inter-reader variability and average time for volumetric assessment were also calculated. RESULTS: Fourteen (20%) of the 70 patients had discordant results in terms of response assessment between the bi-dimensional measurements and MVS. All volumetric response assessments were in keeping with the subjective analysis of tumor (radiology report). Of the 14 patients, 6 had stable disease (SD) on MVS and progressive disease (PD) on 2D assessment, 5 patients had SD on MVS and partial response (PR) on 2D assessment, 2 patients had PD on MVS and SD on 2D assessment, and 1 patient had PR on MVS and SD on 2D analysis. The number of discordant results rises to 21(30%) if minor response is integrated in the response assessment. MVS was relatively fast and showed high inter-reader concordance. CONCLUSION: Our analysis shows that therapeutic response classification may change in a significant number of children by performing a volumetric tumor assessment. Furthermore, MVS is not particularly time consuming and has very good inter-reader concordance.

MRI assessment of treatment delivery for interstitial photodynamic therapy of high-grade glioma in a preclinical model.

BACKGROUND: High-grade gliomas are primary brain tumors that have shown increasing incidence and unfavorable outcomes. Local control is crucial to the management of this pathology. Photodynamic therapy (PDT), based on the light-induced activation of a photosensitizer (PS), achieves local treatment by inducing selective lesions in tumor tissue. OBJECTIVES: Previous studies have reported the outcomes of PDT for glioblastoma via immunohistological data. Our study aimed to evaluate MRI findings, including diffusion, and perfusion sequences, compared with immunohistological data from the same population to address the efficiency of light fractionation. MATERIALS AND METHODS: Twenty-six "nude" rats grafted with human U87 cells into the right putamen underwent PDT. After PS precursor (5-ALA) intake, an optical fiber was introduced into the tumor. The rats were randomized into the following groups: those without illumination and those that received two or five fractions of light. Treatment effects were assessed with early high-field MRI to measure the volume of necrosis and edema using diffusion and perfusion sequences; the MRI results were compared with immunohistology results, including necrosis and apoptosis markers. RESULTS: Elevated diffusion values were observed on MRI in the centers of the tumors of the treated animals, especially in the 5-fraction group (P < 0.01). Perfusion was decreased around the treatment site, especially in the 5-fraction group (P = 0.024). The MRI findings were consistent with previously published histological data. The median volume of necrosis was significantly different between the sham group and treated groups, 0 mm3 versus 2.67 mm3 , P < 0.001. The same trend was previously observed in histology data when grading the absence or presence of necrosis and when the presence of necrosis was significantly more predominant for the treated group than for the untreated group (P < 001). Additionally, cell death represented by apoptosis marker data (TUNEL method) was significantly higher in the 5-fraction group than in the 2-fraction group (P = 0.01). CONCLUSION: Diffusion and perfusion MRI revealed histological lesions. Interstitial PDT (iPDT) induced specific lesions in the tumor tissue, which were observed with MRI and confirmed by histopathological analysis. Thus, MRI may provide a non-invasive and reliable tool to assess treatment outcomes after PDT. Lasers Surg. Med. 50:460-468, 2018. © 2017 Wiley Periodicals, Inc.

ELTD1, an effective anti-angiogenic target for gliomas: preclinical assessment in mouse GL261 and human G55 xenograft glioma models.

Background: Despite current therapies, glioblastoma is a devastating cancer, and validation of effective biomarkers for it will enable better diagnosis and therapeutic intervention for this disease. We recently discovered a new biomarker for high-grade gliomas, ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) via bioinformatics, and validated that ELTD1 protein levels are significantly higher in human and rodent gliomas. The focus of this study was to assess the effect on tumor growth of an antibody against ELTD1 in orthotopic, GL261, and G55 xenograft glioma models. Methods: The effect of anti-ELTD1 antibody therapy was assessed by animal survival, MRI measured tumor volumes, MR angiography, MR perfusion imaging, and immunohistochemistry (IHC) characterization of microvessel density in mouse glioma models. Comparative treatments included anti-vascular endothelial growth factor (VEGF) and anti-c-Met antibody therapies, compared with untreated controls. Results: Tumor volume and survival data in this study show that antibodies against ELTD1 inhibit glioma growth just as effectively or even more so compared with other therapeutic targets studied, including anti-VEGF antibody therapy. Untreated GL261 or G55 tumors were found to have significantly higher ELTD1 levels (IHC) compared with contralateral normal brain. The anti-angiogenic effect of ELTD1 antibody therapy was observed in assessment of microvessel density, as well as from MR angiography and perfusion measurements, which indicated that anti-ELTD1 antibody therapy significantly decreased vascularization compared with untreated controls. Conclusions: Either as a single therapy or in conjunction with other therapeutic approaches, anti-ELTD1 antibodies could be a valuable new clinical anti-angiogenic therapeutic for high-grade gliomas.

Response Assessment in Pediatric Neuro-Oncology: Implementation and Expansion of the RANO Criteria in a Randomized Phase II Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas.

Determination of tumor response to treatment in neuro-oncology is challenging, particularly when antiangiogenic agents are considered. Nontumoral factors (eg, blood-brain barrier disruption, edema, and necrosis) can alter contrast enhancement independent of true tumor response/progression. Furthermore, gliomas are often infiltrative, with nonenhancing components. In adults, the Response Assessment in Neuro-Oncology (RANO) criteria attempted to address these issues. No such guidelines exist yet for children. The ongoing randomized phase II trial, A Study of Avastin (bevacizumab) in Combination With Temolozomide (TMZ) and Radiotherapy in Paediatric and Adolescent Patients With High-Grade Glioma (HERBY), will establish the efficacy and safety of the antiangiogenic agent bevacizumab for the first-line treatment of newly diagnosed high-grade glioma in children (n = 121 patients, enrollment complete). The primary end point is event-free survival (tumor progression/recurrence by central review, second primary malignancy, or death). Determination of progression or response is based on predefined clinical and radiographic criteria, modeled on the RANO criteria and supported by expert pseudoprogression review and the use of standardized imaging protocols. The HERBY trial will also compare conventional MR imaging (T1-weighted and T2/fluid-attenuated inversion recovery sequences) with conventional MR imaging plus diffusion/perfusion imaging for response assessment. It is anticipated that HERBY will provide new insights into antiangiogenic-treated pediatric brain tumors. HERBY will also investigate the practicality of obtaining adequate quality diffusion/perfusion scans in a trial setting, and the feasibility of implementing standard imaging protocols across multiple sites. To date, 61/73 (83.6%) patients with available data have completed diffusion-weighted imaging (uptake of other nonconventional techniques has been limited). Harmonization of imaging protocols and techniques may improve the robustness of pediatric neuro-oncology studies and aid future trial comparability.

Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials clinical outcome assessment endpoints workshop (October 15, 2014, Bethesda MD).

On October 15, 2014, a workshop was held on the use of clinical outcome assessments in clinical trials for high-grade glioma of the brain. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, the Musella Foundation for Brain Tumor Research and Information, and Accelerate Brain Cancer Cure. It was planned and carried out with participation from the US Food and Drug Administration. The workshop also included stakeholders from all aspects of the brain tumor community, including clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to move the field forward and toward greater inclusion of these endpoints in future clinical trials for high-grade gliomas.