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Purpose: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data. Experimental Design: Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS). Results: One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (P < 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68, P < 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (P < 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases. Conclusions: This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination.

BACKGROUND AND PURPOSE: HERBY was a Phase II multicenter trial setup to establish the efficacy and safety of adding bevacizumab to radiation therapy and temozolomide in pediatric patients with newly diagnosed non-brain stem high-grade gliomas. This study evaluates the implementation of the radiologic aspects of HERBY. MATERIALS AND METHODS: We analyzed multimodal imaging compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of different Response Assessment in Neuro-Oncology criteria in the final response, the incidence of pseudoprogression, and the benefit of incorporating multimodal imaging into the decision process. RESULTS: Multimodal imaging compliance rates were the following: diffusion, 82%; perfusion, 60%; and spectroscopy, 48%. Neuroradiologists' responses differed for 50% of scans, requiring adjudication, with a total average reading time per patient of approximately 3 hours. Pseudoprogression occurred in 10/116 (9%) cases, 8 in the radiation therapy/temozolomide arm and 2 in the bevacizumab arm (P < .01). Increased target enhancing lesion diameter was a reason for progression in 8/86 cases (9.3%) but never the only radiologic or clinical reason. Event-free survival was predicted earlier in 5/86 (5.8%) patients by multimodal imaging (diffusion, n = 4; perfusion, n = 1). CONCLUSIONS: The addition of multimodal imaging to the response criteria modified the assessment in a small number of cases, determining progression earlier than structural imaging alone. Increased target lesion diameter, accounting for a large proportion of reading time, was never the only reason to designate disease progression.

INTRODUCTION: The purpose of this study was to evaluate the implementation of the radiological aspects of HERBY trial, and the practicality and feasibility of including multimodal imaging (MMI) to the response assessment in neuro-oncology (RANO) criteria in a pediatric high grade glioma cohort. METHODS: We analyzed MMI compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of the different RANO criteria in the final response, and the benefit of incorporating MMI to the decision process. RESULTS: MMI compliance rates were: diffusion 82%, perfusion 60% and spectroscopy 48%. Of the received data 2% of the structural scans and 23% of the MMI scans were not of sufficient quality. Adjudication rates due to differing neuroradiologist responses were 50%, which resulted in a total average reading time per patient of ~3 hours. Increase in diameters of the target enhancing lesion was a reason for progression in 8/86 cases (9.3%) but never the only radiological or clinical reason. EFS was predicted earlier in 5/86 (5.8%) patients by MMI (diffusion, n=4; perfusion, n=1). CONCLUSION: The addition of MMI to the response criteria was difficult to assess due to low return rates and data quality, but MMI helped to determine progression prediction than structural imaging alone. Increase of target lesion diameter measurement, which accounts for a large proportion of reading time, was never the only reason to stablish disease progression.

To implement adjusted performance imaging metrics on imaging clinical trials of a pharmaceutical company (Roche) in a business relationship with preferred imaging providers and to report on findings and lessons learned.In 2009 the Metrics Champion Consortium provided the first imaging metrics for use in clinical trials as industry consensus. Roche reviewed, adjusted, excluded, and extended these metrics and defined target values per metric in order to implement them in all clinical trials with 7 preferred providers.Roche preferred providers were able to report on all 19 metrics (8 unchanged Metrics Champion Consortium, 7 adjusted, and 4 Roche defined). Seventy-three Roche studies over 27 months form the basis for reporting; data are provided as mean and standard deviation per disease area with number of studies and for all studies reported for the specific metric for all providers. Disease areas are oncology, central nervous system, and inflammation. Seventeen metrics have proven to be useful; 2 metrics did not provide sufficient information; and 4 metrics need adjustments of target values.Imaging trial-related metrics are a new concept, and Roche and providers had to develop the same consistent understanding of content and how to report a specific metric. The 73 studies covered all phases and disease areas, which made it difficult at times to compare results.Imaging metrics in clinical trials are a useful tool in improving timeliness and quality of imaging data, enhancing trial processes, and governing sponsor/provider relationships. It increases the transparency in the business relationship and in the different clinical trial-related process steps. The use of metrics highlights critical topics, such as reading and adjudication, and enables parties to take actions to improve performance. Disease area-related reporting needs more data for specific improvements.

Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined.

Medical imaging serves many roles in patient care and the drug approval process, including assessing treatment response and guiding treatment decisions. These roles often involve a quantitative imaging biomarker, an objectively measured characteristic of the underlying anatomic structure or biochemical process derived from medical images. Before a quantitative imaging biomarker is accepted for use in such roles, the imaging procedure to acquire it must undergo evaluation of its technical performance, which entails assessment of performance metrics such as repeatability and reproducibility of the quantitative imaging biomarker. Ideally, this evaluation will involve quantitative summaries of results from multiple studies to overcome limitations due to the typically small sample sizes of technical performance studies and/or to include a broader range of clinical settings and patient populations. This paper is a review of meta-analysis procedures for such an evaluation, including identification of suitable studies, statistical methodology to evaluate and summarize the performance metrics, and complete and transparent reporting of the results. This review addresses challenges typical of meta-analyses of technical performance, particularly small study sizes, which often causes violations of assumptions underlying standard meta-analysis techniques. Alternative approaches to address these difficulties are also presented; simulation studies indicate that they outperform standard techniques when some studies are small. The meta-analysis procedures presented are also applied to actual [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) test–retest repeatability data for illustrative purposes.

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.

This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity. Murine glioma cells have been inoculated into the right brain frontal lobe of 16 mice. Anti-VEGF antibody was administered to a first group (n = 8), while a second group (n = 8) received a placebo. Magnetic resonance acquisitions, performed at days 10, 12, 15 and 23 following the implantation, allowed the derivation of a three-dimensional features dataset characterising tumour heterogeneity. Three-dimensional ultramicroscopy and standard histochemistry analysis have been performed to verify in vivo results. Placebo-treated mice displayed a highly-vascularised area at the tumour periphery, a monolithic necrotic core and a chaotic dense vasculature across the entire tumour. In contrast, the B20-treated group did not show any highly vascularised regions and presents a fragmented necrotic core. A significant reduction of the number of vessel segments smaller than 17 μm has been observed. There was no difference in overall tumour volume and growth rate between the two groups. Region-specific analysis revealed that VEGF inhibition affects only: (1) highly angiogenic compartments expressing high levels of VEGF and characterised by small capillaries, and also (2) the formation and structure of necrotic regions. These effects appear to be transient and limited in time. • VEGF inhibition affects only the highly angiogenic region and small capillaries network • VEGF inhibition is transient in time • Tumour volume is not affected by anti-angiogenic treatment • VEGF inhibition also influences the architecture of necrotic regions

Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.RSNA, 2011

INTRODUCTION: The HERBY trial assessed the efficacy of adding Bevacizumab (BEV) to postoperative radiotherapy/temozolamide (RT/TMZ) in children with newly diagnosed non-pontine high-grade gliomas (HGG). The trial showed no difference in OS or EFS between BEV and non-BEV treatment arms. METHODS: Radiological, pathological and molecular data were evaluated to characterise pediatric HGG and correlate with outcome measures. RESULTS: 74/124 (59.7%) patients had Cerebral hemispheric and 50/124 (40.3%) Midline tumors. Pathological diagnosis was available in all cases (111 astrocytomas /124), molecular data in 89/124. K27M histone mutations were present in 24/33 Midline cases with molecular data, and G34R/V mutations in 7 Cerebral cases. 116 patients completed treatment (RT/TMZ=56, BEV=60). 54/70 (77%) Cerebral cases underwent total/near-total resection with debulking/biopsy in 16/70 (23%). Fewer (12/46) Midline tumors had total/near-total resections than debulking/biopsy (34/46) (p

To address the error introduced by computed tomography (CT) scanners when assessing volume and unidimensional measurement of solid tumors, we scanned a precision manufactured pocket phantom simultaneously with patients enrolled in a lung cancer clinical trial. Dedicated software quantified bias and random error in the [Formula: see text], and [Formula: see text] dimensions of a Teflon sphere and also quantified response evaluation criteria in solid tumors and volume measurements using both constant and adaptive thresholding. We found that underestimation bias was essentially the same for [Formula: see text], and [Formula: see text] dimensions using constant thresholding and had similar values for adaptive thresholding. The random error of these length measurements as measured by the standard deviation and coefficient of variation was 0.10 mm (0.65), 0.11 mm (0.71), and 0.59 mm (3.75) for constant thresholding and 0.08 mm (0.51), 0.09 mm (0.56), and 0.58 mm (3.68) for adaptive thresholding, respectively. For random error, however, [Formula: see text] lengths had at least a fivefold higher standard deviation and coefficient of variation than [Formula: see text] and [Formula: see text]. Observed [Formula: see text]-dimension error was especially high for some 8 and 16 slice CT models. Error in CT image formation, in particular, for models with low numbers of detector rows, may be large enough to be misinterpreted as representing either treatment response or disease progression.

Motivation Telemedical services for ophthalmology are developed within the OPHTEL project, which has been funded by the European Union and by the Bavarian government in the Bavaria-online initiative. Methods Seven private ophthalmologists, one university eye clinic, one clinical Diabetes center and an informatics research institute are connected within a teleconsultation network. Asynchronous (based on Internet E-Mail) and synchronous (based on ISDN-mediated videoconferencing tools) types of teleconsultations are realized. Results 86 teleconsultations (62 asynchronous, 23 synchronous) took place within the first 10 months. Complex and rare eye diseases as well as interdisciplinary questions (ophthalmology - diabetology) are the main area of medical communication interest. Legal and security problems are discussed. Conclusions Telemedical services must be understood as a complete process of medical care on the basis of modern communication technologies, which influences also the management of this process.

Summary Introduction: The lack of comparability of evaluation results is one of the major obstacles of research and development in Medical Image Processing (MIP). The main reason for that is the usage of different image datasets with different quality, size and Gold standard. Objectives: Therefore, one of the goals of the Working Group on Medical Image Processing of the European Federation for Medical Informatics (EFMI WG MIP) is to develop first parts of a Reference Image Database. Methods: Kernel of the concept is to identify highly relevant medical problems with significant potential for improvement by MIP, and then to provide respective reference datasets. The EFMI WG MIP has primarily the role of a specifying group and an information broker, while the provider user relationships are defined by bilateral co-operation or license agreements. Results: An explorative database prototype has been implemented using the MySQL database software on the Web. Templates for provider user agreements have been worked out and already applied for own ‘pre-RID-MIP’ co-operations of the authors. Discussion and Conclusion: First steps towards a comprehensive reference image database have been done. Issues like funding, motivation, management, provision of Gold standards and evaluation guidelines are to be solved. Due to the interest from research groups and industry the efforts will be continued.

Background: Teleconsultation services have the potential to improve the communication among different medical care providers and between them and the patient. Increasing effectiveness in the shape of a savings in time or cost is often the result of better communication. Methods: A study was performed in order to demonstrate the feasibility of teleconsultation services, using the perioperative management of cataract patients as an example, and to provide data on the quality, acceptance and effectiveness of these services in comparison with a control group experiencing normal treatment. Results: Over a period of 3 months 42 patients of the teleconsultation group and 20 controls were studied. There were two referring ophthalmologists and three surgeons. The teleconsultation group had one consultation fewer with the ophthalmic surgeon because of the teleconsultation service. Patient satisfaction was slightly higher using the new technology. Patients would like to see this technique used again should surgery on the second eye become necessary. Conclusions: Teleconsultation services are ready to support and improve perioperative cataract management. Patients' confidence in their medical treatment was increased by using teleconsultation services. Physicians will expand the use of teleconsultation.

Background: Despite recent therapeutic advances, outcomes in pediatric high-grade glioma (HGG) remain poor. A phase 1 study (Glade-Bender et al., J Clin Oncol. 2008) indicated that bevacizumab (BEV) is well tolerated in children with refractory solid tumors and yielded pharmacokinetic data that support further studies of BEV in childhood cancer. Trial design: A total of 120 eligible patients aged 3 to 18 years with newly diagnosed, localized supratentorial or infratentorial cerebellar or peduncular, histologically confirmed World Health Organization grade 3 or 4 HGG (central independent histologic confirmation) will be randomized to 6 weeks of concomitant temozolomide (TMZ) and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ ± BEV every other week. Children aged 6 months to 3 years with recurrent disease are eligible in a young patient cohort; at relapse, these patients will receive TMZ + BEV without radiotherapy. All patients/parents must provide written informed consent per the local institutional review boards. The primary end point is event-free survival, defined as the time to earliest occurrence of tumor progression/recurrence (by central independent assessment per Response Assessment in Neuro-Oncology criteria), secondary malignancy, or death. Secondary end points include overall survival, response rate, safety, feasibility, and tolerability. The usefulness of multimodal MRI will be explored with respect to the diagnosis of pseudoprogression and prognostication of tumor evolution. All randomized patients will be followed for ≥3 years. A futility analysis will be performed after the first 60 randomized patients have been followed for 1 year. The primary analysis will be performed after all patients have been followed for 1 year. Updated analyses will be performed 3 years after the last patient has been randomized. HERBY is being conducted at 87 clinical sites in 15 countries. The first patient was randomized in October 2011. Among 118 patients screened to date, 79 have been randomized, and 1 has been enrolled in the young patient cohort. Completion of the study is expected in 2016. Some content has been presented at ASCO 2012 (abs TPS9596), SNO 2013 (abs PC-007), and ISPN 2013 (abs P109). Disclosure: D. Hargrave: Advisory board: Roche; P. Varlet: Advisory board: Roche Other substantive relationships: Roche; T. Jaspan: Corporate sponsored research: Roche; C. Jones: Advisory board: Genentech Paediatric Oncology Advisory Board Corporate-sponsored research: Roche/Genentech - HERBY trial M. Massimino: Advisory board: Roche, present study; A.A. Azizi: Advisory board: Roche F. Saran: Advisory board: Roche; P. Morgan: Advisory board: Trial Steering Group for F Hoffmann‐La Roche sponsored HERBY study (BO25041) Corporate-sponsored research: Employing institution receives support for its role in the F Hoffmann‐La Roche sponsored HERBY study (BO25041); G. Zahlmann: Stock ownership: Roche employee program Corporate-sponsored research: Roche employee; M. Zheng: Stock ownership: Genentech/Roche; S. Fuerst-Recktenwald: Other substantive relationships: Roche employee C. Berger: Corporate sponsored research: Roche; E. Bouffet: Advisory board: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

The impact of Information Technology has proliferated the development and uptake of Telecommunication, Compunetic (Computer and Networking) and Simulation technologies. The accessibility and interoperability of (Tele-)medical systems, performing Biomedical and Biomechanical applications, is one of the grand challenges for future healthcare. A new market is being developed dealing in Telemedical technologies. To support the integrated development of such an International Telemedical Information Society (ITIS), a supportive community of web-services has been identified and being setup. This paper presents the framework and building blocks of the emerging Virtual Medical Worlds.

TPS9596 Background: Despite therapeutic advances, outcomes in pediatric HGG remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) indicated that Bv is well tolerated in children with refractory solid tumors and yielded pharmacokinetic (PK) data that support further studies of Bv in childhood cancer. Reports of Bv used in children with solid tumors showed safety profiles consistent with data from adults. Methods: 120 evaluable patients aged 3-18 years with newly diagnosed histologically confirmed WHO grade 3or 4 HGG are randomized to receive standard combined modality therapy as currently adopted worldwide by the pediatric neuro-oncology community with or without Bv. Treatment consists of 6 weeks of concomitant TMZ and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ with or without Bv every other week. Primary endpoint is event-free survival (EFS). Progression is based on RANO criteria. Secondary endpoints are overall survival (OS), safety, feasibility, and tolerability. PK sampling is performed during cycles 1-4 of the adjuvant TMZ phase on all patients randomized to receive Bv. Health-related quality of life, neurocognitive functions, MGMT methylation status, functional changes in tumor based on magnetic resonance diffusion & perfusion imaging and spectroscopy are explored as well as the correlation of biomarkers with clinical activity and adverse events. All randomized patients will be followed for at least 3 years. Analysis of EFS and secondary endpoints will be performed after the 120 patients evaluable for EFS have been followed for 1 year. Multimodal imaging will provide a platform to develop new imaging criteria for pediatric neuro-oncological treatment response. An updated OS and safety analysis will be performed 3 years after the last patient has been randomized. The first patient was randomized in October 2011; completion of the study is expected in 2016.

DIABETEX is a knowledge-based, computer-supported consultation system for the therapy of type I diabetic out-patients. Three knowledge bases contain the medical and technical knowledge for treating either adults, adolescents or children by means of injections or by pumps. For the evaluation of the quality of the decision proposals three groups of patients were studied. The results obtained in test phase 1, i.e. the retrospective evaluation of DIABETEX decision proposals by the experts, and in test phase 2, i.e. the parallel work of DIABETEX and of an expert and the subsequent evaluation by experts, provide the basis for the further development and application of the system by non-expert diabetologists.

Since 1990, the primary criteria used for assessing response to therapy in high-grade gliomas were those developed by Macdonald and colleagues, which incorporated 2-dimensional area measurements of contrast-enhancing tumor regions, corticosteroid dosing, and clinical assessment to arrive at a designation of response, stable disease, or progression. Recent advances in imaging technology and targeted therapeutics, however, have exposed limitations of the Macdonald criteria and have highlighted the need for reevaluation of response assessment criteria. In 2010, the Response Assessment in Neuro-Oncology (RANO) Working Group published updated criteria to address this need and to standardize response assessment for high-grade gliomas. In 2009, prior to the publication of the RANO criteria, the randomized, placebo-controlled, multicenter, phase 3 AVAglio trial was designed and initiated to investigate the effectiveness of radiotherapy and temozolomide with or without bevacizumab in newly diagnosed glioblastoma. The AVAglio protocol enacted specific measures to adapt the Macdonald criteria to the frontline treatment setting and to antiangiogenic agent evaluation, including the incorporation of a T2/fluid-attenuated inversion recovery component, qualitative assessment of irregularly shaped contrast-enhancing lesions, and a decision tree for confirming or ruling out pseudoprogression. Moreover, the protocol outlines practical means by which these adapted response criteria can be implemented in the clinic. This article describes the evolution of radiographic response criteria for high-grade gliomas and highlights the similarities and differences between those implemented in the AVAglio study and those subsequently published by RANO.