Preclinical characterization of [18F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.

PURPOSE: Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[18F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([18F]T-008) and its tritiated analog, [3H]T-008. METHODS: In vitro autoradiography (ARG) studies in the CH24H wild-type (WT) and knockout (KO) mouse brain sections were conducted using [3H]T-008. PET imaging was conducted in two adult rhesus macaques using [18F]T-008. Each macaque received two test-retest baseline scans and a series of two blocking doses of soticlestat administered prior to [18F]T-008 to determine the CH24H enzyme occupancy. PET data were analyzed with Logan graphical analysis using plasma input. A Lassen plot was applied to estimate CH24H enzyme occupancy by soticlestat. RESULTS: In ARG studies, binding of [3H]T-008 was specific to CH24H in the mouse brain sections, which was not observed in CH24H KO or in wild-type mice after pretreatment with soticlestat. In rhesus PET studies, the rank order of [18F]T-008 uptake was striatum > cortical regions > cerebellum, which was consistent with CH24H distribution in the brain. Pre-blocking with soticlestat reduced the maximum uptake and increased the washout in all brain regions in a dose-dependent manner. Calculated global occupancy values for soticlestat at a dose of 0.89 mg/kg were 97-98%, indicating maximum occupancy. CONCLUSION: The preclinical in vitro and in vivo evaluation of labeled T-008 demonstrates that [18F]T-008 is suitable for imaging CH24H in the brain and warrants further studies in humans.

Repeatability of MR Elastography of Liver: A Meta-Analysis.

Purpose To perform a meta-analysis to generate an estimate of the repeatability coefficient (RC) for magnetic resonance (MR) elastography of the liver. Materials and Methods A systematic search of databases was performed for publications on MR elastography during the 10-year period between 2006 and 2015. The identified studies were screened independently and were verified reciprocally by all authors. Two reviewers independently determined the percentage RC and effective sample size from each article. A forest plot was constructed of the percentage RC estimates from the 12 studies. Bootstrap 95% confidence intervals (CIs) were constructed for the summary percentage RCs. Results Twelve studies comprising 274 patients met the eligibility criteria and were included for analysis. A flow diagram of studies included according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was prepared for the inclusion and exclusion criteria. All studies included in the meta-analysis fulfilled four or more of the seven categories of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2. The estimated summary RC was 22% (95% CI: 16.1%, 28.2%). The three main sources for this heterogeneity were the trained versus untrained operator drawing contours to choose regions of interest, the time between two replicate examinations, and, finally, the field strength of the MR imaging unit. The RC estimates tended to be higher for studies that did not use a well-trained operator, those with 1.5-T field strength imaging units, and those with longer time intervals between examinations. Conclusion The meta-analysis results provide the basis for the following draft longitudinal Quantitative Imaging Biomarkers Alliance MR elastography claim: A measured change in hepatic stiffness of 22% or greater, at the same site and with use of the same equipment and acquisition sequence, indicates that a true change in stiffness has occurred with 95% confidence. © RSNA, 2017.

Hypoxia mediated pulmonary edema: potential influence of oxidative stress, sympathetic activation and cerebral blood flow.

BACKGROUND: Neurogenic pulmonary edema (NPE) is a non-cardiogenic form of pulmonary edema that can occur consequent to central neurologic insults including stroke, traumatic brain injury, and seizure. NPE is a public health concern due to high morbidity and mortality, yet the mechanism(s) are unknown. We hypothesized that NPE, evoked by cerebral hypoxia in the presence of systemic normoxia, would be accompanied by sympathetic activation, oxidative stress, and compensatory antioxidant mechanisms. METHODS: Thirteen Walker hounds were assigned to cerebral hypoxia (SaO2 ~ 55 %) with systemic normoxia (SaO2 ~ 90 %) (CH; n = 6), cerebral and systemic (global) hypoxia (SaO2 ~ 60 %) (GH; n = 4), or cerebral and systemic normoxia (SaO2 ~ 90 %) (CON; n = 3). Femoral venous (CH and CON) perfusate was delivered via cardiopulmonary bypass to the brain and GH was induced by FiO2 = 10 % to maintain the SaO2 at ~60 %. Lung wet to lung dry weight ratios (LWW/LDW) were assessed as an index of pulmonary edema in addition to hemodynamic measurements. Plasma catecholamines were measured as markers of sympathetic nervous system (SNS) activity. Total glutathione, protein carbonyls, and malondialdehyde were assessed as indicators of oxidative stress. Brain and lung compensatory antioxidants were measured with immunoblotting. RESULTS: Compared to CON, LWW/LDW and pulmonary artery pressure were greater in CH and GH. Expression of hemeoxygenase-1 in brain was higher in CH compared to GH and CON, despite no group differences in oxidative damage in any tissue. Catecholamines tended to be higher in CH and GH. CONCLUSION: Cerebral hypoxia, with systemic normoxia, is not systematically associated with an increase in oxidative stress and compensatory antioxidant enzymes in lung, suggesting oxidative stress did not contribute to NPE in lung. However, increased SNS activity may play a role in the induction of NPE during hypoxia.

The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data.

In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

Perspective: The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partner Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not-for-profit partners in ADNI can collaborate, share information, and offer scientific and private-sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.

Robustness of automated hippocampal volumetry across magnetic resonance field strengths and repeat images.

BACKGROUND: Low HCV has recently been qualified by the European Medicines Agency as a biomarker for enrichment of clinical trials in predementia stages of Alzheimer's disease. For automated methods to meet the necessary regulatory requirements, it is essential they be standardized and their performance be well characterized. METHODS: The within-image and between-field strength reproducibility of automated hippocampal volumetry using the Learning Embeddings for Atlas Propagation (or LEAP) algorithm was assessed on 153 Alzheimer's Disease Neuroimaging Initiative subjects. RESULTS: Tests/retests at 1.5 T and 3 T, and a comparison between 1.5 T and 3 T, yielded average unsigned variabilities in HCVs of 1.51%, 1.52%, and 2.68%. A small bias between field strengths (mean signed difference, 1.17%; standard deviation, 3.07%) was observed. CONCLUSIONS: The measured reproducibility characteristics confirm the suitability of using automated magnetic resonance imaging analyses to assess HCVs quantitatively and to represent a fundamental characterization that is critical to meet the regulatory requirements for using hippocampal volumetry in clinical trials and health care.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Magnetic Resonance Enterography Assessment of Transmural Healing with Vedolizumab in Moderate to Severe Crohn's Disease: Feasibility in the VERSIFY Phase 3 Clinical Trial.

Purpose: The VERSIFY phase 3 trial in patients with Crohn's disease (CD) treated with vedolizumab was the first to include a substudy that used a standardized magnetic resonance enterography (MRE) protocol to assess features of transmural inflammation (bowel edema and wall thickness) and extramural disease activity (enlarged lymph nodes). Patients and Methods: Patients received intravenous vedolizumab (300 mg) at weeks 0 (baseline), 2, and 6, and then every 8 weeks for 26 or 52 weeks. Post hoc analyses included a subpopulation with a Magnetic Resonance Index of Activity score of ≥7 in at least one bowel segment at baseline and at least one postbaseline MRE assessment. Changes in transmural inflammation, including intramural bowel edema and wall thickness, were evaluated. Patient-level and segment-level analyses were performed. Results: MRE images were evaluated in 27 patients with 83 evaluable bowel segments at baseline and week 26, and 13 patients with 38 evaluable segments at baseline, week 26, and week 52. At baseline, all patients had bowel wall edema and wall thickness of >3 mm in at least one bowel segment. The proportion of patients with edema decreased at weeks 26 (17/27 [63.0%]) and 52 (4/13 [30.8%]) and the proportion with bowel wall thickness of >3 mm decreased at weeks 26 (25/27 [92.6%]) and 52 (10/13 [76.9%]). Conclusion: In patients with CD treated with vedolizumab for 26 and 52 weeks, the number of patients, and bowel segments, with MRE-detected transmural inflammation was reduced. These results highlight the impact of vedolizumab on components of transmural inflammation in CD and demonstrate that using MRE in CD multicenter clinical trials is feasible. Trial Registration: ClinicalTrials.gov NCT02425111, April 23, 2015, http://www.clinicaltrials.gov NCT02425111; EU Clinical Trials Register EudraCT 2014-003509-13, https://www.clinicaltrialsregister.eu.

Standardization of analysis sets for reporting results from ADNI MRI data.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly.

Predicting how individuals approach enrichment: regulatory focus in cotton-top tamarins (Sanguinus oedipus).

Evidence is mounting that personality is associated with health and well-being in humans and other animals. In a step towards increasing our understanding of this link, we applied regulatory focus theory, a motivational perspective from social psychology, to the behavior of zoo-housed cotton top tamarins. We tested whether regulatory focus "personality," that is stable differences in whether an individual is motivated by gains versus safety, would 1) produce individual differences in behavior and 2) predict how individuals interact with enrichment. First, we characterized individuals with respect to several key behaviors: eating in the open, hiding, and time spent near the front of the exhibit. The monkeys were consistent in their behavioral tendencies across the 6-month study, allowing regulatory focus classification. One monkey showed evidence of being a promotion-individual, that is, more motivated by gains than safety. One monkey showed evidence of being a prevention-individual, that is, more motivated by safety than gains. The other monkeys were stable in their behavior and showed evidence of being intermediate-individuals, that is, they favored neither gains nor safety. Using these characterizations, we predicted distinct patterns of individual-object interactions with enrichment. For example, we predicted that a promotion-individual (favoring gains over safety) would approach potential gains faster than a prevention-individual (favoring safety over gains). Counter-intuitively, however, we also predicted that a promotion-individual would approach non-gains slower than a prevention-individual concerned with safety. We found support for our predictions, which suggests that regulatory focus theory could be a useful tool for understanding how and why individuals interact with environmental enrichment.

Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial.

BACKGROUND: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood-brain barrier penetration. OBJECTIVE: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). METHODS: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18-45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. RESULTS: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. CONCLUSIONS: Darolutamide did not significantly alter CBF, consistent with its low blood-brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. TRIAL REGISTRATION NUMBER: NCT03704519; date of registration: October 2018.

Androgens, or male sex hormones, bind to androgen receptors within prostate cells and can cause growth of prostate cancer. The treatment of prostate cancer often includes drugs that bind to androgen receptors, called androgen receptor inhibitors, keeping androgens from binding to the receptors and preventing prostate cancer growth. In clinical studies, these drugs may have adverse effects on the central nervous system, or brain, including dizziness, falls, and impaired thinking and problem solving. This study compared the effects of two androgen receptor inhibitors, darolutamide and enzalutamide, and placebo on blood flow in the brain. Blood flow was measured by a type of magnetic resonance imaging in healthy men after receiving a single dose of treatment. Blood flow in the brain was reduced by enzalutamide compared with both placebo and darolutamide. Darolutamide did not decrease brain blood flow. This lack of effect on brain blood flow is in line with preclinical studies that showed darolutamide's limited ability to cross the blood­brain barrier, which is the naturally occurring barrier that protects the brain from harmful substances. In clinical studies of patients with prostate cancer treated with darolutamide, adverse effects on the brain have occurred in similar proportions of patients receiving darolutamide and placebo. In contrast, enzalutamide treatment has an increased risk of adverse effects on the brain versus placebo. The results of this study provide information on the effects of these androgen receptor inhibitors on brain blood flow that may be related to their adverse effects on the brain and its functioning.

Assessing Indiana's Health and Safety in early care and education programs: identifying areas for improvement.

The objective of this study is to describe the key National Health and Safety Standards (NHS) met in early care and education (ECE) programs in Indiana and to establish reliability for the Indiana Health and Safety Checklist. The Indiana Health and Safety Checklist, modified from the California Childcare Health Program's Health and Safety Checklist, includes 87 items and 11 subscales. It was completed in 2 h by trained child care health consultants in 82 ECE programs to assess the number of key NHS met. The 82 ECE programs met the majority of NHS items. Thirteen items were not met in more than 50% of the programs. The items with the lowest compliance were emergency food supplies, children's hand washing, special health care plans, cleaning and sanitizing counters, and impact surfaces under playground equipment. The Indiana Health and Safety Checklist had moderate internal reliability for 6 of the 9 subscales analyzed. ECE programs strive to provide high quality care and the programs met the majority of NHS on the checklist. The Checklist is a reliable instrument that helped identify health and safety gaps and thus, identified the targeted interventions for child care health consultation.

89Zr-3,2-HOPO-Mesothelin Antibody PET Imaging Reflects Tumor Uptake of Mesothelin-Targeted 227Th-Conjugate Therapy in Mice.

The mesothelin (MSLN)-targeted 227Th conjugate is a novel α-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with 89Zr to evaluate whether PET imaging with 89Zr-MSLN matches 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Methods: Serial PET imaging with protein doses of 4, 20, or 40 µg of 89Zr-MSLN and 89Zr-control was performed up to 168 h after tracer injection in human tumor-bearing nude mice with high (HT29-MSLN) and low (BxPc3) MSLN expression. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time points in HT29-MSLN and in medium-MSLN-expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Results: 89Zr-MSLN PET imaging showed an SUVmean of 2.2 ± 0.5 in HT29-MSLN tumors. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. Pretreatment SUVmean was 2.2 ± 0.2 in HT29-MSLN tumors, which decreased in volume on 227Th-MSLN treatment. BxPc3 tumors showed an SUVmean of 1.2 ± 0.3 and remained similar in size after 227Th-MSLN treatment. Conclusion: 89Zr-MSLN PET imaging reflected MSLN expression and matched 227Th-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities.

UNLABELLED: 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. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.

Global issues in drug development for Alzheimer's disease.

The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer's disease.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.

BACKGROUND: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. METHODS AND RESULTS: The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. CONCLUSIONS: Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

In Vitro and In Vivo Comparison of 3,2-HOPO Versus Deferoxamine-Based Chelation of Zirconium-89 to the Antimesothelin Antibody Anetumab.

Introduction: [227Th]Th-3,2-HOPO-MSLN-mAb, a mesothelin (MSLN)-targeted thorium-227 therapeutic conjugate, is currently in phase I clinical trial; however, direct PET imaging using this conjugate is technically challenging. Thus, using the same MSLN antibody, we synthesized 3,2-HOPO and deferoxamine (DFO)-based zirconium-89 antibody conjugates, [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb, respectively, and compared them in vitro and in vivo. Methods: [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb were evaluated in vitro to determine binding affinity and immunoreactivity in HT29-MSLN and PDX (NCI-Meso16, NCI-Meso21) cells. For both the zirconium-89 conjugates, in vivo studies (biodistribution/imaging) were performed at days 1, 3, and 6, from which tissue uptake was determined. Results: Both the conjugates demonstrated a low nanomolar binding affinity for MSLN and >95% immunoreactivity. In all the three tumor types, biodistribution of [89Zr]Zr-DFO-MSLN-mAb resulted in higher tumor uptake(15.88-28-33%ID/g) at all time points compared with [89Zr]Zr-3,2-HOPO-MSLN-mAb(7-13.07%ID/g). [89Zr]Zr-3,2-HOPO-MSLN-mAb femur uptake was always higher than [89Zr]Zr-DFO-MSLN-mAb, and imaging results concurred with the biodistribution studies. Conclusions: Even though the conjugates exhibited a high binding affinity for MSLN, [89Zr]Zr-DFO-MSLN-mAb showed a higher tumor and lower femur uptake than [89Zr]Zr-3,2-HOPO-MSLN-mAb. Nevertheless, [89Zr]Zr-3,2-HOPO-MSLN-mAb could be used to study organ distribution and lesion uptake with the caveat of detecting MSLN-positive bone lesions. Clinical trial (NCT03507452).

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.

The Alzheimer's disease neuroimaging initiative: perspectives of the Industry Scientific Advisory Board.

The Industry Scientific Advisory Board (ISAB) consists of representatives from the private companies and nonprofit foundations participating as sponsors of Alzheimer's Disease Neuroimaging Initiative (ADNI). Currently 21 companies are represented including pharmaceutical, imaging, and biotech concerns, and two foundations including the Alzheimer's Association. ISAB members meet regularly by teleconference or face-to-face at ADNI meetings and participate in the ADNI Core groups, all administered and organized by the Foundation for the National Institutes of Health. ISAB 'deliverables' include dissemination of information to sponsors, assisting in scientific review of protocols and results, initiation and consideration of "add-on" studies and analyses, and generation of consensus positions on industry priorities and concerns. Although positioned as an advisory body, ISAB also actively contributes to the ADNI mission of identifying biomarkers of disease progression.