Selecting trial centers using a standardized, automated site assessment survey instrument (SASI).

BACKGROUND: To improve the site selection process for clinical trials, we expanded a site survey to include standardized assessments of site commitment time, team experience, feasibility of tight timelines, and local medical community equipoise as factors that might better predict performance. We also collected contact information about institutional research services ahead of site onboarding. AIM: As a first step, we wanted to confirm that an expanded survey could be feasible and generalizable-that asking site teams for more details upfront was acceptable and that the survey could be completed in a reasonable amount of time, despite the assessment length. METHODS: A standardized, two-part Site Assessment Survey Instrument (SASI), examining qualitative components and with multiple contact list sections, was developed using a publicly accessible dashboard and later transferred to a REDCap platform. After multiple rounds of internal testing, the SASI was deployed 11 times for multicenter trials. Follow-up questionnaires were sent to site teams to confirm that an expanded survey instrument is acceptable to the research community and could be completed during a brief work shift. RESULTS: Respondents thought the SASI collected useful and relevant information about their sites (100%). Sites were "comfortable" (90%) supplying detailed information early in the site selection process and 57% completed the SASI in one to two hours. CONCLUSIONS: Coordinating centers and sites found the SASI tool to be acceptable and helpful when collecting data in consideration of multicenter trial site selection.

EHR-based cohort assessment for multicenter RCTs: a fast and flexible model for identifying potential study sites.

OBJECTIVE: The Recruitment Innovation Center (RIC), partnering with the Trial Innovation Network and institutions in the National Institutes of Health-sponsored Clinical and Translational Science Awards (CTSA) Program, aimed to develop a service line to retrieve study population estimates from electronic health record (EHR) systems for use in selecting enrollment sites for multicenter clinical trials. Our goal was to create and field-test a low burden, low tech, and high-yield method. MATERIALS AND METHODS: In building this service line, the RIC strove to complement, rather than replace, CTSA hubs' existing cohort assessment tools. For each new EHR cohort request, we work with the investigator to develop a computable phenotype algorithm that targets the desired population. CTSA hubs run the phenotype query and return results using a standardized survey. We provide a comprehensive report to the investigator to assist in study site selection. RESULTS: From 2017 to 2020, the RIC developed and socialized 36 phenotype-dependent cohort requests on behalf of investigators. The average response rate to these requests was 73%. DISCUSSION: Achieving enrollment goals in a multicenter clinical trial requires that researchers identify study sites that will provide sufficient enrollment. The fast and flexible method the RIC has developed, with CTSA feedback, allows hubs to query their EHR using a generalizable, vetted phenotype algorithm to produce reliable counts of potentially eligible study participants. CONCLUSION: The RIC's EHR cohort assessment process for evaluating sites for multicenter trials has been shown to be efficient and helpful. The model may be replicated for use by other programs.

A National-Scale Assessment of Mercury Bioaccumulation in United States National Parks Using Dragonfly Larvae As Biosentinels through a Citizen-Science Framework.

We conducted a national-scale assessment of mercury (Hg) bioaccumulation in aquatic ecosystems, using dragonfly larvae as biosentinels, by developing a citizen-science network to facilitate biological sampling. Implementing a carefully designed sampling methodology for citizen scientists, we developed an effective framework for a landscape-level inquiry that might otherwise be resource limited. We assessed the variation in dragonfly Hg concentrations across >450 sites spanning 100 United States National Park Service units and examined intrinsic and extrinsic factors associated with the variation in Hg concentrations. Mercury concentrations ranged between 10.4 and 1411 ng/g dry weight across sites and varied among habitat types. Dragonfly total Hg (THg) concentrations were up to 1.8-fold higher in lotic habitats than in lentic habitats and 37% higher in waterbodies with abundant wetlands along their margins than those without wetlands. Mercury concentrations in dragonflies differed among families but were correlated (r2 > 0.80) with each other, enabling adjustment to a consistent family to facilitate spatial comparisons among sampling units. Dragonfly THg concentrations were positively correlated with THg concentrations in both fish and amphibians from the same locations, indicating that dragonfly larvae are effective indicators of Hg bioavailability in aquatic food webs. We used these relationships to develop an integrated impairment index of Hg risk to aquatic ecosytems and found that 12% of site-years exceeded high or severe benchmarks of fish, wildlife, or human health risk. Collectively, this continental-scale study demonstrates the utility of dragonfly larvae for estimating the potential mercury risk to fish and wildlife in aquatic ecosystems and provides a framework for engaging citizen science as a component of landscape Hg monitoring programs.

Non-invasive in vivo assessment of IDH1 mutational status in glioma.

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI.

MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T(1) -weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T(2) lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti-proliferative properties as opposed to having a direct effect on tumor cell viability.

Assessment of perfusion MRI-derived parameters in evaluating and predicting response to antiangiogenic therapy in patients with newly diagnosed glioblastoma.

The paradigm for treating patients with glioblastoma multiforme (GBM) is shifting from a purely cytotoxic approach to one that incorporates antiangiogenic agents. These are thought to normalize the tumor vasculature and have shown improved disease management in patients with recurrent disease. How this vascular remodeling evolves during the full course of therapy for patients with newly diagnosed GBM and how it relates to radiographic response and outcome remain unclear. In this study, we examined 35 patients who were newly diagnosed with GBM using dynamic susceptibility contrast (DSC) MRI in order to identify early predictors of radiographic response to antiangiogenic therapy and to evaluate changes in perfusion parameters that may be predictive of progression. After surgical resection, patients received enzastaurin and temozolomide, both concurrent with and adjuvant to radiotherapy. Perfusion parameters, peak height (PH) and percent recovery, were calculated from the dynamic curves to assess vascular density and leakage. Six-month radiographic responders showed a significant improvement in percent recovery between baseline and 2 months into therapy, whereas 6-month radiographic nonresponders showed significantly increased PH between baseline and 1 month. At 2 months into therapy, percent recovery was predictive of progression-free survival. Four months prior to progression, there was a significant increase in the standard deviation of percent recovery within the tumor region. DSC perfusion imaging provides valuable information about vascular remodeling during antiangiogenic therapy, which may aid clinicians in identifying patients who will respond at the pretherapy scan and as an early indicator of response to antiangiogenic therapy.

Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activities in vivo.

Methods for the simultaneous polarization of multiple 13C-enriched metabolites were developed to probe several enzymatic pathways and other physiologic properties in vivo, using a single intravenous bolus. A new method for polarization of 13C sodium bicarbonate suitable for use in patients was developed, and the co-polarization of 13C sodium bicarbonate and [1-(13)C] pyruvate in the same sample was achieved, resulting in high solution-state polarizations (15.7% and 17.6%, respectively) and long spin-lattice relaxation times (T1) (46.7 s and 47.7 s respectively at 3 T). Consistent with chemical shift anisotropy dominating the T1 relaxation of carbonyls, T1 values for 13C bicarbonate and [1-(13)C] pyruvate were even longer at 3 T (49.7s and 67.3s, respectively). Co-polarized 13C bicarbonate and [1-(13)C] pyruvate were injected into normal mice and a murine prostate tumor model at 3T. Rapid equilibration of injected hyperpolarized 13C sodium bicarbonate with 13C CO2 allowed calculation of pH on a voxel by voxel basis, and simultaneous assessment of pyruvate metabolism with cellular uptake and conversion of [1-(13)C] pyruvate to its metabolic products. Initial studies in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model demonstrated higher levels of hyperpolarized lactate and lower pH within tumor, relative to surrounding benign tissues and to the abdominal viscera of normal controls. There was no significant difference observed in the tumor lactate/pyruvate ratio obtained after the injection of co-polarized 13C bicarbonate and [1-(13)C] pyruvate or polarized [1-(13)C] pyruvate alone. The technique was extended to polarize four 13C labelled substrates potentially providing information on pH, metabolism, necrosis and perfusion, namely [1-(13)C]pyruvic acid, 13C sodium bicarbonate, [1,4-(13)C]fumaric acid, and 13C urea with high levels of solution polarization (17.5%, 10.3%, 15.6% and 11.6%, respectively) and spin-lattice relaxation values similar to those recorded for the individual metabolites. These studies demonstrated the feasibility of simultaneously measuring in vivo pH and tumor metabolism using nontoxic, endogenous species, and the potential to extend the multi-polarization approach to include up to four hyperpolarized probes providing multiple metabolic and physiologic measures in a single MR acquisition.

3D 1H MRSI of brain tumors at 3.0 Tesla using an eight-channel phased-array head coil.

PURPOSE: To implement proton magnetic resonance spectroscopic imaging (1H MRSI) at 3 Tesla (3T) using an eight-channel phased-array head coil in a population of brain-tumor patients. MATERIALS AND METHODS: A total of 49 MRI/MRSI examinations were performed on seven volunteers and 34 patients on a 3T GE Signa EXCITE scanner using body coil excitation and reception with an eight-channel phased-array head coil. 1H MRSI was acquired using point-resolved spectroscopy (PRESS) volume selection and three-dimensional (3D) phase encoding using a 144-msec echo time (TE). RESULTS: The mean choline to N-acetyl aspartate ratio (Cho/NAA) was similar within regions of normal-appearing white matter (NAWM) in volunteers (0.5 +/- 0.04) and patients (0.6 +/- 0.1, P = 0.15). This ratio was significantly higher in regions of T2-hyperintensity lesion (T2L) relative to NAWM for patients (1.4 +/- 0.7, P = 0.001). The differences between metabolite intensities in lesions and NAWM were similar, but there was an increase in SNR of 1.95 when an eight-channel head coil was used at 3T vs. previous results at 1.5T. CONCLUSION: The realized increase in SNR means that clinically relevant data can be obtained in five to 10 minutes at 3T and used to predict the spatial extent of tumor in a manner similar to that previously used to acquire 1.5T data in 17 minutes.

Dynamic susceptibility contrast perfusion imaging of radiation effects in normal-appearing brain tissue: changes in the first-pass and recirculation phases.

PURPOSE: To identify radiation-induced changes in the cerebral vasculature of healthy tissue in the first four months following radiotherapy through the analysis of dynamic-susceptibility contrast perfusion imaging. MATERIALS AND METHODS: Dynamic gradient-echo imaging was performed on 22 patients during injection of a bolus of Gd-DTPA contrast. The relative cerebral blood volume (rCBV), maximum DeltaR2* of the first passage of the bolus, and a recirculation parameter were derived from gamma-variate fits of the dynamic data. The white matter (WM) rCBV and peak heights were estimated through correlation with segmented T1-weighted images. A percent recovery to baseline was also computed to further describe the recirculation phase. RESULTS: A significant elevation of the recirculation phase was observed at doses>15 Gy at two months following radiotherapy. This was reflected in an increased recirculation parameter in the fitted curves in the 15-30, 30-45, and >45 Gy dose groups to 2.8%, 3.8%, and 2.4% above the <15 Gy voxels, as well as in a decline in percent recovery to baseline. A trend toward lower rCBV and peak heights was observed at that same time point. CONCLUSION: The observed results suggest a dose-dependent decline in vessel density and increase in vascular permeability and/or tortuosity in irradiated normal-appearing brain tissue at two months following radiotherapy.

Assessment of metastatic cervical adenopathy using dynamic contrast-enhanced MR imaging.

BACKGROUND AND PURPOSE: Morphologic assessment by conventional imaging methods of lymph node metastases in patients with squamous cell carcinoma of the head and neck is, at best, insensitive. Doppler sonography has shown that lymph node metastases exhibit alterations in the number of vessels and blood flow. We assessed the ability of dynamic contrast-enhanced MR imaging to differentiate normal from diseased nodes in this patient population. METHODS: Twenty-one patients with newly diagnosed squamous cell carcinoma and no previous treatment were studied with the use of a head and neck phased array surface coil. Anatomic imaging included high resolution T1-weighted, fat-saturated fast spin-echo T2-weighted, and contrast-enhanced T1-weighted imaging (0.99-1.32 mm(3) voxels). The dynamic contrast-enhanced MR imaging was performed by using a 2D fast spoiled gradient recalled sequence with single dose bolus injection of contrast agent. Calculated values included time to peak, peak enhancement, maximum slope, and washout slope for the enhancement. All patients underwent neck dissection as part of their indicated treatment, and imaging results were correlated with pathologic findings. RESULTS: Dynamic contrast-enhanced MR imaging and pathology comparisons were obtained for 68 nodes. There was significantly longer time to peak (P <.001), lower peak enhancement (P <.05), lower maximum slope (P <.01), and slower washout slope (P <.05) in the tumor-involved nodes compared with the normal nodes. CONCLUSION: Analysis of dynamic contrast-enhanced MR imaging can differentiate normal from diseased lymph nodes in patients with squamous cell carcinoma of the head and neck.