Next-generation technologies unlock new possibilities to track rangeland productivity and quantify multi-scale conservation outcomes.

Historically, relying on plot-level inventories impeded our ability to quantify large-scale change in plant biomass, a key indicator of conservation practice outcomes in rangeland systems. Recent technological advances enable assessment at scales appropriate to inform management by providing spatially comprehensive estimates of productivity that are partitioned by plant functional group across all contiguous US rangelands. We partnered with the Sage Grouse and Lesser Prairie-Chicken Initiatives and the Nebraska Natural Legacy Project to demonstrate the ability of these new datasets to quantify multi-scale changes and heterogeneity in plant biomass following mechanical tree removal, prescribed fire, and prescribed grazing. In Oregon's sagebrush steppe, for example, juniper tree removal resulted in a 21% increase in one pasture's productivity and an 18% decline in another. In Nebraska's Loess Canyons, perennial grass productivity initially declined 80% at sites invaded by trees that were prescriptively burned, but then fully recovered post-fire, representing a 492% increase from nadir. In Kansas' Shortgrass Prairie, plant biomass increased 4-fold (966,809 kg/ha) in pastures that were prescriptively grazed, with gains highly dependent upon precipitation as evidenced by sensitivity of remotely sensed estimates (SD ± 951,308 kg/ha). Our results emphasize that next-generation remote sensing datasets empower land managers to move beyond simplistic control versus treatment study designs to explore nuances in plant biomass in unprecedented ways. The products of new remote sensing technologies also accelerate adaptive management and help communicate wildlife and livestock forage benefits from management to diverse stakeholders.

Evaluation of Dynamic Contrast-Enhanced MRI Measures of Lung Congestion and Endothelial Permeability in Heart Failure: A Prospective Method Validation Study.

BACKGROUND: Methods for accurate quantification of lung fluid in heart failure (HF) are needed. Dynamic contrast-enhanced (DCE)-MRI may be an appropriate modality. PURPOSE: DCE-MRI evaluation of fraction of fluid volume in the interstitial lung space (ve ) and vascular permeability (Ktrans ). STUDY TYPE: Prospective, single-center method validation. POPULATION: Seventeen evaluable healthy volunteers (HVs), 12 participants with HF, and 3 with acute decompensated HF (ADHF). FIELD STRENGTH/SEQUENCE: T1 mapping (spoiled gradient echo variable flip angle acquisition) followed by dynamic series (three-dimensional spoiled gradient-recalled echo acquisitions [constant echo time, repetition time, and flip angle at 1.5 T]). ASSESSMENT: Three whole-chest scans were acquired: baseline (Session 1), 1-week later (Session 2), following exercise (Session 3). Extended Tofts model quantified ve and Ktrans (voxel-wise basis); total lung median measures were extracted and fitted via repeat measure analysis of variance (ANOVA) model. Patient tolerability of the scanning protocol was assessed. STATISTICAL TESTS: This was constructed as an experimental medicine study. PRIMARY ENDPOINTS: Ktrans and ve at baseline (HV vs. HF), change in Ktrans and ve following exercise, and following lung congestion resolution (ADHF). Ktrans and ve were fitted separately using ANOVA. Secondary endpoint: repeatability, that is, within-participant variability in ve and Ktrans between sessions (coefficient of variation estimated via mixed effects model). RESULTS: There was no significant difference in mean Ktrans between HF and HV (P ≤ 0.17): 0.2216 minutes-1 and 0.2353 minutes-1 (Session 1), 0.2044 minutes-1 and 0.2567 minutes-1 (Session 2), 0.1841 minutes-1 and 0.2108 minutes-1 (Session 3), respectively. ve was greater in the HF group (all scans, P ≤ 0.02). Results were repeatable between Sessions 1 and 2; mean values for HF and HV were 0.4946 and 0.3346 (Session 1), 0.4353 and 0.3205 (Session 2), respectively. There was minimal difference in Ktrans or ve between scans for participants with ADHF (small population precluded significance testing). Scanning was well tolerated. DATA CONCLUSION: While no differences were detected in Ktrans , ve was greater in chronic HF patients vs. HV, augmented beyond plasma and intracellular volume. DCE-MRI is a valuable diagnostic and physiologic tool to evaluate changes in fluid volume in the interstitial lung space associated with symptomatic HF. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Tracking spatial regimes as an early warning for a species of conservation concern.

In this era of global environmental change and rapid regime shifts, managing core areas that species require to survive and persist is a grand challenge for conservation. Wildlife monitoring data are often limited or local in scale. The emerging ability to map and track spatial regimes (i.e., the spatial manifestation of state transitions) using advanced geospatial vegetation data has the potential to provide earlier warnings of habitat loss because many species of conservation concern strongly avoid spatial regime boundaries. Using 23 yr of data for the lek locations of Greater Prairie-Chicken (Tympanuchus cupido; GPC) in a remnant grassland ecosystem, we demonstrate how mapping changes in the boundaries between grassland and woodland spatial regimes provide a spatially explicit early warning signal for habitat loss for an iconic and vulnerable grassland-obligate known to be highly sensitive to woody plant encroachment. We tested whether a newly proposed metric for the quantification of spatial regimes captured well-known responses of GPC to woody plant expansion into grasslands. Resource selection functions showed that the grass:woody spatial regime boundary strength explained the probability of 80% of relative lek occurrence, and GPC strongly avoided grass:woody spatial regime boundaries at broad scales. Both findings are consistent with well-known expectations derived from GPC ecology. These results provide strong evidence for vegetation-derived delineations of spatial regimes to serve as generalized signals of early warning for state transitions that have major consequences to biodiversity conservation. Mapping spatial regime boundaries over time provided interpretable early warnings of habitat loss. Woody plant regimes displaced grassland regimes starting from the edges of the study area and constricting inward. Correspondingly, the relative probability of lek occurrence constricted in space. Similarly, the temporal trajectory of spatial regime boundary strength increased over time and moved closer to the observed limit of GPC lek site usage relative to grass:woody boundary strength. These novel spatial metrics allow managers to rapidly screen for early warning signals of spatial regime shifts and adapt management practices to defend and grow habitat cores at broad scales.

Nine-banded armadillo (Dasypus novemcinctus) activity patterns are influenced by human activity.

As the human footprint upon the landscape expands, wildlife seeking to avoid human contact are losing the option of altering their spatial distribution and instead are shifting their daily activity patterns to be active at different times than humans. In this study, we used game cameras to evaluate how human development and activity were related to the daily activity patterns of the nine-banded armadillo (Dasypus novemcinctus) along an urban to rural gradient in Arkansas, USA during the winter of 2020-2021. We found that armadillos had substantial behavioral plasticity in regard to the timing of their activity patterns; >95% of armadillo activity was nocturnal at six of the study sites, whereas between 30% and 60% of activity occurred during the day at three other sites. The likelihood of diurnal armadillo activity was best explained by the distance to downtown Fayetteville (the nearest population center) and estimated ambient sound level (both indices of human activity) with armadillos being most active during the day at quiet sites far from Fayetteville. Furthermore, armadillo activity occurred later during the night period (minutes after sunset) at sites near downtown and with higher anthropogenic sound. Anecdotal evidence suggests that the observed activity shift may be in response to not only human activity but also the presence of domestic dogs. Our results provide further evidence that human activity has subtle nonlethal impacts on even common, widespread wildlife species. Because armadillos have low body temperatures and basal metabolism, being active during cold winter nights likely has measurable fitness costs. Nature reserves near human population centers may not serve as safe harbors for wildlife as we intend, and managers could benefit from considering these nonlethal responses in how they manage recreation and visitation in these natural areas.

Dynamic contrast-enhanced MRI of synovitis in knee osteoarthritis: repeatability, discrimination and sensitivity to change in a prospective experimental study.

OBJECTIVES: Evaluate test-retest repeatability, ability to discriminate between osteoarthritic and healthy participants, and sensitivity to change over 6 months, of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarkers in knee OA. METHODS: Fourteen individuals aged 40-60 with mild-moderate knee OA and 6 age-matched healthy volunteers (HV) underwent DCE-MRI at 3 T at baseline, 1 month and 6 months. Voxelwise pharmacokinetic modelling of dynamic data was used to calculate DCE-MRI biomarkers including Ktrans and IAUC60. Median DCE-MRI biomarker values were extracted for each participant at each study visit. Synovial segmentation was performed using both manual and semiautomatic methods with calculation of an additional biomarker, the volume of enhancing pannus (VEP). Test-retest repeatability was assessed using intraclass correlation coefficients (ICC). Smallest detectable differences (SDDs) were calculated from test-retest data. Discrimination between OA and HV was assessed via calculation of between-group standardised mean differences (SMD). Responsiveness was assessed via the number of OA participants with changes greater than the SDD at 6 months. RESULTS: Ktrans demonstrated the best test-retest repeatability (Ktrans/IAUC60/VEP ICCs 0.90/0.84/0.40, SDDs as % of OA mean 33/71/76%), discrimination between OA and HV (SMDs 0.94/0.54/0.50) and responsiveness (5/1/1 out of 12 OA participants with 6-month change > SDD) when compared to IAUC60 and VEP. Biomarkers derived from semiautomatic segmentation outperformed those derived from manual segmentation across all domains. CONCLUSIONS: Ktrans demonstrated the best repeatability, discrimination and sensitivity to change suggesting that it is the optimal DCE-MRI biomarker for use in experimental medicine studies. KEY POINTS: • Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of synovitis in knee osteoarthritis which may permit early assessment of efficacy in experimental medicine studies. • This prospective observational study compared DCE-MRI biomarkers across domains relevant to experimental medicine: test-retest repeatability, discriminative validity and sensitivity to change. • The DCE-MRI biomarker Ktrans demonstrated the best performance across all three domains, suggesting that it is the optimal biomarker for use in future interventional studies.

Fire legacies in eastern ponderosa pine forests.

Disturbance legacies structure communities and ecological memory, but due to increasing changes in disturbance regimes, it is becoming more difficult to characterize disturbance legacies or determine how long they persist. We sought to quantify the characteristics and persistence of material legacies (e.g., biotic residuals of disturbance) that arise from variation in fire severity in an eastern ponderosa pine forest in North America. We compared forest stand structure and understory woody plant and bird community composition and species richness across unburned, low-, moderate-, and high-severity burn patches in a 27-year-old mixed-severity wildfire that had received minimal post-fire management. We identified distinct tree densities (high: 14.3 ± 7.4 trees per ha, moderate: 22.3 ± 12.6, low: 135.3 ± 57.1, unburned: 907.9 ± 246.2) and coarse woody debris cover (high: 8.5 ± 1.6% cover per 30 m transect, moderate: 4.3 ± 0.7, low: 2.3 ± 0.6, unburned: 1.0 ± 0.4) among burn severities. Understory woody plant communities differed between high-severity patches, moderate- and low-severity patches, and unburned patches (all p < 0.05). Bird communities differed between high- and moderate-severity patches, low-severity patches, and unburned patches (all p < 0.05). Bird species richness varied across burn severities: low-severity patches had the highest (5.29 ± 1.44) and high-severity patches had the lowest (2.87 ± 0.72). Understory woody plant richness was highest in unburned (5.93 ± 1.10) and high-severity (5.07 ± 1.17) patches, and it was lower in moderate- (3.43 ± 1.17) and low-severity (3.43 ± 1.06) patches. We show material fire legacies persisted decades after the mixed-severity wildfire in eastern ponderosa forest, fostering distinct structures, communities, and species in burned versus unburned patches and across fire severities. At a patch scale, eastern and western ponderosa system responses to mixed-severity fires were consistent.

Impact of Hurricane Katrina on the coastal systems of southern Louisiana.

Natural disasters, such as hurricanes and forest fires, could trigger collapse and reorganization of social-ecological systems. In the face of external perturbations, a resilient system would have capacity to absorb impacts, adapt to change, learn, and if needed, reorganize within the same regime. Within this context, we asked how human and natural systems in Louisiana responded to Hurricane Katrina, and how the natural disaster altered the status of these systems. This paper discusses community resilience to natural hazards and addresses the limitations for assessing disaster resilience. Furthermore, we assessed social and environmental change in New Orleans and southern Louisiana through both a spatial and temporal lens (i.e., pre- and post-Katrina). By analyzing changes in system condition using social, economic and environmental factors, we identified some of the characteristics of the system's reorganization trajectories. Our results suggest that although the ongoing population recovery may be a sign of revitalization, the city and metropolitan area continue to face socioeconomic inequalities and environmental vulnerability to natural disasters. Further, the spatial distribution of social-ecological condition over time reveals certain levels of change and reorganization after Katrina, but the reorganization did not translate into greater equity. This effort presents an enhanced approach to assessing social-ecological change pre and post disturbance and provides a way forward for characterizing pertinent aspects of disaster resilience.

Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

Doublethink and scale mismatch polarize policies for an invasive tree.

Mismatches between invasive species management policies and ecological knowledge can lead to profound societal consequences. For this reason, natural resource agencies have adopted the scientifically-based density-impact invasive species curve to guide invasive species management. We use the density-impact model to evaluate how well management policies for a native invader (Juniperus virginiana) match scientific guidelines. Juniperus virginiana invasion is causing a sub-continental regime shift from grasslands to woodlands in central North America, and its impacts span collapses in endemic diversity, heightened wildfire risk, and crashes in grazing land profitability. We (1) use land cover data to identify the stage of Juniperus virginiana invasion for three ecoregions within Nebraska, USA, (2) determine the range of invasion stages at individual land parcel extents within each ecoregion based on the density-impact model, and (3) determine policy alignment and mismatches relative to the density-impact model in order to assess their potential to meet sustainability targets and avoid societal impacts as Juniperus virginiana abundance increases. We found that nearly all policies evidenced doublethink and policy-ecology mismatches, for instance, promoting spread of Juniperus virginiana regardless of invasion stage while simultaneously managing it as a native invader in the same ecoregion. Like other invasive species, theory and literature for this native invader indicate that the consequences of invasion are unlikely to be prevented if policies fail to prioritize management at incipient invasion stages. Theory suggests a more realistic approach would be to align policy with the stage of invasion at local and ecoregion management scales. There is a need for scientists, policy makers, and ecosystem managers to move past ideologies governing native versus non-native invader classification and toward a framework that accounts for the uniqueness of native species invasions, their anthropogenic drivers, and their impacts on ecosystem services.

The perpetual state of emergency that sacrifices protected areas in a changing climate.

A modern challenge for conservation biology is to assess the consequences of policies that adhere to assumptions of stationarity (e.g., historic norms) in an era of global environmental change. Such policies may result in unexpected and surprising levels of mitigation given future climate-change trajectories, especially as agriculture looks to protected areas to buffer against production losses during periods of environmental extremes. We assessed the potential impact of climate-change scenarios on the rates at which grasslands enrolled in the Conservation Reserve Program (CRP) are authorized for emergency harvesting (i.e., biomass removal) for agricultural use, which can occur when precipitation for the previous 4 months is below 40% of the normal or historical mean precipitation for that 4-month period. We developed and analyzed scenarios under the condition that policy will continue to operate under assumptions of stationarity, thereby authorizing emergency biomass harvesting solely as a function of precipitation departure from historic norms. Model projections showed the historical likelihood of authorizing emergency biomass harvesting in any given year in the northern Great Plains was 33.28% based on long-term weather records. Emergency biomass harvesting became the norm (>50% of years) in the scenario that reflected continued increases in emissions and a decrease in growing-season precipitation, and areas in the Great Plains with higher historical mean annual rainfall were disproportionately affected and were subject to a greater increase in emergency biomass removal. Emergency biomass harvesting decreased only in the scenario with rapid reductions in emissions. Our scenario-impact analysis indicated that biomass from lands enrolled in the CRP would be used primarily as a buffer for agriculture in an era of climatic change unless policy guidelines are adapted or climate-change projections significantly depart from the current consensus.

Early Warnings for State Transitions.

New concepts have emerged in theoretical ecology with the intent to quantify complexities in ecological change that are unaccounted for in state-and-transition models and to provide applied ecologists with statistical early warning metrics able to predict and prevent state transitions. With its rich history of furthering ecological theory and its robust and broad-scale monitoring frameworks, the rangeland discipline is poised to empirically assess these newly proposed ideas while also serving as early adopters of novel statistical metrics that provide advanced warning of a pending shift to an alternative ecological regime. Were view multivariate early warning and regime shift detection metrics, identify situations where various metrics will be most useful for rangeland science, and then highlight known shortcomings. Our review of a suite of multivariate-based regime shift/early warning indicators provides a broad range of metrics applicable to a wide variety of data types or contexts, from situations where a great deal is known about the key system drivers and a regime shift is hypothesized a priori, to situations where the key drivers and the possibility of a regime shift are both unknown. These metrics can be used to answer ecological state-and-transition questions, inform policymakers, and provide quantitative decision-making tools for managers.

Immunizations challenge healthcare personnel and affects immunization rates.

PURPOSE: This study measured 1. medical office immunization rates and 2. health care personnel competency in managing vaccine practices before and after evidence-based immunization education was provided. METHOD: This descriptive study compared 32 family medicine and pediatric offices and 178 medical assistants, licensed practical nurses, registered nurses, nurse practitioners, and physicians in knowledge-based testing pre-education, post-education, and 12-months post-education. Immunization rates were assessed before and 18-months post-education. RESULTS: Immunization rates increased 10.3% - 18months post-education; knowledge increased 7.8% - 12months post-education. Family medicine offices, licensed practical nurses, and medical assistants showed significant knowledge deficits before and 12-months post-education. All demographic groups scored less in storage/handling 12-months post-education. CONCLUSION: This study is one of the first studies to identify competency challenges in effective immunization delivery among medical assistants, licensed practical nurses, and family medicine offices. Formal and continuous education in immunization administration and storage/handling is recommended among these select groups.

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

Expert modeling, expert/self-modeling versus lecture: a comparison of learning, retention, and transfer of rescue skills in health professions students.

BACKGROUND: It is unclear whether traditional lecture followed by simulation leads to the best learning and knowledge and skill retention over time. METHOD: A 3×4 mixed design study used three modes of education-traditional lecture with self-guided learning, expert modeling/dual viewing with brief questioning, and expert plus self-modeling-at four time points to compare knowledge, time to treat, and correct steps over time. RESULTS: No significant differences were found in knowledge or time to treat between training methods. An expert modeling/ dual viewing group with brief questioning performed more steps correctly (p = 0.05) than did the other two groups. CONCLUSION: Expert modeling may help students remember and perform a complex series of tasks in a scenario. Further research is needed to explore expert modeling for novice learners.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD.

OBJECTIVES: Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS: COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9µg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9µg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS: OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS: In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a ß2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis. METHODS: Patients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard '3 + 3' design that was guided by toxicity and, for the final dose escalation, by arsenic PK data. RESULTS: A total of 34 patients were treated with GSAO across 9 dose levels (1.3-44.0 mg/m(2)). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/m(2) dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0 mg/m(2) dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation). CONCLUSIONS: The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.

Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies.

About 100 early-phase clinical trials and investigator-led studies of targeted antivascular therapies--both anti-angiogenic and vascular-targeting agents--have reported data derived from T1-weighted dynamic contrast-enhanced (DCE)-MRI. However, the role of DCE-MRI for decision making during the drug-development process remains controversial. Despite well-documented guidelines on image acquisition and analysis, several key questions concerning the role of this technique in early-phase trial design remain unanswered. This Review describes studies of single-agent antivascular therapies, in which DCE-MRI parameters are incorporated as pharmacodynamic biomarkers. We discuss whether these parameters, such as volume transfer constant (K(trans)), are reproducible and reliable biomarkers of both drug efficacy and proof of concept, and whether they assist in dose selection and drug scheduling for subsequent phase II trials. Emerging evidence indicates that multiparametric analysis of DCE-MRI data offers greater insight into the mechanism of drug action than studies measuring a single parameter, such as K(trans). We also provide an overview of current data and appraise the future directions of this technique in oncology trials. Finally, major hurdles in imaging biomarker development, validation and qualification that hinder a wide application of DCE-MRI techniques in clinical trials are addressed.

The effect of blood inflow and B(1)-field inhomogeneity on measurement of the arterial input function in axial 3D spoiled gradient echo dynamic contrast-enhanced MRI.

A major potential confound in axial 3D dynamic contrast-enhanced magnetic resonance imaging studies is the blood inflow effect; therefore, the choice of slice location for arterial input function measurement within the imaging volume must be considered carefully. The objective of this study was to use computer simulations, flow phantom, and in vivo studies to describe and understand the effect of blood inflow on the measurement of the arterial input function. All experiments were done at 1.5 T using a typical 3D dynamic contrast-enhanced magnetic resonance imaging sequence, and arterial input functions were extracted for each slice in the imaging volume. We simulated a set of arterial input functions based on the same imaging parameters and accounted for blood inflow and radiofrequency field inhomogeneities. Measured arterial input functions along the vessel length from both in vivo and the flow phantom agreed with simulated arterial input functions and show large overestimations in the arterial input function in the first 30 mm of the vessel, whereas arterial input functions measured more centrally achieve accurate contrast agent concentrations. Use of inflow-affected arterial input functions in tracer kinetic modeling shows potential errors of up to 80% in tissue microvascular parameters. These errors emphasize the importance of careful placement of the arterial input function definition location to avoid the effects of blood inflow.

Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

PURPOSE: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. EXPERIMENTAL DESIGN: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. RESULTS: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P