Quantitative iron-neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification.

Background: Neuromelanin- and iron-sensitive MRI studies in Parkinson's disease (PD) are limited by small sample sizes and lack detailed clinical correlation. In a large case-control PD cohort, we evaluated the diagnostic accuracy of quantitative iron-neuromelanin MRI parameters from the substantia nigra (SN), their radiological utility, and clinical association. Methods: PD patients and age-matched controls were prospectively recruited for motor assessment and midbrain neuromelanin- and iron-sensitive [quantitative susceptibility mapping (QSM) and susceptibility map-weighted imaging (SMWI)] MRI. Quantitative neuromelanin-iron parameters from the SN were assessed for their discriminatory performance in PD classification using ROC analysis compared to those of qualitative visual classification by radiological readers of differential experience and used to predict motor severity. Results: In total, 191 subjects (80 PD, mean age 65.0 years; 111 controls, 65.6) were included. SN masks showed (a) higher mean susceptibility (p < 0.0001) and smaller sizes after thresholding for low susceptibility (p < 0.0001) on QSM and (b) lower contrast range (p < 0.0001) and smaller sizes after thresholding for high-signal voxels (p < 0.0001) on neuromelanin-sensitive MRI in patients than in controls. Quantitative iron and neuromelanin parameters showed a moderate correlation with motor dysfunction (87.5%: 0.4< | r | <0.6, p < 0.0001), respectively. A composite quantitative neuromelanin-iron marker differentiated the groups with excellent performance (AUC 0.94), matching the diagnostic accuracy of the best-performing reader (accuracy 97%) using SMWI. Conclusion: Quantitative neuromelanin-iron MRI is associated with PD motor severity and matched best-performing radiological PD classification using SMWI, with the potential to improve diagnostic confidence in the clinics and track disease progression and response to neuroprotective therapies.

Ultra-high-field 7T MRI in Parkinson's disease: ready for clinical use?-a narrative review.

Background and Objective: The maturation of ultra-high-field magnetic resonance imaging (MRI) [≥7 Tesla (7T)] has improved our capability to depict and characterise brain structures efficiently, with better signal-to-noise ratio (SNR) and spatial resolution. We evaluated whether these improvements benefit the clinical detection and management of Parkinson's disease (PD). Methods: We performed a literature search in March 2023 in PubMed (MEDLINE), EMBASE and Google Scholar for articles on "7T MRI" AND "Parkinson*", written in English, published between inception and 1st March, 2023, which we synthesised in narrative form. Key Content and Findings: In deep-brain stimulation (DBS) surgical planning, early studies show that 7T MRI can distinguish anatomical substructures, and that this results in reduced adverse effects. In other areas, while there is strong evidence for improved accuracy and precision of 7T MRI-based measurements for PD, there is limited evidence for meaningful clinical translation. In particular, neuromelanin-iron complex quantification and visualisation in midbrain nuclei is enhanced, enabling depiction of nigrosomes 1-5, improved morphometry and vastly improved radiological assessments; however, studies on the related clinical outcomes, diagnosis, subtyping, differentiation of atypical parkinsonisms, and monitoring of treatment response using 7T MRI are lacking. Moreover, improvements in clinical utility must be great enough to justify the additional costs. Conclusions: Together, current evidence supports feasible future clinical implementation of 7T MRI for PD. Future impacts to clinical decision making for diagnosis, differentiation, and monitoring of progression or treatment response are likely; however, to achieve this, further longitudinal studies using 7T MRI are needed in prodromal, early-stage PD and parkinsonism cohorts focusing on clinical translational potential.

Serial deep gray nuclear DTI changes in Parkinson's disease over twelve years.

Background: Deep gray nuclear pathology relates to motor deterioration in idiopathic Parkinson's disease (PD). Inconsistent deep nuclear diffusion tensor imaging (DTI) findings in cross-sectional or short-term longitudinal studies have been reported. Long-term studies in PD are clinically challenging; decade-long deep nuclear DTI data are nonexistent. We investigated serial DTI changes and clinical utility in a case-control PD cohort of 149 subjects (72 patients/77 controls) over 12 years. Methods: Participating subjects underwent brain MRI at 1.5T; DTI metrics from segmented masks of caudate, putamen, globus pallidus and thalamus were extracted from three timepoints with 6-year gaps. Patients underwent clinical assessment, including Unified Parkinson Disease Rating Scale Part 3 (UPDRS-III) and Hoehn and Yahr (H&Y) staging. A multivariate linear mixed-effects regression model with adjustments for age and gender was used to assess between-group differences in DTI metrics at each timepoint. Partial Pearson correlation analysis was used to correlate clinical motor scores with DTI metrics over time. Results: MD progressively increased over time and was higher in the putamen (p < 0.001) and globus pallidus (p = 0.002). FA increased (p < 0.05) in the thalamus at year six, and decreased in the putamen and globus pallidus at year 12. Putaminal (p = 0.0210), pallidal (p = 0.0066) and caudate MD (p < 0.0001) correlated with disease duration. Caudate MD (p < 0.05) also correlated with UPDRS-III and H&Y scores. Conclusion: Pallido-putaminal MD showed differential neurodegeneration in PD over 12 years on longitudinal DTI; putaminal and thalamic FA changes were complex. Caudate MD could serve as a surrogate marker to track late PD progression.

Corrigendum: Topology of diffusion changes in corpus callosum in Alzheimer's disease: An exploratory case-control study.

[This corrects the article DOI: 10.3389/fneur.2022.1005406.].

Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I.

DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. Given recent evidence of Dicer's role as a haploinsufficient tumor suppressor regulating RNA polymerase I (Pol I), Pol I inhibition could abrogate mutant Dicer-mediated accumulation of stalled polymerases to trigger apoptosis. Hence, we developed a novel subpleural orthotopic PPB patient-derived xenograft (PDX) model that retained both RNase IIIa and IIIb hotspot mutations and recapitulated the cardiorespiratory physiology of intra-thoracic disease, and with it evaluated the tolerability and efficacy of first-in-class Pol I inhibitor CX-5461. In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.

Microstructure of Brain Nuclei in Early Parkinson's Disease: Longitudinal Diffusion Kurtosis Imaging.

BACKGROUND: Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson's disease. OBJECTIVE: To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson's disease over two years, and whether they correlate with disease progression. METHODS: We conducted a longitudinal case-control study of early Parkinson's disease. 262 people (Parkinson's disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. RESULTS: At baseline, mean kurtosis was higher in Parkinson's disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson's disease group while remaining stable for the control group; evident in significant "group ×time" interaction effects for the putamen, thalamus and globus pallidus (ηp2= 0.08-0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson's disease group. CONCLUSION: Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.

Topology of diffusion changes in corpus callosum in Alzheimer's disease: An exploratory case-control study.

Aim: This study aims to assess the integrity of white matter in various segments of the corpus callosum in Alzheimer's disease (AD) by using metrics derived from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI) and white matter tract integrity model (WMTI) and compare these findings to healthy controls (HC). Methods: The study was approved by the institutional ethics board. 12 AD patients and 12 HC formed the study population. All AD patients were recruited from a tertiary neurology memory clinic. A standardized battery of neuropsychological assessments was administered to the study participants by a trained rater. MRI scans were performed with a Philips Ingenia 3.0T scanner equipped with a 32-channel head coil. The protocol included a T1-weighted sequence, FLAIR and a dMRI acquisition. The dMRI scan included a total of 71 volumes, 8 at b = 0 s/mm2, 15 at b = 1,000 s/mm2 and 48 at b = 2,000 s/mm2. Diffusion data fit was performed using DKI REKINDLE and WMTI models. Results and discussion: We detected changes suggesting demyelination and axonal degeneration throughout the corpus callosum of patients with AD, most prominent in the mid-anterior and mid-posterior segments of CC. Axial kurtosis was the most significantly altered metric, being reduced in AD patients in almost all segments of corpus callosum. Reduced axial kurtosis in the CC segments correlated with poor cognition scores in AD patients in the visuospatial, language and attention domains.

Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson's Disease.

BACKGROUND: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. OBJECTIVE: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). METHODS: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. RESULTS: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. CONCLUSION: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

Utility of quantitative susceptibility mapping and diffusion kurtosis imaging in the diagnosis of early Parkinson's disease.

OBJECTIVE: To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson's disease (PD) and their clinical correlates to aid in diagnosis of PD. METHOD: Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). RESULTS: There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (ß = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p < 0.0001) and had "good" classification performance (AUC = 0.88). CONCLUSIONS: QSM and DKI are complementary tools allowing a better understanding of the complex contribution of iron deposition and microstructural changes in the pathophysiology of PD.

New Advances in Magnetic Resonance Techniques in Abdomen and Pelvis.

This article explores new acquisition methods in magnetic resonance (MR) imaging to provide high spatial and temporal resolution imaging for a wide spectrum of clinical applications in the abdomen and pelvis. We present an overview of some of these advanced MR techniques, such as non-cartesian image acquisition, fast sampling and compressed sensing, diffusion quantification and quantitative MR that can improve data sampling, enhance image quality, yield quantitative measurements, and/or optimize diagnostic performance in the body.

Corrigendum: Increased Activation of Default Mode Network in Early Parkinson's With Excessive Daytime Sleepiness.

[This corrects the article DOI: 10.3389/fnins.2019.01334.].

Persistent changes in liver methylation and microbiome composition following reversal of diet-induced non-alcoholic-fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups. Moreover, the diet-induced NAFLD phenotype was reversed, as measured by the recovery of glucose intolerance and high cholesterol levels when mice were given normal chow diet. However, surprisingly, the elevated serum triglyceride levels persisted. Metagenomic analysis revealed dietary-induced changes of microbiome composition, some of which remained altered even after reversing the diet to normal chow, as illustrated by species of the Odoribacter genus. Genome-wide DNA methylation analysis revealed a "priming effect" through changes in DNA methylation in key liver genes. For example, the lipid-regulating gene Apoa4 remained hypomethylated in both groups even after introduction to normal chow diet. Our results support that dietary change, in part, reverses the NAFLD phenotype. However, some diet-induced effects remain, such as changes in microbiome composition, elevated serum triglyceride levels, and hypomethylation of key liver genes. While the results are correlative in nature, it is tempting to speculate that the dietary-induced changes in microbiome composition may in part contribute to the persistent epigenetic modifications in the liver.

Increased Activation of Default Mode Network in Early Parkinson's With Excessive Daytime Sleepiness.

BACKGROUND AND OBJECTIVES: The underlying neuropathology of excessive daytime sleepiness (EDS) remains elusive in Parkinson's disease (PD). We aim to investigate neural network changes that underlie EDS in PD. METHODS: Early PD patients comprising eighty-one patients without EDS (EDS-) and seventeen patients with EDS (EDS+) received a resting state functional MRI scan and the Epworth Sleepiness Scale (ESS). Connectivities within the default mode network (DMN), motor and basal ganglia networks were compared between the EDS+ and EDS- groups. Correlations between network connectivity and the severity of EDS were investigated through linear regression. RESULTS: EDS+ patients displayed a trend of increased network connectivity of the posterior DMN (pDMN). A significant positive correlation was found between connectivity of the ventromedial prefrontal cortex in the pDMN and ESS. CONCLUSION: EDS+ patients are likely to display increased activation in the DMN, suggesting neural compensation in early PD or impaired attentiveness due to mechanisms such as mind-wandering.

Intravoxel incoherent imaging of renal fibrosis induced in a murine model of unilateral ureteral obstruction.

PURPOSE: To evaluate non-invasive imaging biomarkers for assessing renal fibrosis. DWI is used to assess renal function; intravoxel incoherent motion (IVIM) provides additional measures of perfusion-related diffusion (D*, blood flow; f, perfusion fraction). We aim to determine if reduced ADC seen in renal fibrosis is attributable to perfusion-related diffusion changes or to known reduction in tissue diffusivity (D). MATERIALS AND METHODS: Unilateral ureteral obstruction (UUO) was created in six mice to induce renal fibrosis. DWI was performed the day before and 7 days post-UUO. A range of b-values from 0 to 1200 s/mm(2) were used. IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of both kidneys was performed in all mice. Results were analyzed using the paired t-test with P<0.05 considered statistically significant. RESULTS: D and f were significantly lower in the ligated kidneys at Day 7 compared to before ligation and no significant difference was found for D*. Comparing non-ligated and ligated kidneys within the same mouse at Day 7, significantly lower D values were observed in the ligated kidneys, while no significant difference was found for f and D*, although the values of f were generally lower. Histopathological analysis confirmed development of fibrosis and reduction in glomeruli in all the ligated kidneys at Day 7. CONCLUSION: Our study shows that the reduction in ADC seen in renal fibrosis is attributable not only to reduced D as previously encountered but also a decrease in vascularity as assessed by f. Reduction in f is possibly related to a reduction in glomeruli.

Assessment of tumor necrotic fraction by dynamic contrast-enhanced MRI: a preclinical study of human tumor xenografts with histopathologic correlation.

Contrary to the common notion that tumor necrotic regions are non-enhancing after contrast administration, recent evidence has shown that necrotic regions exhibit delayed and slow uptake of gadolinium tracer on dynamic contrast-enhanced MRI (DCE MRI). The purpose of this study is to explore whether the mapping of tumor voxels with delayed and slow enhancement on DCE MRI can be used to derive estimates of tumor necrotic fraction. Patient-derived tumor xenograft lines of seven human cancers were implanted in 26 mice which were subjected to DCE MRI performed using a spoiled gradient recalled sequence. Gadolinium tracer concentration was estimated using the variable flip angle technique. To identify tumor voxels exhibiting delayed and slow uptake of contrast medium, clustering analysis was performed using a k-means clustering algorithm that classified tumor voxels according to their contrast enhancement patterns. Comparison of the percentage of tumor voxels exhibiting delayed and slow enhancement with the tumor necrotic fraction estimated on histology showed a strong correlation (r = 0.962, p < 0.001). The mapping of tumor regions with delayed and slow contrast uptake on DCE MRI correlated strongly with tumor necrotic fraction, and can potentially serve as a non-invasive imaging surrogate for the in vivo assessment of necrotic fraction.

Dynamic contrast-enhanced computed tomography in metastatic nasopharyngeal carcinoma: reproducibility analysis and observer variability of the distributed parameter model.

OBJECTIVES: To determine the reproducibility and observer variability of distributed parameter analysis of dynamic contrast-enhanced computed tomography (DCE-CT) data in metastatic nasopharyngeal carcinoma, and to compare 2 approaches of region-of-interest (ROI) analyses. METHODS: Following ethical approval and informed consent, 17 patients with nasopharyngeal carcinoma underwent paired DCE-CT examinations on a 64-detector scanner, measuring tumor blood flow (F, mL/100 mL/min), permeability surface area product (PS, mL/100 mL/min), fractional intravascular blood volume (v1, mL/100 mL), and fractional extracellular-extravascular volume (v2, mL/100 mL). Tumor parameters were derived by fitting (i) the ROI-averaged concentration-time curve, and (ii) the median value of parameters from voxel-level concentration-time curves. Measurement reproducibility and inter- and intraobserver variability were estimated using Bland-Altman statistics. RESULTS: Mean F, PS, v1, and v2 are 44.9, 20.4, 7.1, and 34.1 for ROI analysis, and 49.0, 18.7, 6.7, and 34.0 for voxel analysis, respectively. Within-subject coefficients of variation are 38.8%, 49.5%, 54.2%, and 35.9% for ROI analysis, and 15.0%, 35.1%, 33.0%, and 21.0% for voxel analysis, respectively. Repeatability coefficients are 48.2, 28.0, 10.7, and 33.9 for ROI analysis, and 20.3, 18.2, 6.1 and 19.8 for voxel analysis, respectively. Intra- and interobserver correlation coefficient ranged from 0.94 to 0.97 and 0.90 to 0.95 for voxel analysis, and 0.73 to 0.87 and 0.72 to 0.94 for ROI analysis, respectively. CONCLUSION: Measurements of F and v2 appear more reproducible than PS and v1. Voxel-level analysis improves both reproducibility and observer variability compared with ROI-averaged analysis and may retain information about tumor spatial heterogeneity.

Wash-out of hepatocellular carcinoma: quantitative region of interest analysis on CT.

INTRODUCTION: This study aims to determine if the quantitative method of region-of-interest (ROI) analysis of lesion attenuation on CT may be a useful adjunct to the conventional approach of diagnosis by visual assessment in assessing tracer wash-out in hepatocellular carcinomas. MATERIALS AND METHODS: From a surgical database of 289 patients from 2 institutions, all patients with complete surgical, pathological and preoperative multiphasic CT scans available for review were selected. For each phase of scanning, HU readings of lesion obtained (Lesion(arterial), Lesion(PV) and Lesion(equilibrium)) were analysed using receiver operating curves (ROC) to determine the optimal method and cut-off value for quantitative assessment of tumour wash-out (Lesion(arterial - equilibrium), Lesion(PV - equilibrium) or Lesion(peak - equilibrium)). RESULTS: Ninety-four patients with one lesion each met the inclusion criteria. The area under the curve (AUC) values for Lesion(arterial - equilibrium) (0.941) was higher than the AUC for Lesion(pv - equilibrium) (0.484) and for Lesion(peak - equilibrium) (0.667). Based on ROC analysis, a cut-off of 10HU value for Lesion(arterial - equilibrium) would yield sensitivity and specificity of 91.5% and 80.9%, respectively. ROI analysis detected 9/21 (42.9%) of lesions missed by visual analysis. Combined ROI and visual analysis yields a sensitivity of 82/94 (87.2%) compared to 73/94 (77.7%) for visual analysis alone. CONCLUSION: Using a cut-off of 10 HU attenuation difference between the arterial and equilibrium phases is a simple and objective method that can be included as an adjunct to visual assessment to improve sensitivity for determining lesion wash-out on CT.

Deconvolution assessment of splenic and splanchnic contributions to portal venous blood flow in liver cirrhosis.

PURPOSE: To devise a noninvasive imaging method for resolving the relative contribution of splenic and splanchnic blood flow to portal venous flow and derive quantitative estimates for parameters pertaining to splenic and portal hemodynamics. METHODS: Tracer concentration-time curves of the aorta, portal vein, and spleen can be extracted from dynamic contrast-enhanced (DCE) CT or MR images. A combination of two tracer analysis approaches, namely arterial-venous sampling and residual tracer deconvolution, is proposed to model these concentration-time curves and derive hemodynamic parameters pertaining to splenic and portal circulation. Clinical feasibility of the proposed method was explored using DCE CT datasets of eight cirrhotic patients. Monte Carlo simulations were performed to evaluate the confidence of the parameter estimates. RESULTS: Portal blood flow was estimated to be 763.8 +/- 438.1 ml/min in cirrhotic patients and the splenic contribution was found to be elevated (0.75 +/- 0.22). Estimates of splenic blood flow (582 +/- 420 ml/min) and transit time (15.3 +/- 10.1 s) in cirrhotic patients were consistent with reported values obtained using duplex Doppler ultrasound and dynamic scintigraphy, respectively. CONCLUSIONS: This study shows the feasibility of noninvasive assessment of splenic and portal hemodynamic parameters by DCE imaging using a combination of tracer kinetics modeling techniques.

A comparative study of dynamic contrast-enhanced MRI parameters as biomarkers for anti-angiogenic drug therapy.

The aim of the present study was to compare three tracer kinetics methods for the analysis of dynamic contrast-enhanced (DCE) MRI data, namely the generalized kinetics model, the distributed-parameter model and the initial area under the tumor tracer curve (IAUC) method, in a Phase I study of an anti-angiogenic drug ABT -869; and to explore their utility as biomarkers. Twenty-eight patients with a range of tumors formed the study population. DCE MRI performed at baseline and 2 weeks post-treatment was analyzed using all three methods, yielding percentage changes for various tracer kinetics parameters. Correlation analyzes were performed between these parameters and in relation to drug exposure. The association of these parameters with time-to-progression was examined using receiver-operating characteristic and Kaplan-Meier curves. Significant correlation with drug exposure was found for the following parameters: normalized IAUC (IAUC(norm)), fractional interstitial volume v(e), fractional intravascular volume v(1) and permeability PS. However, only v(e) and PS were effective in predicting late progression. A decrease in v(e) of more than 1.7% and a decrease in PS of more than 25.1% observed at 2 weeks post-treatment could be associated with late progression. All three tracer kinetics methods have biomarker potential for assessing the effects of anti-angiogenic therapy.

Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies.

PURPOSE: To determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies. PATIENTS AND METHODS: Patients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously. RESULTS: Thirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004). CONCLUSION: ABT-869 by continuous once-daily dosing was tolerable at doses