Septian Hartono

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 </= 0.25 mg/kg/d. Biomarker evidence of antiangiogenic activity and DCE-MRI evidence of tumor antiangiogenesis were observed together with promising clinical activity.

Hepatic Metastases: In Vivo Assessment of Perfusion Parameters at Dynamic Contrast-enhanced MR Imaging with Dual-Input Two-Compartment Tracer Kinetics Model

This study was institutional review board approved, with waived patient consent for retrospective analysis of the data. The hepatic perfusion at dynamic contrast material-enhanced magnetic resonance (MR) imaging was commonly described and assessed by using a dual-input one-compartment tracer kinetics model. Although the tracer kinetics in normal liver parenchyma can be described by using a single compartment, functional changes in the tumor microenvironment can result in distinctly different tracer behavior that entails a second tissue compartment. A dual-input two-compartment model is proposed to describe the tracer behavior in hepatic metastases. The authors applied this model to the dynamic MR imaging data obtained in three patients. Perfusion parameter maps and region-of-interest analysis revealed that tracer behavior in hepatic metastases-in contrast to that in surrounding normal liver tissue, which effectively involves one compartment-can be described by using two compartments.

Dynamic contrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modeling

Dynamic contrast-enhanced (DCE) CT imaging of four patients with hepatocellular carcinoma (HCC) was performed using a dual-phase imaging protocol designed with initial rapid dynamic imaging to capture the initial increase in contrast medium enhancement in order to assess perfusion, followed by a delayed imaging phase with progressively longer intervals to monitor subsequent tissue enhancement behaviour in order to assess tissue permeability. The DCE CT images were analysed using a dual-input two-compartment distributed parameter model to yield separate estimates for blood flow and permeability, as well as fractional intravascular and extravascular volumes. The HCCs and surrounding cirrhotic liver tissues were found to exhibit enhancement curves that can be appropriately described by two distinct compartments separated by a semipermeable barrier. Early contrast arrival was also found for HCC as compared with background liver. These findings are consistent with the current understanding of sinusoidal capillarization and hepatocarcinogenesis.

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.

A phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.

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 (IAUCnorm), fractional interstitial volume ve, fractional intravascular volume v1 and permeability PS. However, only ve and PS were effective in predicting late progression. A decrease in ve 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. Copyright

In vivo measurement of gadolinium diffusivity by dynamic contrast-enhanced MRI: A preclinical study of human xenografts

Compartmental tracer kinetic models currently used for analysis of dynamic contrast‐enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Ficks law of diffusion as an alternative method for analysis of dynamic contrast‐enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast‐enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k‐means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Ficks diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (±0.88) × 10−4 mm2/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions. Magn Reson Med, 2013.

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.

Intravoxel incoherent motion and diffusion tensor imaging of early renal fibrosis induced in a murine model of streptozotocin induced diabetes

INTRODUCTION To assess if parameters in intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) can be used to evaluate early renal fibrosis in a mouse model of diabetic nephropathy. MATERIALS & METHODS In a population of 38 male CD1 mice (8weeks old, 20-30g), streptozotocin induced diabetes was created in 20 mice via a single intraperitoneal injection of streptozotocin at 150mg/kg, while 18 mice served as control group. IVIM parameters were acquired at 0, 12 and 24weeks after injection of streptozotocin using a range of b values from 0 to 1200s/mm2. DTI parameters were obtained using 12 diffusion directions and lower b values of 0, 100 and 400s/mm2. DTI and IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of the right kidney was performed in all mice. Results were analyzed using an unpaired t-test with P<0.05 considered statistically significant. RESULTS Renal cortex fractional anisotropy (FA) was significantly lower in the diabetes group at week 12 as compared with the control group. Renal cortex apparent diffusion coefficient and tissue diffusivity were significantly higher in the diabetes group at week 12 compared with the control group at 12weeks. Blood flow was significantly decreased at the renal medulla at 24weeks. Histopathological analysis confirmed fibrosis in the diabetes group at 24weeks. CONCLUSION FA is significantly reduced in diabetic nephropathy. FA might serve a potential role in the detection and therapy monitoring of early diabetic nephropathy.

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. Copyright