Initial Area Under The Curve Research Articles

Dynamic contrast enhanced‑magnetic resonance imaging for the early evaluation of the response to docetaxel in rats with epithelial ovarian cancer.

Dynamic contrast enhanced‑magnetic resonance imaging (DCE‑MRI) contributes to the early detection and prediction of responses to chemotherapy in cancer. The aim of the present study was to investigate the feasibility of quantitative DCE‑MRI parameters for noninvasively predicting the early response to DTX in epithelial ovarian cancer (EOC). In the present study, using 7,12‑dimethylbenz (A) anthracene, orthotopic EOC was induced in Sprague Dawley rats. Rats with EOC were treated with docetaxel (DTX) on day 0. DCE‑MRI was applied on days 0, 3, 7, 14 and 21. On day 21, the treated tumor types were categorized into sensitive and insensitive groups according to their change in size. Quantitative DCE‑MRI parameters were used to assess the early response to therapy. The experiment was performed again, the treatment group was divided into sensitive and insensitive groups according to their initially obtained cut-off values, and histopathological analyses were performed. Comparing the sensitive group with the insensitive group, there were significant differences in the percentage change in the volume transfer constant (Ktrans), rate constant (kep) and initial area under the curve (IAUC) from day 3 and tumor size from day 14. During the early stages of treatment (on day 3), the percentage change of Ktrans combined with kep produced an AUC of 1, and a sensitivity and specificity of 100 and 100%, respectively, using a cut-off value of a 17.59% reduction in Ktrans and kep. From day 7, there were significant differences in the quantitative index percentage change in angiogenesis in the sensitive group compared with the insensitive group. The percentage change in Ktrans, kep and IAUC were positively correlated with the percentage of change in tumor size and angiogenesis, and negatively correlated with the percentage of change in necrosis. The results of the present study indicated that quantitative DCE‑MRI parameters were superior to imaging tumor size for the early detection and prediction of the response to DTX chemotherapy in EOC.

The value of DCE-MRI in assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas

BackgroundTo investigate dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas (EOCs).Methods7,12-dimethylbenz[A]anthracene (DMBA) was applied to induce EOCs in situ in 46 SD rats. Conventional MRI and DCE-MRI were performed to evaluate the morphology and perfusion features of the tumors, including the time-signal intensity curve (TIC), volume transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume ratio (Ve) and initial area under the curve (IAUC). DCE-MRI parameters were correlated with histological grade, microvascular density (MVD), vascular endothelial growth factor (VEGF) and fraction of Ki67-positive cells and the serum level of cancer antigen 125 (CA125).ResultsThirty-five of the 46 rats developed EOCs. DCE-MRI showed type III TIC more frequently than type II (29/35 vs. 6/35, p < 0.001) in EOCs. The two types of TIC of tumors had significant differences in the histological grade, MVD, expression of VEGF and Ki67, and the serum level of CA125 (all p < 0.01). Ktrans, Kep and IAUC values showed significant differences in different histological grades in overall and pairwise comparisons except for IAUC in grade 2 vs. grade 3 (all p < 0.01). There was no significant difference in Ve values among the three grade groups (p > 0.05). Ktrans, Kep and IAUC values were positively correlated with MVD, VEGF and Ki67 expression (all p < 0.01). Ve was not significantly correlated with MVD, VEGF expression, Ki67 expression and the CA125 level (all p > 0.05).ConclusionsTIC types and perfusion parameters of DCE-MRI can reflect tumor grade, angiogenesis and cell proliferation to some extent, thereby helping treatment planning and predicting prognosis.

Focal osteonecrosis in the femoral head following stable anatomic fixation of displaced femoral neck fractures.

Femoral head (FH) osteonecrosis (ON) and subsequent segmental collapse is a major concern following displaced femoral neck fractures (FNF). We aimed to quantify residual perfusion to the FH following FNF and evaluate the viability of the FH overtime after surgical fixation. Twenty-three patients with FNF underwent dynamic contrast-enhanced (DCE)-MRI to estimate bone perfusion in the FH, using the contralateral side as control. Following open anatomic reduction and a length/angle-stable fixation, a special MRI sequence evaluated the FH for ON changes over time at 3 and 12months after surgery. We found significant compromise of both arterial inflow [83.1%-initial area under the curve (IAUC) and 73.8%-peak) and venous outflow (243.2%-elimination rate (K el)] in the FH of the fractured side. The supero-medial quadrant suffered the greatest decrease in arterial inflow with a significant decrease of 71.6% (IAUC) and 68.5% (peak). Post-operative MRI revealed a high rate (87%-20/23) of small ON segments within the FH, and all developed in the anterior aspect of the supero-medial quadrants. Fracture characteristics, including subcapital FNF, varus deformity, posterior roll-off ≥20° and Pauwel's angle of 30°-50° demonstrated a greater decrease in perfusion compared to contralateral controls. FNF significantly impaired the vascular supply to the FH, resulting in high incidence of small ON segments in the supero-medial quadrant of the FH. However, maintained perfusion, probably through the inferior retinacular system, coupled with urgent open anatomic reduction and stable fixation resulted in excellent clinical and radiographic outcomes despite a high rate of small ON segments noted on MRI. Level I: Prognostic Investigation.

Primary central nervous system lymphoma and atypical glioblastoma: differentiation using the initial area under the curve derived from dynamic contrast-enhanced MR and the apparent diffusion coefficient.

To evaluate the ability of the initial area under the curve (IAUC) derived from dynamic contrast-enhanced MR imaging (DCE-MRI) and apparent diffusion coefficient (ADC) in differentiating between primary central nervous system lymphoma (PCNSL) and atypical glioblastoma (GBM). We retrospectively identified 19 patients with atypical GBM (less than 13% necrosis of the enhancing tumour), and 23 patients with PCNSL. The histogram parameters of IAUC at 30, 60, 90s (IAUC30, IAUC60, and IAUC90), and ADC were compared between PCNSL and GBM. The diagnostic performances and added values of the IAUC and ADC for differentiating between PCNSL and GBM were evaluated. Interobserver agreement was assessed via intraclass correlation coefficient (ICC). The IAUC and ADC parameters were higher in GBM than in PCNSL. The 90th percentile (p90) of IAUC30 and 10th percentile (p10) of ADC showed the best diagnostic performance. Adding p90 of IAUC30 to p10 of ADC improved the differentiation between PCNSL and GBM (area under the ROC curve [AUC] = 0.886), compared to IAUC30 or ADC alone (AUC = 0.789 and 0.744; P < 0.05 for all). The ICC was 0.96 for p90 of IAUC30. The IAUC may be a useful parameter together with ADC for differentiating between PCNSL and atypical GBM. • High reproducibility is essential for practical implementation of advanced MRI parameters. • IAUC and ADC are highly reproducible parameters. • IAUC values were higher in atypical GBM than in PCNSL. • Adding IAUC to ADC improved the differentiation between PCNSL and GBM. • IAUC with ADC are useful for differentiating PCNSL from GBM.

Quantitative magnetic resonance imaging in the transgenic APC(Δ468) mouse model of hereditary colon cancer.

In this study, we investigated the use of high-resolution magnetic resonance imaging (MRI) methods for in vivo detection and quantitative characterization of colorectal tumors in the transgenic APC(Δ468) mouse model. High-resolution T(1)-weighted (T(1)W) images, T(2)-weighted (T(2)W) images, and dynamic contrast-enhanced (DCE) measurements were performed using a 7.0 T small-animal imaging system (N = 10). Individual tumors were identified on both T(1)W and T(2)W images. Twenty-eight tumors (2.8 ± 0.9 mm, mean ± SD) were detected with high-resolution MRI across a distance of roughly 3 cm from the rectum to the splenic flexure, whereas 29 tumors were found within corresponding colon tissue samples examined at gross necropsy in the same area. T(2) values were significantly different between tumor, skeletal muscle, and normal intestinal wall tissues (p < .05). For analysis of the vascular characteristics of colon tumor tissues using DCE measurements, the initial area under the curve (IAUC) for Gd contrast concentration curve (time) (C(Gd) [t]) was calculated with integration times of 60 and 120 seconds post-contrast infusion; two integration times were selected to capture both tracer wash-in and wash-out characteristics. IAUC measurements were significantly larger in tumor tissues compared to both normal intestinal wall and skeletal muscle tissues (p < .001). In vivo anatomic and quantitative MRI measurements were readily feasible in the transgenic APC(Δ468) mouse model. These noninvasive methods should improve experimental efficiencies during longitudinal survival studies that otherwise would require single-end-point necropsy measurements.

Pharmacokinetic modeling of multislice dynamic contrast-enhanced MRI in normal-healing radial fractures: A pilot study.

To define the range of quantitative pharmacokinetic parameters in normal-healing bone with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI is an established technique for characterizing abnormal tissue microvasculature within solid tumors, but has also shown promise for assessing bone and bone marrow. In this study ethical approval for eight patients was obtained. Inclusion criteria were an extra-articular distal radial fracture in patients aged 20-50 years which had united by 6 weeks in plaster cast. This was assessed by an experienced orthopedic surgeon. DCE-MRI was performed at 1.5T 6 weeks after initial injury. The transfer constant (K(trans) ), transfer rate (Kep ), and initial area under the curve (IAUC) values for the fracture site and adjacent marrow were obtained for each patient. The mean T1 , K(trans) , Kep , and IAUC at the fracture site were 1713 (standard deviation [SD] 645), 0.09 (SD 0.07), 0.17 (SD 0.17) and 4.9 (SD 4.4). The relative standard deviation (RSD) for the fracture site ranged from 0.38 to 0.97 and for the adjacent marrow ranged from 0.95-3.88. Within each patient the range of RSDs was 0.04-0.42 for T1 , 0.26-0.91 for K(trans) , 0.14-1.06 for Kep , and 0.35-0.96 for the IAUC. Pharmacokinetic measures of perfusion can be obtained from healing fractures using DCE-MRI with "excellent" intraclass correlation coefficients for inter- and intrarater reliability. The use of these perfusion parameters is limited by wide patient-to-patient variation and slice-to-slice variation within patients.

Ultra-high field 1H magnetic resonance imaging approaches for acute hypoxia

Background. Currently, radiation treatments are being optimised based on in vivo imaging of radioresistant, hypoxic tumour areas. This study aimed at detecting nicotinamide's reduction of acute hypoxia in a mouse tumour model by two clinically relevant magnetic resonance imaging (MRI) methods at ultra-high magnetic field strength. Material and methods. The C3H mammary carcinoma was grown to 200 mm3 in the right rear foot of CDF1 mice. The mice were anaesthetised with ketamine and xylazine prior to imaging. A treatment group received nicotinamide intraperitoneally (i.p.) at the dose 1000 mg/kg, and a control group received saline. MRI was performed at 16.4 T with a spatial resolution of 0.156 × 0.156 × 0.5 mm3. The imaging protocol included BOLD imaging and two DCE-MRI scans. Initial area under the curve (IAUC) and the parameters from the extended Toft's model were estimated from the DCE-MRI data. Tumour median values of 1) T2* mean, 2) T2* standard deviation, 3) DCE-MRI parameters, and 4) DCE-MRI parameter differences between scans were compared between the treatment groups using Student's t-test (significance level p < 0.05). Results. Parametric maps showed intra- and inter-tumour heterogeneity. Blood volume was significantly larger in the nicotinamide-treated group, and also the blood volume difference between the two DCE-MRI scans was significantly larger in the treatment group. Conclusion. Higher blood volume and blood volume variation was observed by DCE-MRI in the treatment group. Other DCE-MRI parameters showed no significant differences, and the higher blood volume was not detected by BOLD MRI. The higher blood volume variation seen with DCE-MRI may be influenced by the drug effect reducing over time, and furthermore the anaesthesia may play an important role.

Abstract 4955: Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients.

Abstract Pegylated recombinant human hyaluronidase PH20 (PEGPH20) is an investigational therapeutic agent under clinical development for use alone or in combination with other cancer therapies for the treatment of patients with non-hematologic malignancies that may accumulate hyaluronan (HA), a glycosaminoglycan that is a significant component of the extracellular matrix of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, decreases tumor interstitial pressure, increases vascular area, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. As dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a clinically translatable MRI perfusion protocol, we used DCE-MRI imaging to evaluate the effects of PEGPH20 treatment on tumor vascular permeability, vascular surface area and/or blood flow. In mice, prostate cancer PC3 cells were implanted adjacent to the right tibial periosteum. When tumors reached ∼500 mg, animals were staged into vehicle or PEGPH20 (4.5 mg/kg) treatment groups. Utilizing gadopentetate dimeglumine (Gd-DTPA) as a contrast agent, pre-treatment baseline DCE scans of the tumors were acquired. Animals were subsequently IV dosed with test article and post-treatment scans were acquired at 24 h. Initial area under the curve (IAUC) and Ktrans were calculated voxel-by-voxel using a 2-compartment PK model. Although vehicle alone did not increase or decrease Ktrans or IAUC, PEGPH20 treatment increased Ktrans (1/sec) and IAUC (mmol.s) by 74% and 78.7%, respectively. Concurrent to preclinical studies, DCE-MRI imaging was conducted pre- and post- PEGPH20 in 9 patients in a Phase 1 dose-escalation, safety, tolerability, PK/PD study of PEGPH20 treatment in patients with advanced solid tumors. Patients were treated with 1.6, 3 or 5 μg/kg PEGPH20 1-2/weekly. Baseline, day 1, day 2-5 and end-of-cycle (EOC) scans were acquired (w/ Gd-DTPA) in 3 patients. Images were fit on a pixel-by-pixel basis to a 2-compartment, 3-parameter, PK model and Ktrans and extracellular volume (Ve) calculated. Results suggest an early and rapid increase in tumor perfusion in target lesions, compared to baseline (mean ΔKtrans = 428%; N=3; Day 2-5 scans), as well as an expansion of the extracellular space with a reduction of these parameters towards baseline by EOC (mean ΔKtrans = 28% above baseline). Taken together, these studies suggest that PEGPH20 increases vessel permeability, blood flow and/or vessel surface area in HA-rich solid tumors. Additional preclinical and clinical studies, complete with DCE-MRI imaging, are ongoing to further evaluate PEGPH20 in the treatment HA-rich malignancies. Citation Format: Curtis B. Thompson, Patrick McConville, Ron Korn, Jenifer Baranski, Meridith Baugher, Deanne Lister, Erin Trachet, Jacob Y. Hesterman, Jack Hoppin, Joy Zhu, Daniel C. Maneval. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4955. doi:10.1158/1538-7445.AM2013-4955

Segmentation of dynamic contrast enhanced magnetic resonance imaging data

Introduction. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) allows in vivo characterization of tumour vasculature. As such, it is applicable for monitoring the effects of treatments targeting vasculature. The aims of this study were to evaluate the properties of tumour areas segmented-out by DCE-MRI parameters and to evaluate the changes induced by the vascular disrupting agent (VDA) combretastatin A-4 disodium phosphate (CA4DP), a leading VDA in clinical trials, in these areas. Material and Methods. Two tumour models previously shown to respond differently to CA4DP were chosen. The C3H mammary carcinoma and the KHT sarcoma were grown in the right rear foot of CDF1 and C3H/km mice, respectively, and treated when at 200 or 800 mm3 in size. DCE-MRI, using the contrast agent Gd-DTPA, was performed on a 7 T spectroscopy/imaging system before and 3 hours after i.p. CA4DP administration at a dose of 100 mg/kg. From the voxel concentration-time curves, the semiquantitative parameter of initial area under the curve (IAUC), the model parameters transfer constant Ktrans, interstitial volume ve, and blood plasma volume vp, were calculated. Tumour images were segmented into three groups based on the DCE-MRI model parameters using the K-means algorithm, and the groups were ranked by IAUC. Results. The resulting voxels of the tumour segments were mainly spatially connected structures. Initial DCE-MRI parameter values showed different dependencies on tumour model and size in the regions. For all regions in all tumour groups, the treatment reduced IAUC by 36–51%, whereas the model parameters showed more dependencies on tumour model and size. Discussion. This segmentation technique identifies tumour regions with different microenvironmental characteristics responding differently to CA4DP and may be valuable in the optimization of combined VDA with radiotherapy or chemotherapy. The method may also prove useful for optimization and monitoring of local treatment such as radiotherapy.

Effect of dietary tetradecylthioacetic acid on colon cancer growth studied by dynamic contrast enhanced MRI

Purpose: To evaluate the effects of diets supplemented with the modified fatty acid tetradecylthioacetic acid (TTA) and fish protein hydrolysate (FPH) on tumor growth of the human colon cancer cell line SW620, and to investigate the properties of tumor vasculature by dynamic contrast-enhanced MRI in a human tumor xenograft. Experimental design: SW620 cells were grown in vitro in presence of TTA and palmitic acid and proliferation was measured by thymidine incorporation. The xenograft study in mice was performed with four distinct diets: (a) control diet; (b) diet with TTA; (c) diet with TTA and FPH; and (d) diet with FPH. SW620 cells were injected subcutaneously, and Dynamic Contrast Enhanced (DCE) MRI was performed on a Bruker BioSpec 7T system. The data was analyzed by two-compartment modeling of the contrast enhancement, initial area under the curve (IAUC) and by use of relative signal intensity (RSI) distributions. Results: The in vitro cell studies revealed that TTA reduced tumor cell proliferation as a function of both dose and time. The in vivo tumor growth was significantly reduced for the two groups fed TTA, as compared to the control group. The mean 10th percentile RSI, ve and IAUC for the TTA group were significant higher than for the control group Conclusions: This study confirms the growth inhibitory effects of TTA, both in vitro and in vivo, in a colon cancer model. The analysis of DCE MRI data showed that TTA influences the vascular properties of the tumor in addition to the growth.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.