Tong San Koh

Quantitative measurements of perfusion and permeability of oropharyngeal and oral cavity cancer, recurrent disease, and associated lymph nodes using first-pass contrast-enhanced computed tomography studies.

Objectives:We sought to evaluate the routine clinical use of perfusion computed tomography in the detection and differentiation of primary and recurrent oropharynx and oral cavity tumors as well as of nodal disease. Materials and Methods:A total of 77 patients with primary cancer as well as suspected recurrent disease and lymph nodes were evaluated. A dynamic acquisition (4 × 6-mm slices) of the largest axial tumor surface was performed and the tumor blood flow (BF), blood volume (BV), and mean transit time (MTT) were calculated by using a modified deconvolution-based analysis taking into account the extravasation of the contrast agent for permeability surface area product imaging (PS). Tumor volume was calculated and region of interest analysis was performed on the pathologic and normal tissue. Results:The mean BF, BV, and PS values in the primary tumors (77.48 mL/min/100 g tissue; 5.29 mL/min; 13.33 mL/min/100 g tissue, respectively) were highly significantly different (P < 0.01) than those obtained in the normal structures. Mean MTT values (9.01 seconds) also were significantly lowered in the tumors compared with normal tissue (P < 0.05). There was no statistical difference in the perfusion values between the primary and the recurrent tumors. Recurrent disease could be differentiated on the basis of BF (P < 0.05) from tissue changes after chemo-radiation-treatment (mean BF: 69.71 versus 45.31 mL/min/100 g tissue, respectively). Differentiation of the lymph nodes was not possible by means of perfusion values. Tumor volume did not significantly correlate with any perfusion parameter. Conclusions:Perfusion CT of oropharyngeal and oral cavity cancer in clinical routine is feasible and helps outlining the malignant tissue as well as differentiating recurrent disease from nonspecific post-therapeutic changes.

Fundamentals of tracer kinetics for dynamic contrast-enhanced MRI.

Tracer kinetic methods employed for quantitative analysis of dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) share common roots with earlier tracer studies involving arterial‐venous sampling and other dynamic imaging modalities. This article reviews the essential foundation concepts and principles in tracer kinetics that are relevant to DCE MRI, including the notions of impulse response and convolution, which are central to the analysis of DCE MRI data. We further examine the formulation and solutions of various compartmental models frequently used in the literature. Topics of recent interest in the processing of DCE MRI data, such as the account of water exchange and the use of reference tissue methods to obviate the measurement of an arterial input, are also discussed. Although the primary focus of this review is on the tracer models and methods for T1‐weighted DCE MRI, some of these concepts and methods are also applicable for analysis of dynamic susceptibility contrast‐enhanced MRI data. J. Magn. Reson. Imaging 2011;.

A physiologic model of capillary-tissue exchange for dynamic contrast-enhanced imaging of tumor microcirculation

We present a multiple compartment, mammillary distributed-parameter model for capillary-tissue exchange, which can be implemented with dynamic contrast-enhanced imaging to study kinetic heterogeneity in tumors. The proposed n-compartment model consists of a vascular distributed-parameter compartment in direct exchange with a number (n-1) of interstitial compartments. It is applied to a prostate tumor case study to illustrate the possible co-existence of two kinetically distinct compartments in the tumor, and the estimation of useful physiological parameters (such as perfusion, mean transit time, fractional volumes, and transfer and rate constants) associated with tissue microcirculation. The present model exhibits the convenient property of a separable impulse residue response function in the time domain, which can be used to provide further insights and understanding on the physiological basis of tissue enhancement parameters commonly used for correlation studies with tumor histological diagnosis.

Distinguishing recurrent high-grade gliomas from radiation injury: a pilot study using dynamic contrast-enhanced MR imaging.

RATIONALE AND OBJECTIVES The accurate delineation of tumor recurrence and its differentiation from radiation injury in the follow-up of adjuvantly treated high-grade gliomas presents a significant problem in neuro-oncology. The aim of this study was to investigate whether hemodynamic parameters derived from dynamic contrast-enhanced (DCE) T1-weighted magnetic resonance imaging (MRI) can be used to distinguish recurrent gliomas from radiation necrosis. MATERIALS AND METHODS Eighteen patients who were being treated for glial neoplasms underwent prospectively conventional and DCE-MRI using a 3T scanner. The pharmacokinetic modelling was based on a two-compartment model that allows for the calculation of K(trans) (transfer constant between intra- and extravascular, extracellular space), v(e) (extravascular, extracellular space), k(ep) (transfer constant from the extracellular, extravascular space into the plasma), and iAUC (initial area under the signal intensity-time curve). Regions of interest (ROIs) were drawn around the entire recurrence-suspected contrast-enhanced region. A definitive diagnosis was established at subsequent surgical resection or clinicoradiologic follow-up. The hemodynamic parameters in the contralateral normal white matter, the radiation injury sites, and the tumor recurrent lesions were compared using nonparametric tests. RESULTS The K(trans), v(e), k(ep), and iAUC values in the normal white matter were significantly different than those in the radiation necrosis and recurrent gliomas (0.01, <P < .0001). The only significantly different hemodynamic parameter between the recurrent tumor lesions and the radiation-induced necrotic sites were K(trans) and iAUC, which were significantly higher in the recurrent glioma group than in the radiation necrosis group (P ≤ .0184). A K(trans) cutoff value higher than 0.19 showed 100% sensitivity and 83% specificity for detecting the recurrent gliomas, whereas an iAUC cutoff value higher than 15.35 had 71% sensitivity and 71% specificity. The v(e) and k(ep) values in recurrent tumors were not significantly higher than those in radiation-induced necrotic lesions. CONCLUSIONS These findings suggest that DCE-MRI may be used to distinguish between recurrent gliomas and radiation injury and thus, assist in follow-up patient management strategy.

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Purpose: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. Experimental Design: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simons optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. Results: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36–68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0–70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Conclusion: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile. Clin Cancer Res; 17(16); 5481–9. ©2011 AACR.

Dynamic contrast-enhanced CT of head and neck tumors: perfusion measurements using a distributed-parameter tracer kinetic model. Initial results and comparison with deconvolution-based analysis

The objective of this work was to evaluate the feasibility of a two-compartment distributed-parameter (DP) tracer kinetic model to generate functional images of several physiologic parameters from dynamic contrast-enhanced CT data obtained of patients with extracranial head and neck tumors and to compare the DP functional images to those obtained by deconvolution-based DCE-CT data analysis. We performed post-processing of DCE-CT studies, obtained from 15 patients with benign and malignant head and neck cancer. We introduced a DP model of the impulse residue function for a capillary-tissue exchange unit, which accounts for the processes of convective transport and capillary-tissue exchange. The calculated parametric maps represented blood flow (F), intravascular blood volume (v(1)), extravascular extracellular blood volume (v(2)), vascular transit time (t(1)), permeability-surface area product (PS), transfer ratios k(12) and k(21), and the fraction of extracted tracer (E). Based on the same regions of interest (ROI) analysis, we calculated the tumor blood flow (BF), blood volume (BV) and mean transit time (MTT) by using a modified deconvolution-based analysis taking into account the extravasation of the contrast agent for PS imaging. We compared the corresponding values by using Bland-Altman plot analysis. We outlined 73 ROIs including tumor sites, lymph nodes and normal tissue. The Bland-Altman plot analysis revealed that the two methods showed an accepted degree of agreement for blood flow, and, thus, can be used interchangeably for measuring this parameter. Slightly worse agreement was observed between v(1) in the DP model and BV but even here the two tracer kinetic analyses can be used interchangeably. Under consideration of whether both techniques may be used interchangeably was the case of t(1) and MTT, as well as for measurements of the PS values. The application of the proposed DP model is feasible in the clinical routine and it can be used interchangeably for measuring blood flow and vascular volume with the commercially available reference standard of the deconvolution-based approach. The lack of substantial agreement between the measurements of vascular transit time and permeability-surface area product may be attributed to the different tracer kinetic principles employed by both models and the detailed capillary tissue exchange physiological modeling of the DP technique.

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.

An automatic approach for estimating bolus arrival time in dynamic contrast MRI using piecewise continuous regression models

We present two regression models for the automatic estimation of bolus arrival times (BATs) in dynamic contrast MRI datasets. Results of Monte Carlo simulation experiments show that the means and standard deviations of the estimated BATs are within the sampling interval even in the presence of significant noise.

Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast‐enhanced MRI. Using a dual‐input two‐compartment distributed parameter model, we analyzed the dynamic contrast‐enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration‐time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases. Magn Reson Med, 2010.

Correlative assessment of tumor microcirculation using contrast‐enhanced perfusion MRI and intravoxel incoherent motion diffusion‐weighted MRI: is there a link between them?

The purpose of this study was to correlate intravoxel incoherent motion (IVIM) imaging with classical perfusion‐weighted MRI metrics in human gliomas. Parametric images for slow diffusion coefficient (D), fast diffusion coefficient (D*), and fractional perfusion‐related volume (f) in patients with high‐grade gliomas were generated. Maps of Fp (plasma flow), vp (vascular plasma volume), PS (permeability surface–area product), ve (extravascular, extracellular volume), E (extraction ratio), ke (influx ratio into the interstitium), and tc (vascular transit time) from dynamic contrast‐enhanced (DCE) and dynamic susceptibility contrast‐enhanced (DSC) MRI were also generated. A region‐of‐interest analysis on the contralateral healthy white matter and on the tumor areas was performed and the extracted parameter values were tested for any significant differences among tumor grades or any correlations. Only f could be significantly correlated to DSC‐derived vp and tc in healthy brain tissue. Concerning the tumor regions, Fp was significantly positively correlated with D* and inversely correlated with f in DSC measurements. The D*, f, and f × D* values in the WHO grade III gliomas were non‐significantly different from those in the grade IV gliomas. There was a trend to significant negative correlations between f and PS as well as between f × D* and ke in DCE experiments. Presumably due to different theoretical background, tracer properties and modeling of the tumor vasculature in the IVIM theory, there is no clearly evident link between D*, f and DSC‐ and DCE‐derived metrics. Copyright