Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study.

OBJECTIVES: To compare blood flow measurements of tumors assessed by perfusion computed tomography (pCT) and the clinical gold standard of 15O-labeled water positron emission tomography (15O-PET). METHODS: Blood flows were estimated by pCT (4-row multidetector, CT Perfusion 3.1) and 15O-PET (Posicam, first-pass model) in 14 patients with solid tumors, totaling 22 index tumors and 57 matched pairs of examinations. Blood flow estimates were compared using t test, Bland-Altman, and linear mixed regression analyses. RESULTS: There was no significant difference between the mean (SD) blood flow values measured by pCT and 15O-PET: 25.9 +/- 15.4 and 27.8 +/- 14.0 mL/min per 100 g, respectively. CONCLUSIONS: The demonstration of a good correlation between pCT and 15O-PET potentially enables the use of pCT, which is more widely available than 15O-PET, when tumor blood flow estimates are required, particularly in the context of clinical studies.

Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: a comparison with 15O-labeled water-measured blood flow.

UNLABELLED: PET molecular imaging of 15O-labeled water is the gold standard for measuring blood flow in humans. However, this requires an on-site cyclotron to produce the short-lived 15O tracer, which is cost-prohibitive for most clinical PET centers. The purpose of this study was to determine if the early uptake of 18F-FDG could be used to measure regional blood flow in tumors in the absence of 15O-water. METHODS: PET scans were obtained in patients being evaluated for tumor perfusion and glucose metabolism in a phase I dose-escalating protocol for endostatin, a novel antiangiogenic agent. A 2-min perfusion scan was performed with a bolus injection of 2,220 MBq (60 mCi) of 15O-water, which was followed by a 370-MBq (10 mCi) dose of 18F-FDG. Four sequential scans of 18F-FDG uptake were acquired, consisting of an early 2-min uptake scan-or first-pass scan-and 3 sequential 15-min late 18F-FDG uptake scans. Regions of interest (ROIs) were drawn on 2 or more tumor sites and on back muscle, as a control ROI, for each patient. Arterial blood concentration was derived from the PET scans by drawing an ROI over a large artery in the field of view. Blood flow was computed with a simple 1-compartment blood flow model using the first 2 min of data after injection. RESULTS: Blood flow estimated from the early uptake of 18F-FDG was linearly correlated with 15O-measured blood flow, with an intercept of 0.01, a slope of 0.86, and an R2 regression coefficient of 0.74 (r = 0.86). The 18F-FDG tumor extraction fraction relative to 15O-water averaged 0.86. A preliminary case study of a patient with prostate cancer confirms the utility of the first-pass 18F-FDG blood flow analysis in tumor diagnosis. CONCLUSION: These results suggest that the first-pass uptake of 18F-FDG may provide an estimate of perfusion in a tumor within the limitations of incomplete extraction of 18F-FDG compared with 15O-water.

DermLite II: an innovative portable instrument for dermoscopy without the need of immersion fluids.

The DermLite II is an improvement on a previous instrument allowing for dermoscopy to be carried out without the need of immersion oil. It consists of a magnifying lens encircled by light-emitting diodes that can be adjusted for polarization or can be customized by the manufacturer to produce colors of specific wavelengths for visualizing pigmentation and structures of various dermal depths. This new version of the DermLite makes it very convenient for the evaluation of not just pigmented lesions, but nonpigmented skin cancers, scalp disease, and vascular patterns. It can be attached to a camera to record images and has a retractable faceplate for use with immersion oil.

Quantitative analysis of biomarkers defines an optimal biological dose for recombinant human endostatin in primary human tumors.

PURPOSE: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15-600 mg/m(2)) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose. EXPERIMENTAL DESIGN: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1alpha were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model. RESULTS: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m(2) (95% confidence interval, 159-338) and 257 mg/m(2) (95% confidence interval, 183-331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1alpha and minimal EC Bcl-2 levels were observed at approximately 250 mg/m(2), although the changes did not reach statistical significance. CONCLUSIONS: The data suggest that endostatin had optimal biological activity at doses approximately 250 mg/m(2) in our cohort of patients. Endostatin's failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.

Phase I study of recombinant human endostatin in patients with advanced solid tumors.

PURPOSE: Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors. PATIENTS AND METHODS: Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers. RESULTS: Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo's activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed. CONCLUSION: rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.

Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin.

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P =.027) and endothelial cell apoptosis (P =.027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.