Computer aided analysis of epi-illumination and transillumination images of skin lesions for diagnosis of skin cancers.

Skin lesion pigmentation area from surface, or, epi-illumination (ELM) images and blood volume area from transillumination (TLM) images are useful features to aid a dermatologist in the diagnosis of melanoma and other skin cancers in early curable stages. However, segmentation of these areas is difficult. In this work, we present an automatic segmentation tool for ELM and TLM images that also provides additional choices for user selection and interaction with adaptive learning. Our tool uses a combination of k-means clustering, wavelet analysis, and morphological operations to segment the lesion and blood volume, and then presents the user with six segmentation suggestions for both ELM and TLM images. The final selection of segmentation boundary may then be iteratively improved through scoring by multiple users. The ratio of TLM to ELM segmented areas is an indicator of dysplasia in skin lesions for detection of skin cancers, and this ratio is found to show a statistically significant trend in association with lesion dysplasia on a set of 81 pathologically validated lesions (p = 0.0058). We then present a support vector machine classifier using the results from the interactive segmentation method along with ratio, color, texture, and shape features to characterize skin lesions into three degrees of dysplasia with promising accuracy.

Multispectral optical imaging of skin-lesions for detection of malignant melanomas.

Optical imaging of skin-lesions for early detection and management of the most fatal skin-cancer malignant melanoma is of significant interest in mass screening of skin-lesions with high-risk population. Surface illumination based optical imaging methods such as epiluminescence light microscopy (ELM) through "Dermascopy" has shown a significant potential in improving early diagnosis of malignant melanomas. Limitations of surface reflectance based imaging systems have been realized in analyzing images for important vascular and depth dependent information. We have developed a novel optical imaging system, the Nevoscope, that uses multispectral transillumination as to provide images of skin-lesions showing sub-surface pigmentation as well as vascular architecture based blood volume information. This paper presents multispectral Nevoscope transillumination method to compare and analyze ratiometric measurements to epiluminescence imaging for its ability to discriminate malignant melanomas from dysplastic nevi and other normal skin-lesions.

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.

SVM-based texture classification and application to early melanoma detection.

We have recently developed a decision support system for early skin cancer detection that relies on analysis of the pigmentation characteristics of a skin lesion, detected using crosspolarization imaging, and the increased vasculature associated with malignant lesions that is detected using transillumination imaging. Current system uses size difference based on lesion physiology and achieves great overall accuracy (86.9%). In this paper, we explore texture information, one of the criteria dermatologists use in the diagnosis of skin cancer, but has been found very difficult to utilize in an automatic manner. The overarching goal is to improve the overall decision support capability of the DSS. The objective is to use texture information ONLY to classify the benign and malignancy of the skin lesion. A three-layer mechanism that inherent to the support vector machine (SVM) methodology is employed to improve the generalization error rate and the computational efficiency. The performance of the algorithm is validated with a series of benchmark texture images and then tested on 22 pairs of real clinical skin lesion images. Our experimental results show that a 4th-order polynomial kernel can reach an average accuracy of 70% in determining the malignancy of any pixel within any given skin lesion image. Further study will look at whether multi-channel filtering based feature extraction algorithm will improve the accuracy rate, and the performance comparison between SVM-based texture classification and decision tree-based texture classification in both the spatial and frequency domain.

Uptake of a fluorescent deoxyglucose analog (2-NBDG) in tumor cells.

PURPOSE: A new fluorescent analog of D -glucose was recently developed by [Yoshioka K, Takahashi H, Homma T, Sato M, Ki Bong O, Nemoto Y, Matsuoka H (1996) A novel fluorescent derivative of glucose applicable to the assessment of glucose uptake activity of Escherichia coli. Biochim Biophys Acta 1289:5-9] and shown to be transported into normal cells. The purpose of this preliminary study was to assess the use of this fluorescent 2-deoxyglucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG), as a sensitive probe for monitoring glucose uptake into malignant tumor cells. PROCEDURES: MCF-7 breast cancer epithelial cells were grown and plated on coverslips for analysis of 2-NBDG uptake via fluorescence imaging microscopy. RESULTS: Steady-state fluorescence analysis of 2-NBDG uptake displayed rapid uptake for the first one to five minutes, then slowed, reaching an apparent maximum uptake near 20-30 minutes. Addition of 5 mM D -glucose to the media markedly reduced 2-NBDG uptake. Uptake of 2-NBDG in nonmalignant epithelial cells (M-1 epithelial cells) was slow, averaging less than 20% of that observed for tumorigenic cells, the MCF-7 breast cancer cells and the HepG2 liver cancer cell line. CONCLUSIONS: The preliminary data clearly demonstrate a rapid uptake of 2-NBDG into tumor cells that can be monitored by fluorescence imaging analysis. The uptake displays saturation and competition with D -glucose, all properties expected for 2-NBDG uptake and retention in cancer cells. Additional studies, including comparisons among other malignant cell lines and control cells, will be needed to fully characterize the kinetic properties of 2-NBDG uptake and the potential use of this 2-DG analog as a probe for glucose uptake in malignant cells.

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.

Combined intense lifestyle and pharmacologic lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared with usual-care cholesterol-lowering drugs in coronary artery disease.

OBJECTIVES: The purpose of this study was to determine if combined intense lifestyle and pharmacologic lipid treatment reduce myocardial perfusion abnormalities and coronary events in comparison to usual-care cholesterol-lowering drugs and whether perfusion changes predict outcomes. BACKGROUND: Lifestyle and lipid drugs separately benefit patients with coronary artery disease (CAD). METHODS: A total of 409 patients with CAD, who underwent myocardial perfusion imaging by dipyridamole positron emission tomography at baseline and after 2.6 years, had quantitative size/severity of perfusion defects measured objectively by automated software with follow-up for five additional years for coronary artery bypass graft, percutaneous coronary intervention, myocardial infarction, or cardiac death. Patients were categorized blindly according to prospective, predefined criteria as "poor" treatment without diet or lipid drugs, or smoking; "moderate" treatment on American Heart Association diet and lipid-lowering drugs or on strict low-fat diet (<10% of calories) without lipid drugs; and "maximal" treatment with diet <10% of calories as fat, regular exercise, and lipid active drugs dosed to target goals of low-density lipoproteins <2.3 mmol/l (90 mg/dl), high-density lipoproteins >1.2 mmol/l (45 mg/dl), and triglycerides <1.1 mmol/l (100 mg/dl). RESULTS: Over five years, coronary events occurred in 6.6%, 20.3%, and 30.6% of patients on maximal, moderate, and poor treatment, respectively (p = 0.001). Size/severity of perfusion abnormalities significantly decreased for patients receiving maximal treatment and increased for patients undergoing moderate and poor treatment (p = 0.003 and 0.0001, respectively). Combined intense lifestyle change plus lipid active drugs and severity/change of perfusion abnormalities independently predicted cardiac events. CONCLUSIONS: Intense lifestyle and pharmacologic lipid treatment reduce size/severity of myocardial perfusion abnormalities and cardiac events compared with usual-care cholesterol-lowering drugs. Perfusion changes parallel treatment intensity and predict outcomes.

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.

Effects of Electroconvulsive Therapy on Brain Glucose Metabolism: A Preliminary Study.

We measured (15)O water uptake and [(18)F]fluorodeoxyglucose (FDG) uptake in four depressed individuals before electroconvulsive therapy (ECT) and 24 h after completion of a series of six to 11 bilateral ECT treatments. Studies of radioactive uptake were done using positron emission tomography, with FDG as a measure for glucose metabolism and with oxygen-15-labeled water as a measure for cerebral blood flow. The four patients showed decreased uptake of FDG in the frontal cortex after ECT treatment. Two of the three patients in whom (15)O water was measured showed decreased uptake in the frontal cortex after ECT.