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Various optical techniques were used to investigate relevant parameters involved in photodynamic therapy (PDT) of human basal cell carcinomas (BCCs). The aim of the study was to compare the diagnostic and therapeutic outcome when using topically applied methyl-esterified delta -aminolevulinic acid (ALA-ME) and delta -aminolevulinic acid (ALA). A total of 35 pathologically verified BCCs in 14 patients were investigated. A diode laser. emitting continuous light at 633 nm, was used to induce PDT. The diagnostic measurements were performed before, during, and after PDT. Laser-induced fluorescence (LIF) was used to monitor the build-up of the ALA/ALA-ME-induced protoporphyrin IX (PpIX), The superficial tissue perfusion was measured with laser-Doppler perfusion imaging (LDPI) and the temperature of the lesion and the surrounding tissue was imaged with an IR-camera. A clear demarcation between the lesion and the normal skin was detected with LIF before the treatment for both PpIX precursors. The fluorescence measurements suggest that PpIX builds up to a higher degree and more selectively in the tumour following ALA-ME as compared to ALA. The LDPI measurements indicate a local transient restriction in blood perfusion immediately post-PDT. The measurement with the IR-camera revealed a temperature rise of about 1-2 degreesC during the treatment. (Less)

Colposcopy is a primary diagnostic method used to detect cancer and precancerous lesions of the uterine cervix. During the examination, the metaplastic and abnormal tissues exhibit different degrees of whiteness (acetowhitening effect) after applying a 3%–5% acetic acid solution. Colposcopists evaluate the color and density of the acetowhite tissue to assess the severity of lesions for the purpose of diagnosis, telemedicine, and annotation. However, the color and illumination of the colposcopic images vary with the light sources, the instruments and camera settings, as well as the clinical environments. This makes assessment of the color information very challenging even for an expert. In terms of developing a Computer-Aided Diagnosis (CAD) system for colposcopy, these variations affect the performance of the feature extraction algorithm for the acetowhite color. Non-uniform illumination from the light source is also an obstacle for detecting acetowhite regions, lesion margins, and anatomic features. There fore, in digital colposcopy, it is critical to map the color appearance of the images taken with different colposcopes into one standard color space with normalized illumination. This paper presents a novel image calibration technique for colposcopic images. First, a specially designed calibration unit is mounted on the colposcope to acquire daily calibration data prior to performing subject examinations. The calibration routine is fast, automated, accurate and reliable. We then use our illumination correction algorithm and a color calibration algorithm to calibrate the exam data. In this paper we describe these techniques and demonstrate their applications in clinical studies.

Endoscopic images suffer from a fundamental spatial distortion due to the wide angle design of the endoscope lens. This barrel-type distortion is an obstacle for subsequent Computer Aided Diagnosis (CAD) algorithms and should be corrected. Various methods and research models for the barrel-type distortion correction have been proposed and studied. For industrial applications, a stable, robust method with high accuracy is required to calibrate the different types of endoscopes in an easy of use way. The correction area shall be large enough to cover all the regions that the physicians need to see. In this paper, we present our endoscope distortion correction procedure which includes data acquisition, distortion center estimation, distortion coefficients calculation, and look-up table (LUT) generation. We investigate different polynomial models used for modeling the distortion and propose a new one which provides correction results with better visual quality. The method has been verified with four types of colonoscopes. The correction procedure is currently being applied on human subject data and the coefficients are being utilized in a subsequent 3D reconstruction project of colon.

Fluorescence spectroscopy is one of many optical methods that are potentially clinically useful for noninvasive detection and characterization of disorders on the cervical part of uterus, including precancerous lesions. The cervix uteri exhibits a biologically complex tissue and the morphology of a biopsy is generally not homogenous. The standard histopathological protocol accounts only for the most severe condition found within the biopsy and no information is given on other constituents potentially influencing the recorded fluorescence spectra. Spectra are usually correlated, using multivariate techniques, to the histopathological diagnosis of the biopsies. Since the probe volume of fluorescence spectroscopy is considerably smaller than the extension of the biopsy, this can cause problems in the search for correlation between the fluorescence signals and the pathological structures. In addition, the orientation and location of the biopsies are normally not recorded. We now report on the first detailed histopathological protocol where numerous tissue parameters, such as thickness and type of the epithelium and the number of blood vessels, glands, and inflammatory cells, are tabulated and the orientation and location of the biopsy are recorded as precisely as possible. Hopefully, the use of this protocol together with sophisticated mathematical methods will increase the probability to classify cervical disorders of the uterus, including precancerous lesions, with high sensitivity and specificity.

To overcome the limited treatment depth of superficial photodynamic therapy we investigate interstitial light delivery. In the present work the treatment light was delivered using a system in which three or six clear-cut fibers were placed in direct contact with the tumor area. This placement was thought to represent a step toward general purpose interstitial PDT. Twelve nodular basal cell carcinomas were treated employing delta-aminolevulinic acid and 635 nm laser irradiation. Fluorescence measurements were performed monitoring the buildup and subsequent bleaching of the produced sensitizer protoporphyrin IX. The treatment efficacy, judged at a 28-month follow-up, showed a 100% complete response. Two punch excisions at 7 months converted two partial responses to complete responses. One patient failed to appear at all follow-up sessions. The outcome of the treatments was comparable to superficial photodynamic therapy in terms of histological, clinical, and cosmetic results.

Colposcopy is a primary diagnostic method used to detect cancer and precancerous lesions of the uterine cervix. During the examination, the metaplastic and abnormal tissues exhibit different degrees of whiteness (acetowhitening effect) after applying a 3%-5% acetic acid solution. Colposcopists evaluate the color and density of the acetowhite tissue to assess the severity of lesions for the purpose of diagnosis, telemedicine, and annotation. However, the color and illumination of the colposcopic images vary with the light sources, the instruments and camera settings, as well as the clinical environments. This makes assessment of the color information very challenging even for an expert. In terms of developing a Computer-Aided Diagnosis (CAD) system for colposcopy, these variations affect the performance of the feature extraction algorithm for the acetowhite color. Non-uniform illumination from the light source is also an obstacle for detecting acetowhite regions, lesion margins and anatomic features. Therefore, in digital colposcopy, it is critical to map the color appearance of the images taken with different colposcopes into one standard color space with normalized illumination. This paper presents a novel image calibration technique for colposcopic images. First, a specially designed calibration unit is mounted on the colposcope to acquire daily calibration data prior to performing patient examinations. The calibration routine is fast, automated, accurate and reliable. We then use our illumination correction algorithm and a color calibration algorithm to calibrate the patient data. In this paper we describe these techniques and demonstrate their applications in clinical studies.

A system for interstitial photodynamic therapy is used in the treatment of thick skin tumors. The system allows simultaneous measurements of light fluence rate, sensitizer fluorescence, and tissue oxygen saturation by using the same fibers as for therapeutic light delivery. Results from ten tumor treatments using delta-aminolevulinic acid (ALA)-induced protoporphyrin IX show a significant, treatment-induced increase in tissue absorption at the therapeutic wavelength, and rapid sensitizer photobleaching. The changes in oxy- and deoxyhemoglobin content are monitored by means of near-infrared spectroscopy, revealing a varying tissue oxygenation and significant changes in blood volume during treatment. These changes are consistent with the temporal profiles of the light fluence rate at the therapeutic wavelength actually measured. We therefore propose the observed absorption increase to be due to treatment-induced deoxygenation in combination with changes in blood concentration within the treated volume. A higher rate of initial photobleaching is found to correlate with a less pronounced increase in tissue absorption. Based on the measured signals, we propose how real-time treatment supervision and feedback can be implemented. Simultaneous study of the fluence rate, sensitizer fluorescence, and local tissue oxygen saturation level may contribute to the understanding of the threshold dose for photodynamic therapy. (c) 2006 Society of Photo-Optical Instrumentation Engineers.

A system for interstitial photodynamic therapy with delta-aminolaevulinic acid and multiple optical fibers has been developed. The system enables photodynamic treatment of large embedded tumor volumes and utilizes real-time measurements to allow on-line dosimetry. Important parameters such as light fluence rate, sensitizer fluorescence intensity, and changes in local blood oxygen saturation are measured with the same fibers that deliver the therapeutic light. Data from the first clinical treatments on nodular basal cell carcinomas indicate a major treatment-induced light absorption increase, rapid sensitizer photo-bleaching, and a relatively constant global tissue oxygen saturation level during the treatment.

An interactive system for interstitial PDT using Δ-aminolevulinic acid and multiple fibres for light delivery has been developed. Interactive control is achieved by measuring light fluence distribution, sensitizer concentration and oxygenation level throughout the tissue.

To develop PDT beyond treatment of thin superficial tumors, to also be an efficient treatment alternative to deeply located and/or thick tumors, a system based on interstitial illumination using multiple fibers has been developed. Conditions that could benefit from such a treatment modality are for instance malignant brain tumors and tumors in the oral cavity. In interstitial PDT one needs to use multiple fibers for light delivery in order to allow treatments of tumors larger than a few millimeters in diameter. Our sytem consists of a laser light source, a beam-splitting system dividing the light into three or six output fibers and a custom-made dosimetry program. The concept is then to use these fibers not only for delivering the treatment light, but also to measure parameters of interest for the treatment outcome. The fluence rate of the light emitted by each fiber is measured at the positions of the other fiber tips. From these results the light dose at all positions could be recalculated. Changes in optical properties as well as bleaching and concentration of the photosensitizer during the treatment could be monitored and compensated for in the dosimetry. Tumors have been treated both in experimental studies and in patients with thick superficial Basal Cell Carcinomas. Almost all treated skin lesions responded with complete response.

An imaging spectrograph, designed and built by Science and Technology International (STI), and a point monitoring system, developed at the Lund Institute of Technology, have been used to measure the fluorescence and reflectance of cervical tissue in vivo . The instruments have been employed in a clinical trial in Vilnius, Lithuania, where 111 patients were examined. Patients were initially screened by Pap smear, examined by colposcopy and a tissue sampling procedure was performed. Detailed histopathological assessments were performed on the biopsies, and these assessments were correlated with spectra and images. The results of the spectroscopic investigations are illustrated by a thorough discussion of a case study for one of the patients, suggesting that the techniques are useful in the management of cervical malignancies.

A hyperspectral imaging spectrograph has been used to measure the fluorescence and reflectance of cervical tissue in vivo. The instrument was employed in a clinical trial in Vilnius, Lithuania, where 111 patients were examined. The patients were initially screened by Pap smear, examined by colposcopy and a tissue sampling procedure was performed. Detailed histopathological assessments were performed on the biopsies, and these assessments were correlated with spectra and images. The results of the spectroscopic investigations show that different tissue types within one biopsy region exhibit different spectral signatures. A spectral analysis of the entire image localizes dysplastic regions in both fluorescence and reflectance, suggesting that the hyperspectral imaging technique is useful in the management of cervical malignancies.

A novel photodynamic therapy system based on interstitial illumination using multiple fibres is under development. The aim with this system is to enable treatment of large tumour volumes and also to utilise real-time measurements to allow on-line dosimetry. Important dosimetric parameters to measure are light fluence rate, sensitizer fluorescence intensity and local blood oxygenation. A construction which allows all functions to be readily performed with a single system is presented. We believe that interstitial PDT utilising this technique may be attractive in many clinical situations.

The use of fluorescence and reflectance spectroscopy in the analysis of cervical histopathology is a growing field of research. The majority of this research is performed with point-like probes. Typically, clinicians select probe sites visually, collecting a handful of spectral samples. An exception to this methodology is the Hyperspectral Diagnostic Imaging (HSDI®) instrument developed by Science and Technology International. This non-invasive device collects contiguous hyperspectral images across the entire cervical portio. The high spatial and spectral resolution of the HSDI instruments make them uniquely well suited for addressing the issues of coupled spatial and spectral variability of tissues in vivo. Analysis of HSDI data indicates that tissue spectra vary from point to point, even within histopathologically homogeneous regions. This spectral variability exhibits both random and patterned components, implying that point monitoring may be susceptible to significant sources of noise and clutter inherent in the tissue. We have analyzed HSDI images from clinical CIN (cervical intraepithelial neoplasia) patients to quantify the spatial variability of fluorescence and reflectance spectra. This analysis shows the spatial structure of images to be fractal in nature, in both intensity and spectrum. These fractal tissue textures will limit the performance of any point-monitoring technology.

A system for the photodynamic laser treatment of massive tumors that employs multiple optical fibers to be inserted into the tumor mass is described. The light flux through the tumor can be assessed by use of the individual fibers both as transmitters and as receivers. With a computer model that describes the diffusive light propagation, optical dosimetry is under development. The system has been tested in an experimental animal tumor model in preparation for clinical work. Currently, delta-aminolevulinic acid is used as a sensitizer, activated by 635-nm radiation from a 2.0-W compact diode laser system. With the availability of future, highly selective drugs absorbing approximately 750 nm, larger tumor volumes should be treatable, and surrounding, sensitive normal tissue should be spared.

A recently developed multiple fibre system for treating malignant tumours with interstitial photodynamic therapy was used in studies on rats with colon adenocarcinoma inoculated into the muscles of the hind legs. The animals were intraperitonially administrated delta -aminolevulinic acid (ALA), which is metabolised to protoporphyrin IX (PpIX) in the tissue. The treatment system consists of a laser light source, a beam-splitting system dividing the light into three or six output fibres and a dosimetry programme calculating the optimal fibre position within the tumour as well as the treatment time needed to obtain a given threshold value of the light dose. One aim of the study was to compare the treatment outcome with the modelled dosimetry predictions. Tumour reduction was examined three days post treatment. A volume decrease was found in 85\% of the treated tumours. The mean volume reduction was 44\%, with one tumour completely disappearing. Histopathological examination three days post treatment showed substantial necrotic parts which, however, to a smaller extent were present also for non-treated tumours. These results indicated that the tumours have been under treated and the light dose has to be increased. Measurements of the build-up and photo-induced bleaching of PpIX using laser-induced fluorescence were also performed during the experiments. (Less)

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