Marcelo Soto Thompson

Clinical system for interstitial photodynamic therapy with combined on-line dosimetry measurements

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 photobleaching, and a relatively constant global tissue oxygen saturation level during the treatment.

In vivo measurement of parameters of dosimetric importance during interstitial photodynamic therapy of thick skin tumors

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.

Feasibility study of a system for combined light dosimetry and interstitial photodynamic treatment of massive tumors

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.

System for integrated interstitial photodynamic therapy and dosimetric monitoring

Photodynamic therapy for the treatment of cancer relies on the presence of light, sensitizer and oxygen. By monitoring these three parameters during the treatment a better understanding and treatment control could possibly be achieved. Here we present data from in vivo treatments of solid skin tumors using an instrument for interstitial photodynamic therapy with integrated dosimetric monitoring. By using intra-tumoral ALA-administration and interstitial light delivery solid tumors are targeted. The same fibers are used for measuring the fluence rate at the treatment wavelength, the sensitizer fluorescence and the local blood oxygen saturation during the treatment. The data presented is based on 10 treatments in 8 patients with thick basal cell carcinomas. The fluence rate measurements at 635 nm indicate a major treatment induced absorption increase, leading to a limited light penetration at the treatment wavelength. This leads to a far from optimal treatment since the absorption increase prevents peripheral tumor regions from being fully treated. An interactive treatment has been implemented assisting the physician in delivering the correct light dose. The absorption increase can be compensated for by either prolonging the treatment time or increasing the output power of each individual treatment fiber. The other parameters of importance, i.e. the sensitizer fluorescence at 705 nm and the local blood oxygen saturation, are monitored in order to get an estimate of the amount of photobleaching and oxygen consumption. Based on the oxygen saturation signal, a fractionized irradiation can be introduced in order to allow for a re-oxygenation of the tissue.

Analysis of spatial variability in hyperspectral imagery of the uterine cervix in vivo

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.

In-vivo fluorescence and reflectance imaging of human cervical tissue

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.

Interstitial photodynamic therapy - diagnostic measurements and treatment in rat malignant experimental tumours

A recently developed multiple fiber system for treating malignant tumors 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 metabolized 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 fibers and a dosimetry program calculating the optimal fiber position within the tumor 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. Tumor reduction was examined three days post treatment. A volume decrease was found in 85% of the treated tumors. The mean volume reduction was 44%, with one tumor completely disappearing. Histopathological examination three days post treatment showed substantial necrotic parts which, however, to a smaller extent were present also for non-treated tumors. These results indicated that the tumors 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.

Interactive system for interstitial photodynamic therapy

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.

Integrated system for interstitial photodynamic therapy

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.