The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

Registration is a fundamental task in image processing used to match two or more pictures taken, for example, at different times, from different sensors, or from different viewpoints. Virtually all large systems which evaluate images require the registration of images, or a closely related operation, as an intermediate step. Specific examples of systems where image registration is a significant component include matching a target with a real-time image of a scene for target recognition, monitoring global land usage using satellite images, matching stereo images to recover shape for autonomous navigation, and aligning images from different medical modalities for diagnosis.Over the years, a broad range of techniques has been developed for various types of data and problems. These techniques have been independently studied for several different applications, resulting in a large body of research. This paper organizes this material by establishing the relationship between the variations in the images and the type of registration techniques which can most appropriately be applied. Three major types of variations are distinguished. The first type are the variations due to the differences in acquisition which cause the images to be misaligned. To register images, a spatial transformation is found which will remove these variations. The class of transformations which must be searched to find the optimal transformation is determined by knowledge about the variations of this type. The transformation class in turn influences the general technique that should be taken. The second type of variations are those which are also due to differences in acquisition, but cannot be modeled easily such as lighting and atmospheric conditions. This type usually effects intensity values, but they may also be spatial, such as perspective distortions. The third type of variations are differences in the images that are of interest such as object movements, growths, or other scene changes. Variations of the second and third type are not directly removed by registration, but they make registration more difficult since an exact match is no longer possible. In particular, it is critical that variations of the third type are not removed. Knowledge about the characteristics of each type of variation effect the choice of feature space, similarity measure, search space, and search strategy which will make up the final technique. All registration techniques can be viewed as different combinations of these choices. This framework is useful for understanding the merits and relationships between the wide variety of existing techniques and for assisting in the selection of the most suitable technique for a specific problem.

A survey of image registration techniques

The authors have applied estimation theory to the problem of determining primary current distributions from measured neuromagnetic fields. In this procedure, essentially nothing is assumed about the source currents, except that they are spatially restricted to a certain region. Simulation experiments show that the results can describe the structure of the current flow fairly well. By increasing the number of measurements, the estimate can be made more localised. The current distributions may be also used as an interpolation and an extrapolation for the measured field patterns.

Interpreting magnetic fields of the brain: minimum norm estimates

Light-activated, photosensitizer-based therapies have been established as safe modalities of tumour ablation for numerous cancer indications. Two main approaches are available: photodynamic therapy, which results in localized chemical damage in the target lesions, and photothermal therapy, which results in localized thermal damage. Whereas the administration of photosensitizers is a key component of photodynamic therapy, exogenous photothermal contrast agents are not required for photothermal therapy but can enhance the efficiency and efficacy of treatment. Over the past decades, great strides have been made in the development of phototherapeutic drugs and devices as cancer treatments, but key challenges have restricted their widespread clinical use outside of certain dermatological indications. Improvements in the tumour specificity of photosensitizers, achieved through targeting or localized activation, could provide better outcomes with fewer adverse effects, as could combinations with chemotherapies or immunotherapies. In this Review, we provide an overview of the current clinical progress of phototherapies for cancer and discuss the emerging preclinical bioengineering approaches that have the potential to overcome challenges in this area and thus improve the efficiency and utility of such treatments.

Clinical development and potential of photothermal and photodynamic therapies for cancer

The authors present general descriptive models for spatiotemporal MEG (magnetoencephalogram) data and show the separability of the linear moment parameters and nonlinear location parameters in the MEG problem. A forward model with current dipoles in a spherically symmetric conductor is used as an example: however, other more advanced MEG models, as well as many EEG (electroencephalogram) models, can also be formulated in a similar linear algebra framework. A subspace methodology and computational approach to solving the conventional least-squares problem is presented. A new scanning approach, equivalent to the statistical MUSIC method, is also developed. This subspace method scans three-dimensional space with a one-dipole model, making it computationally feasible to scan the complete head volume. >

Multiple dipole modeling and localization from spatio-temporal MEG data

Thirty-five patients with tumors within the tracheobronchial tree were treated with photoradiation therapy (PRT) employing the photodynamic action of hematoporphyrin derivative (HPD). An effective protocol has been developed consisting of 3.0 mg/kg HPD given intravenously 72 hours prior to the bronchoscopic illumination of the endobronchial tumor sites with red light (630 nm) from an argon pumped dye laser. Light applicators were developed that provided surface (area) and insertion (volume) illumination of tumor masses. Average light dosages of 100 J/cm2 and 200 J/cm were used for surface and insertion illumination, respectively. Delivery rates were 200 mW/cm2 and 400 mW/cm. There was no immediate visible effect such as coagulation or charring noted. All malignant endobronchial tumors responded. Tumors included primary and metastatic lesions of various histologic types. Response was complete for tumor within the bronchus after one treatment in 80% of instances. The remaining cases required two treatments to obtain a complete response due to the extensive length of bronchus involved or because multiple sites were present. A complete response, that is, the full opening up of the lumen to the bronchial wall, was accomplished in all but one instance. Atelectatic lungs or lobes were re-expanded and reaerated. Dyspnea and cough became significantly less. The follow-up achieved to date indicates improvement in symptoms, activity level, and the return to work in a significant number of cases.

Photoradiation therapy of endobronchial lung cancers employing the photodynamic action of hematoporphvrin derivative

A fluorescence bronchoscope system has been developed for imaging lung tumors by fluorescence of a previously injected, tumor-specific agent hematoporphyrin derivative. Carcinoma in situ has been localized, but there are too many false positives and negatives. A new system has been implemented which allows rapid switching between viewing of fluorescence, and viewing of the same area under white light illumination as in conventional bronchoscopy. The excitation source is a violet krypton ion laser coupled to a fused quartz fiber light conductor, with a diverging microlens to spread the light uniformly. A third-generation, microchannel plate image intensifier amplifies the weak fluorescence for viewing and video display, recording, and analysis. A movable mirror and periscope bypasses the intensifier for normal color viewing and video display and recording, with the laser shutter closed and the white light shutter open. This facilitates accurate localization, comparison of the color and fluorescence images, and precise sampling during biopsy. The improved system should reduce the false positive rate due to biopsy sampling error, and together with the video analyzer should reduce indeterminate results.

Fluorescence bronchoscopy for localization of carcinoma in situ

Mercuric iodide (HgI2) platelets for x-ray spectroscopy produced by polymer controlled growth

In response to specific stimuli, the human brain emits a measurable magnetic field from regions actively involved in processing the stimulus. We have implemented an iterative algorithm to reconstruct images from the neuromagnetic field. Computer simulation studies performed to develop the algorithm are reported. Experimental measurements of a human visually-evoked field and images reconstructed therefrom are also reported. The results demonstrate, for the first time, the feasibility of imaging multiple sources within the brain that produce a magnetic field.

Reconstruction of Images from Neuromagnetic Fields

A quantitative assessment of changes among a set of images has considerable importance in nuclear medicine. The set may consist of images obtained from different radionuclides, or those obtained from the same isotope administered at different times or under varying physiologic conditions. We have developed an operator-interactive digital technique for producing an accurate differential image, wherefrom minute changes which cannot be seen from an inspection of the original images alone, can be detected and quantified. This \"change detection\" procedure is quite general in nature and can be applied to analyze digital images of various types, including those obtained by different sensors. For example, a similar technique is being used in our laboratory to

G.C. Huth

Papers

Photoradiation therapy of endobronchial lung cancers employing the photodynamic action of hematoporphvrin derivative

Fluorescence bronchoscopy for localization of carcinoma in situ

Mercuric iodide (HgI2) platelets for x-ray spectroscopy produced by polymer controlled growth

Reconstruction of Images from Neuromagnetic Fields

A Digital Technique for Accurate Change Detection in Nuclear Medical Images - With Application to Myocardial Perfusion Studies Using Thallium-201