Arjen Bogaards

Volume CT with a flat-panel detector on a mobile, isocentric C-arm: pre-clinical investigation in guidance of minimally invasive surgery.

A mobile isocentric C-arm (Siemens PowerMobil) has been modified in our laboratory to include a large area flat-panel detector (in place of the x-ray image intensifier), providing multi-mode fluoroscopy and cone-beam computed tomography (CT) imaging capability. This platform represents a promising technology for minimally invasive, image-guided surgical procedures where precision in the placement of interventional tools with respect to bony and soft-tissue structures is critical. The image quality and performance in surgical guidance was investigated in pre-clinical evaluation in image-guided spinal surgery. The control, acquisition, and reconstruction system are described. The reproducibility of geometric calibration, essential to achieving high three-dimensional (3D) image quality, is tested over extended time scales (7 months) and across a broad range in C-arm angulation (up to 45 degrees), quantifying the effect of improper calibration on spatial resolution, soft-tissue visibility, and image artifacts. Phantom studies were performed to investigate the precision of 3D localization (viz., fiber optic probes within a vertebral body) and effect of lateral projection truncation (limited field of view) on soft-tissue detectability in image reconstructions. Pre-clinical investigation was undertaken in a specific spinal procedure (photodynamic therapy of spinal metastases) in five animal subjects (pigs). In each procedure, placement of fiber optic catheters in two vertebrae (L1 and L2) was guided by fluoroscopy and cone-beam CT. Experience across five procedures is reported, focusing on 3D image quality, the effects of respiratory motion, limited field of view, reconstruction filter, and imaging dose. Overall, the intraoperative cone-beam CT images were sufficient for guidance of needles and catheters with respect to bony anatomy and improved surgical performance and confidence through 3D visualization and verification of transpedicular trajectories and tool placement. Future investigation includes improvement in image quality, particularly regarding x-ray scatter, motion artifacts and field of view, and integration with optical tracking and navigation systems.

Vascular-targeted photodynamic therapy (padoporfin, WST09) for recurrent prostate cancer after failure of external beam radiotherapy: a study of escalating light doses

To report on the efficacy of TOOKAD® (WST 09; NegmaLerads, Magny‐Les‐Hameaux, France) vascular‐targeted photodynamic therapy (VTP) as a method of whole‐prostate ablation in patients with recurrent localized prostate cancer after the failure of external beam radiotherapy (EBRT).

Photodynamic Therapy for Urological Malignancies: Past to Current Approaches

PURPOSE Modern PDT for urological tumors is a potentially selective approach in which in situ photosensitization by a nontoxic drug, locally activated by light, generates cytotoxic reactive oxygen species, causing cell death. While urological clinical experience with PDT is largely limited to treatment for superficial bladder cancer, the advent of novel photosensitizers and technologies for treatment planning, light delivery and dosimetry, PDT for prostate and other urological cancers appears increasingly realistic. MATERIALS AND METHODS We reviewed the current literature on PDT for urological tumors, in addition to recent emerging data from our laboratory and elsewhere. RESULTS Remarkable progress has been made in the field of photochemistry and photobiology. Together with improved optical delivery and imaging systems PDT holds promise as an alternative, minimally invasive and potentially curative treatment for localized solid tumors as well as for palliative treatment for isolated, clinically problematic metastases. CONCLUSIONS Current experience with photodynamic therapy using contemporary photosensitizing agents and light sources is mainly restricted to in vivo experimental models and early phase clinical trails. However, ongoing preclinical work and clinical trials indicate that safer and effective PDT treatments in uro-oncology are imminent.

Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer.

With the development of new photosensitizers that are activated by light at longer wavelengths, interstitial photodynamic therapy (PDT) is emerging as a feasible alternative for the treatment of larger volumes of tissue. Described here is the application of PDT treatment planning software developed by our group to ensure complete coverage of larger, geometrically complex target volumes such as the prostate. In a phase II clinical trial of TOOKAD vascular targeted photodynamic therapy (VTP) for prostate cancer in patients who failed prior radiotherapy, the software was used to generate patient-specific treatment prescriptions for the number of treatment fibres, their lengths, their positions and the energy each delivered. The core of the software is a finite element solution to the light diffusion equation. Validation against in vivo light measurements indicated that the software could predict the location of an iso-fluence contour to within approximately +/-2 mm. The same software was used to reconstruct the treatments that were actually delivered, thereby providing an analysis of the threshold light dose required for TOOKAD-VTP of the post-irradiated prostate. The threshold light dose for VTP-induced prostate damage, as measured one week post-treatment using contrast-enhanced MRI, was found to be highly heterogeneous, both within and between patients. The minimum light dose received by 90% of the prostate, D(90), was determined from each patients dose-volume histogram and compared to six-month sextant biopsy results. No patient with a D(90) less than 23 J cm(-2) had complete biopsy response, while 8/13 (62%) of patients with a D(90) greater than 23 J cm(-2) had negative biopsies at six months. The doses received by the urethra and the rectal wall were also investigated.

Autofluorescence-guided surveillance for oral cancer.

Early detection of oral premalignant lesions (OPL) and oral cancers (OC) is critical for improved survival. We evaluated if the addition of autofluorescence visualization (AFV) to conventional white-light examination (WLE) improved the ability to detect OPLs/OCs. Sixty high-risk patients, with suspicious oral lesions or recently diagnosed untreated OPLs/OCs, underwent sequential surveillance with WLE and AFV. Biopsies were obtained from all suspicious areas identified on both examinations (n = 189) and one normal-looking control area per person (n = 60). Sensitivity, specificity, and predictive values were calculated for WLE, AFV, and WLE + AFV. Estimates were calculated separately for lesions classified by histopathologic grades as low-grade lesions, high-grade lesions (HGL), and OCs. Sequential surveillance with WLE + AFV provided a greater sensitivity than WLE in detecting low-grade lesions (75% versus 44%), HGLs (100% versus 71%), and OCs (100% versus 80%). The specificity in detecting OPLs/OCs decreased from 70% with WLE to 38% with WLE + AFV. Thirteen of the 76 additional biopsies (17%) obtained based on AFV findings were HGLs/OCs. Five patients (8%) were diagnosed with a HGL/OC only because of the addition of AFV to WLE. In seven patients, additional HGL/OC foci or wider OC margins were detected on AFV. Additionally, AFV aided in the detection of metachronous HGL/OC in 6 of 26 patients (23%) with a history of previously treated head and neck cancer. Overall, the addition of AFV to WLE improved the ability to detect HGLs/OCs. In spite of the lower specificity, AFV + WLE can be a highly sensitive first-line surveillance tool for detecting OPLs/OCs in high-risk patients.

In vivo quantification of fluorescent molecular markers in real-time: A review to evaluate the performance of five existing methods

With the advent of molecular-targeted fluorescent markers, there is a renewed interest in fluorescence quantification methods that are based on continuous wave excitation and multi-spectral image acquisition. However, little is known about their in vivo quantification performance. We reviewed the performance of five selected methods by analytically describing these and varying input parameters of irradiance, excitation geometry, collection efficiency, autofluorescence, melanin content, blood volume, blood oxygenation and tissue scattering using optical properties representing those for human skin. We identified one method that corrects for variations in all parameters. This requires image acquisition before and after marker administration, under identical geometry. Hence, it is suited for applications where the site of interest can be relocated (e.g. anaesthetized animals and dermatology). For applications where relocation is not possible, we identified a second method where the uncertainty in the fluorescence signal was ±20%. Hence, use of these methods can substantially aid in vivo fluorescence quantification compared to use of the raw fluorescence signal, as this changed by more than 3 orders of magnitude. Since these methods can be computed in real-time, they are of particular interest for applications where direct feedback is critical, as diagnostic screening or image-guided surgery.

A Ratiometric Fluorescence Imaging System for Surgical Guidance

Correspondence should be addressed to Brian C. Wilson, wilson@uhnres.utoronto.caReceived 3 March 2008; Accepted 28 June 2008Recommended by Stoyan TanevA 3-chip CCD imaging system has been developed for quantitative in vivo fluorescence imaging. This incorporates a ratiometricalgorithm to correct for the effects of tissue optical absorption and scattering, imaging “geometry” and tissue autofluorescencebackground. The performance was characterized, and the algorithm was validated in tissue-simulating optical phantoms forquantitative measurement of the fluorescent molecule protoporphyrin IX (PpIX). The technical feasibility to use this system forfluorescence-guided surgical resection of malignant brain tumor tissue was assessed in an animal model in which PpIX was inducedexogenously in the tumor cells by systemic administration of aminolevulinic acid (ALA).Copyright

Metronomic photodynamic therapy (mPDT): concepts and technical feasibility in brain tumor

The concept of metronomic photodynamic therapy (mPDT) is presented, in which both the photosensitizer and light are delivered continuously at low rates over extended periods in order to increase selective tumor cell kill through apoptosis. The focus of the present work is on mPDT treatment of malignant brain tumors, in which selectivity between damage to tumor cells versus normal brain tissue is critical. Previous studies have shown that low-dose PDT using aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis in either tumor or normal brain tissue or apoptosis in the latter. In order to produce enough tumor cell kill to be an effective therapy, multiple PDT treatments, such as hyperfractionation or metronomic delivery, are likely requried, based on the levels of apoptosis achieved and model calculations of tumor growth rates. mPDT poses two substantial technical challenges: extended delivery of ALA and implantation of interstitial devices for extended light delivery while allowing free movement. In rat models ALA administration via the drinking water has been accomplished at significant doses for up to 10 days, and ex vivo spectrofluorimetry of tumore, normal brain and other tissues post mortem demonstrates a 3-4 increase in the tumor-to-brain concentration of PpIX, without toxicity. Prototype light sources and delivery devices are also shown to be practical, either using a laser diode or light emitting diode (LED) coupled to an implanted optical fiber in the case of the rat model or a directly-implanted LED in rabbits. The combined delivery of both drug and light over an extended period, with survival of the animals, is demonstrated. Preliminary evidence of selective apoptosis of tumor under these conditions is presented.

Fluorescence-guided resection of intracranial VX2 tumor in a preclinical model using 5-aminolevulinic acid (ALA): preliminary results

Fluorescence-guided brain tumor resection may help the neurosurgeon to identify tumor margins that merge imperceptibly into the normal brain tissue and are difficult to identify under white light illumination even using an operating microscope. We compared the amount of residual tumor after white light resection using an operating microscope versus that after fluorescnece-guided resection of an intracranial VX2 tumor in a preclinical model using our previously developed co-axial fluorscence imaging and spectroscopy system, exciting and detecting PpIX fluorescence at 405nm and 635nm respectively. Preliminary results: No fluorescence was present in 3 non-tumor-bearing animals. Fluorescence was present in all 15 tumor-bearing animals after white light resection was completed. To date in 4 rabbits, a decrease in residual tumor was found when using additional fluorescence guided resection compared to white light resection only. Conclusions: ALA induced PpIX fluorescence detects tumor margins not seen under an operation microscope using while light. Using fluorescence imaging to guide tumor resection resulted in a 3-fold decrease in the amount of residual timor. However, these preliminary results indicate that also an additional amount of normal brain is resected, which will be further investigated.

Bioluminescence monitoring of photodynamic therapy response of rat gliosarcoma in vitro and in vivo

Photodynamic Therapy (PDT) is a promising modality for tumor treatment that combines a photosensitizing agent and visible light resulting in the production of cytotoxic reactive oxygen species leading to cell death. Bioluminescence detection/imaging is a noninvasive technique that uses luciferase gene transfection together with administration of luciferin to generate detectable visible light. It can provide real-time assessment of tumor growth and therapeutic response. The aim of this study is to investigate the potential fo bioluminescence following animolevulinic acid (ALA)-mediated PDT. The in vitro results show a decrease of luminescence, with an excellent correlation to the number of viable cells. In vivo, the tumor growth was monitored using a cooled CCD camera, and ALA-PDT was performed 7-10 days post tumor implantation. The results show a decrease of the bioluminescence signal from the tumor that corresponds to a decrease of viable cells within the tumor, followed by re-growth at the sub-curative PDT doses used.