Biomedical subjects

Brian C Wilson

Publications and source records attributed to Brian C Wilson.

At least 19 recordsLinked to original sources

PubMed2007

Multimodality imaging for vertebral metastases in a rat osteolytic model.

Imaging modalities facilitate the detection of early bony metastases. Few studies specifically address vertebral metastases in animal models for preclinical (early, asymptomatic) disease. We performed intracardiac injection of human breast cancer (MT-1) cells in 35 athymic nude rats. We evaluated potential temporal differences in appendicular versus axial metastases as detectable by longitudinal in vivo conventional radiography (ie, fine detail radiography and two-dimensional fluoroscopy). We compared bioluminescent reporter imaging with conventional radiographs in the detection of vertebral metastasis, and compared bioluminescent imaging with subsequent ex vivo microcomputed tomography analysis of osteolysis. The mean survival was 25 days in the animals that had metastases develop. Conventional radiographs identified appendicular osteolysis by 14 days; however, vertebral osteolysis was identified late in the metastatic spread (Days 25-28). Bioluminescence imaging was more sensitive in earlier detection of vertebral lesions in all imaged animals at Day 21, which corresponded to microcomputed tomography evaluation of osteolysis. Conventional radiographs do not appear useful for early detection of vertebral metastasis. Early identification of metastasis is important when considering the use of this model to evaluate therapeutic outcomes directed toward vertebral metastasis.

Animals↗

PubMed2006

Doppler optical coherence tomography with a micro-electro-mechanical membrane mirror for high-speed dynamic focus tracking.

An elliptical microelectromechanical system (MEMS) membrane mirror is electrostatically actuated to dynamically adjust the optical beam focus and track the axial scanning of the coherence gate in a Doppler optical coherence tomography (DOCT) system at 8 kHz. The MEMS mirror is designed to maintain a constant numerical aperture of approximately 0.13 and a spot size of approximately 6.7 microm over an imaging depth of 1mm in water, which improves imaging performance in resolving microspheres in gel samples and Doppler shift estimation precision in a flow phantom. The mirror's small size (1.4 mm x 1 mm) will allow integration with endoscopic MEMS-DOCT for in vivo applications.

Computer Systems↗

PubMed2006

Photodynamic therapy of brain tumors--a work in progress.

BACKGROUND AND OBJECTIVES: PDT has been used in the treatment of malignant brain tumors. This communication updates our series of unselected malignant gliomas treated with Photofrin-PDT. STUDY DESIGN AND METHODS: We examined the records of 112 patients with malignant gliomas, metastatic brain tumors and meningiomas treated with Photofrin-PDT at St. Michael's Hospital, Toronto. These patients were treated prior to the onset of ongoing randomized trials in Photofrin PDT or had pathology that excluded them from such trials. RESULTS: The overall post-PDT survival of 96 patients with supratentorial gliomas was 42 weeks, with a 40 and 22% 1- and 2-year survival, respectively. The greater the degree of oligodendroglial involvement the longer was the survival. Seventy-five percent of patients had no significant post-operative complications. CONCLUSIONS: Photofrin-PDT was safe. However, higher light doses than were used in these patients may be required for improved responses.

Adolescent↗

PubMed2006

Magnetic resonance imaging correlated with the histopathological effect of Pd-bacteriopheophorbide (Tookad) photodynamic therapy on the normal canine prostate gland.

BACKGROUND AND OBJECTIVE: To determine the optimal magnetic resonance imaging (MRI) methodology to assess photodynamic therapy (PDT)-induced histopathological responses in the prostate. STUDY DESIGN/MATERIALS AND METHODS: Laparotomy was performed in five healthy dogs. Cylindrical diffuser was placed in the prostates to deliver light of 50-300 J/cm at 150 mW/cm and 763 nm to activate IV-injected Tookad (1 mg/kg b.w.). Fast spin echo (FSE) T2-weighted, post-contrast-enhanced T1-(CE-T1) and diffusion weighted images (DWI) were obtained pre- and 2 days, 7 days, and 1 month post-PDT. Radiological-histopathological correlation was performed at 7 days (n = 4) and 1 month (n = 1) after PDT. A qualitative assessment of signal changes and apparent diffusion coefficient (ADC) mapping was performed. RESULTS: At 2 or 7 days post-PDT, there was good spatial correlation between PDT-induced hemorrhagic necrosis and unenhanced regions on CE-T1 images. There was a rapidly and persistently enhancing rim corresponding to edema and inflammation. FSE T2 and DWI showed altered signal but did not clearly define necrosis in all cases. At 1 month, it was hard to correlate MR images to histopathologic changes as they represented a mixture of necrosis and developing fibrosis, which led to a mixed signal intensity and less demarcated contrast enhancement. CONCLUSIONS: At 7 days after PDT, gadolinium DTPA contrast-enhanced MRI is superior to DWI and T2 imaging in assessing the boundary of Tookad PDT-induced tissue necrosis in the normal canine prostate.

Animals↗

PubMed2006

Feasibility of interstitial Doppler optical coherence tomography for in vivo detection of microvascular changes during photodynamic therapy.

INTRODUCTION: Doppler optical coherence tomography (DOCT) is an emerging imaging modality that provides subsurface microstructural and microvascular tissue images with near histological resolution and sub-mm/second velocity sensitivity. A key drawback of OCT for some applications is its shallow (1-3 mm) penetration depth. This fundamentally limits DOCT imaging to transparent, near-surface, intravascular, or intracavitary anatomical sites. Consequently, interstitial Doppler OCT (IS-DOCT) was developed for minimally-invasive in vivo imaging of microvasculature and microstructure at greater depths, providing access to deep-seated solid organs. Using Dunning prostate cancer in a rat xenograft model, this study evaluated the feasibility of IS-DOCT monitoring of microvascular changes deep within a tumor caused by photodynamic therapy (PDT). MATERIALS AND METHODS: The DOCT interstitial probe was constructed using a 22 G (diameter approximately 0.7 mm) needle, with an echogenic surface finish for enhanced ultrasound visualization. The lens of the probe consisted of a gradient-index fiber, fusion spliced to an angle-polished coreless tip to allow side-view scanning. The lens was then fusion spliced to a single-mode optical fiber that was attached to the linear scanner via catheters and driven along the longitudinal axis of the needle to produce a 2D subsurface DOCT image. The resultant IS-DOCT system was used to monitor microvascular changes deep within the tumor mass in response to PDT in the rat xenograft model of Dunning prostate cancer. Surface PDT was delivered at 635 nm with 40 mW of power, for a total light dose of 76 J/cm(2), using 12.5 mg/kg of Photofrin as the photosensitizer dose. RESULTS: IS-DOCT demonstrated its ability to detect microvasculature in vivo and record PDT-induced changes. A reduction of detected vascular cross sectional area during treatment and partial recovery post-treatment were observed. CONCLUSIONS: IS-DOCT is a potentially effective tool for real-time visualization and monitoring of the progress of PDT treatments. This capability may play an important role in elucidating the mechanisms of PDT in tumors, pre-treatment planning, feedback control for treatment optimization, determining treatment endpoints and post-treatment assessments.

Animals↗

PubMed2006

Spectroscopy and fluorescence in esophageal diseases.

Malignant tumors of the esophagus continue to be a major health issue associated with high mortality primarily because most present with symptoms of dysphagia or anaemia. The disease at that stage is advanced and not likely curable. The big issue for squamous dysplasia and that associated with BE is that only a small proportion are discovered in surveillance programs when they are asymptomatic, either because the patient lives in a high-incidence geographical area, has a family history, previously diagnosed head and neck cancer or chronic reflux, as in Barrett's. Current endoscopic methods are hampered by the endoscopist's inability to recognize subtle topographic clues of dysplasia, sampling errors related to biopsy protocols, and confounding inflammation-induced artifacts both for the endoscopist and pathologist. What is desperately needed would be a biomarker (e.g. serological, fecal, urinary) that selects patients for endoscopy. However, such a test is not yet on the horizon. This article examines the current status in practice and research of novel optically based 'bioendoscopic' devices (i.e. fluorescence spectroscopy and imaging, confocal fluorescence microendoscopy (CFM), light scattering spectroscopy (LSS), Raman spectroscopy (RS), and immunophotodiagnostic endoscopy) which may enhance the diagnosis of dysplasia in all patients undergoing conventional white light endoscopy. Perhaps these new technologies will lead to more cost-effective diagnosis, mapping (e.g. surface), and staging (e.g. depth) of dysplasia, thereby allowing timely cure by endoscopic means (e.g. EMR and/or PDT), biological interventions (e.g. Cox-2 inhibitors) rather than esophajectomy.

Endoscopy, Gastrointestinal↗

PubMed2006

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.

Genital Neoplasms, Male↗

PubMed2006

High throughput quantification of protein expression of cancer antigens in tissue microarray using quantum dot nanocrystals.

We developed and validated a novel method for quantifying protein expression of cancer tumors in an accurate, sensitive, and high throughput format. This technique integrates quantum dots, tissue microarray, optical spectroscopy, and algorithm design for analysis of tumor biopsies. The integration of this method for tissue analysis in the clinic bears potential impact for improving the diagnosis and treatment of cancer.

Animals↗

PubMed2005

Pre-clinical in vitro and in vivo studies to examine the potential use of photodynamic therapy in the treatment of osteomyelitis.

Osteomyelitis can lead to severe morbidity and even death resulting from an acute or chronic inflammation of the bone and contiguous structures due to fungal or bacterial infection. Incidence approximates 1 in 1000 neonates and 1 in 5000 children in the United States annually and increases up to 0.36% and 16% in adults with diabetes or sickle cell anaemia, respectively. Current regimens of treatment include antibiotics and/or surgery. However, the increasing number of antibiotic resistant pathogens suggests that alternate strategies are required. We are investigating photodynamic therapy (PDT) as one such alternate treatment for osteomyelitis using a bioluminescent strain of biofilm-producing staphylococcus aureus (S. aureus) grown onto kirschner wires (K-wire). S. aureus-coated K-wires were exposed to methylene blue (MB) or 5-aminolevulinic acid (ALA)-mediated PDT either in vitro or following implant into the tibial medullary cavity of Sprague-Dawley rats. The progression of S. aureus biofilm was monitored non-invasively using bioluminescence and expressed as a percentage of the signal for each sample immediately prior to treatment. S. aureus infections were subject to PDT 10 days post inoculation. Treatment comprised administration of ALA (300 mg kg(-1)) intraperitoneally followed 4 h later by light (635 +/- 10 nm; 75 J cm(-2)) delivered transcutaneously via an optical fiber placed onto the tibia and resulted in significant delay in bacterial growth. In vitro, MB and ALA displayed similar cell kill with > or =4 log(10) cell kill. In vivo, ALA-mediated PDT inhibited biofilm implants in bone. These results confirm that MB or ALA-mediated PDT have potential to treat S. aureus cultures grown in vitro or in vivo using an animal model of osteomyelitis.

Aminolevulinic Acid↗

PubMed2005

Relaxin-induced reduction of infarct size in male rats receiving MCAO is dependent on nitric oxide synthesis and not estrogenic mechanisms.

Relaxins are members of the insulin peptide superfamily. Previous evidence has shown that relaxin pretreatment reduces cortical infarct size in anesthetized, male rats receiving permanent middle cerebral artery occlusion (MCAO). Therefore, the current study was designed to determine if estrogenic mechanisms or nitric oxide production are involved in mediating this relaxin-induced neuroprotection. In separate groups of rats (n=4-6), the following drugs were injected directly into the cortex 30 min prior to MCAO: (a) relaxin, (b) relaxin and estrogen, and (c) relaxin and an estrogen receptor antagonist (ICI 182,780). To investigate the involvement of nitric oxide, relaxin or relaxin and an inhibitor of endothelial nitric oxide synthase (L-NIO) were injected i.v. 30 min prior to MCAO. Saline-treated rats (both intracortical (i.c.) and intravenously (i.v.)) served as controls. Brains were harvested 4h post stroke, coronally sectioned using a brain matrix and stained using 2,3,5-triphenoltetrazolium chloride (TTC). Digital photographs were taken of brain sections and the ratio comparing the area of the infarct to the area of the ipsilateral hemisphere was calculated. Mean ratios were compared using ANOVA and Tukey's test. Intracortical and intravenous relaxin pretreatment significantly reduced the infarct area in the cortex by 33.7 and 58.6%, respectively compared to saline-treated controls. This effect was not dependent on an interaction with estrogenic receptors as co-injection of relaxin and ICI 182,780 did not reverse this effect. However, inhibition of nitric oxide synthase significantly reduced the relaxin-mediated neuroprotection suggesting that relaxin may induce the endothelin-NOS cascade in cerebral vasculature causing vasodilation and improved perfusion of neural tissue.

Analysis of Variance↗

PubMed2005

Interstitial Doppler optical coherence tomography.

Doppler optical coherence tomography (OCT) can image tissue structure and blood flow at micrometer-scale resolution but has limited imaging depth. We report a novel, linear-scanning, needle-based Doppler OCT system using angle-polished gradient-index or ball-lensed fibers. A prototype system with a 19-guage (diameter of approximately 0.9 mm) echogenic needle is constructed and demonstrates in vivo imaging of bidirectional blood flow in rat leg and abdominal cavity. To our knowledge, this is the first demonstration of Doppler OCT through a needle probe in interstitial applications to visualize deeply situated microcirculation.

Animals↗

PubMed2005

The microenvironment effect on the generation of reactive oxygen species by Pd-bacteriopheophorbide.

Generation of reactive oxygen species (ROS) is the hallmark of important biological processes and photodynamic therapy (PDT), where ROS production results from in situ illumination of certain dyes. Here we test the hypothesis that the yield, fate, and efficacy of the species evolved highly depend on the dye's environment. We show that Pd-bacteriopheophorbide (Pd-Bpheid), a useful reagent for vascular targeted PDT (VTP) of solid tumors, which has recently entered into phase II clinical trials under the code name WST09 (trade name TOOKAD), forms appreciable amounts of hydroxyl radicals, superoxide radicals, and probably hydrogen peroxide in aqueous medium but not in organic solvents where singlet oxygen almost exclusively forms. Evidence is provided by pico- and nanosecond time-resolved spectroscopies, ESR spectroscopy with spin-traps, time-resolved singlet oxygen phosphorescence, and chemical product analysis. The quantum yield for singlet oxygen formation falls from approximately 1 in organic solvents to approximately 0.5 in membrane-like systems (micelles or liposomes), where superoxide and hydroxyl radicals form at a minimal quantum yield of 0.1%. Analysis of photochemical products suggests that the formation of oxygen radicals involves both electron and proton transfer from (3)Pd-Bpheid at the membrane/water interface to a colliding oxygen molecule, consequently forming superoxide, then hydrogen peroxide, and finally hydroxyl radicals, with no need for metal catalysis. The ability of bacteriochlorophyll (Bchl) derivatives to form such radicals upon excitation at the near infrared (NIR) domain opens new avenues in PDT and research of redox regulation in animals and plants.

Bacteriochlorophylls↗

PubMed2005

Fluorescence image-guided brain tumour resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development.

Fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have previously been investigated separately with the objectives, respectively, of increasing the extent of brain tumour resection and of selectively destroying residual tumour post-resection. Both techniques have demonstrated trends towards improved survival, pre-clinically and clinically. We hypothesize that combining these techniques will further delay tumour re-growth. In order to demonstrate technical feasibility, we here evaluate fluorescence imaging and PDT treatment techniques in a specific intracranial tumour model. The model was the VX2 carcinoma grown by injection of tumour cells into the normal rabbit brain. An operating microscope was used for white light imaging and a custom-built fluorescence imaging system with co-axial excitation and detection was used for FGR. PDT treatment light was applied by intracranially-implanted light emitting diodes (LED). The fluorescent photosensitizer used for both FGR and PDT was ALA-induced PpIX. For PDT, ALA (100 mg kg(-1)) and low light doses (15 and 30 J) were administered over extended periods, which we refer to as metronomic PDT (mPDT). Eighteen tumour bearing rabbits were divided equally into three groups: controls (no resection); FGR; and FGR followed by mPDT. Histological whole brain sections (H&E stain) showed primary and recurrent tumours. No bacteriological infections were found by Gram staining. Selective tumour cell death through mPDT-induced apoptosis was demonstrated by TUNEL stain. These results demonstrate that the combined treatment is technically feasible and this model is a candidate to evaluate it. Further optimization of mPDT treatment parameters (drug/light dose rates) is required to improve survival.

Aminolevulinic Acid↗

PubMed2005

Techniques for delivery and monitoring of TOOKAD (WST09)-mediated photodynamic therapy of the prostate: clinical experience and practicalities.

Photodynamic therapy of solid organs requires sufficient PDT dose throughout the target tissue while minimizing the dose to proximal normal structures. This requires treatment planning for position and power of the multiple delivery channels, complemented by on-line monitoring during treatment of light delivery, drug concentration and oxygen levels. We describe our experience in implementing this approach in Phase I/II clinical trials of the Pd-bacteriophephorbide photosensitizer TOOKAD (WST09)-mediated PDT of recurrent prostate cancer following radiation failure. We present several techniques for delivery and monitoring of photodynamic therapy, including beam splitters for light delivery to multiple delivery fibers, multi-channel light dosimetry devices for monitoring the fluence rate in the prostate and surrounding organs, methods of measuring the tissue optical properties in situ, and optical spectroscopy for monitoring drug pharmacokinetics of TOOKAD in whole blood samples and in situ in the prostate. Since TOOKAD is a vascular-targeted agent, the design and implementation of the techniques are different than for cellular-targeted agents. Further development of these delivery and monitoring techniques will permit full on-line monitoring of the treatment that will enable real-time, patient-specific and optimized delivery of PDT.

Bacteriochlorophylls↗

PubMed2005

Studies of a vascular-acting photosensitizer, Pd-bacteriopheophorbide (Tookad), in normal canine prostate and spontaneous canine prostate cancer.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) mediated with Tookad (Pd-bacteriopheophorbide, WST09) was investigated pre-clinically as part of a program to develop an alternative modality for treating prostate cancer. STUDY DESIGN/MATERIALS AND METHODS: Spontaneous canine prostate cancer and normal canine prostate were used as the animal models. Interstitial PDT was performed by IV infusion of the photosensitizer and irradiating the prostates with a diode laser (763 nm). The prostates were harvested 1-week post-PDT and subjected to histopathologic examinations. The effects of the drug doses and light doses were studied for one- and two-session PDT. Pharmacokinetics were studied using HPLC assay. The feasibility of using perfusing CT scans for assessing PDT lesions was also evaluated. RESULTS: Tookad is a vascular-acting drug and clears rapidly from the circulation. Tookad-PDT-induced lesions, in both normal and cancerous prostates, were characterized by marked hemorrhagic necrosis. CONCLUSIONS: Tookad-PDT is very effective in ablating prostatic tissue through its vascular effects.

Animals↗

PubMed2005

Endoscopic detection of early upper GI cancers.

The detection of early-stage neoplastic lesions in the upper GI tract is associated with improved survival and the potential for complete endoscopic resection that is minimally invasive and less morbid than surgery. Despite technological advances in standard white-light endoscopy, the ability of the endoscopist to reliably detect dysplastic and early cancerous changes in the upper GI tract remains limited. In conditions such as Barrett's oesophagus, practice guidelines recommend periodic endoscopic surveillance with multiple biopsies, a methodology that is hindered by random sampling error, inconsistent histopathological interpretation, and delay in diagnosis. Early detection may be enhanced by several promising diagnostic modalities such as chromoendoscopy, magnification endoscopy, and optical spectroscopic/imaging techniques, as these modalities offer the potential to identify in real-time lesions that are inconspicuous under conventional endoscopy. The combination of novel diagnostic techniques and local endoscopic therapies will provide the endoscopist with much needed tools that can considerably enhance the detection and management of early stage lesions in the upper GI tract.

Barrett Esophagus↗

PubMed2005

Endoscopic Doppler optical coherence tomography in the human GI tract: initial experience.

BACKGROUND: Expanding the current endoscopic optical coherence tomography (OCT) system with Doppler capability may augment this novel high-resolution cross-sectional imaging technique with functional blood flow information. The aim of this feasibility study was to assess the clinical feasibility of an endoscopic Doppler OCT (EDOCT) system in the human GI tract. METHODS: During routine endoscopy, 22 patients were imaged by using a prototype EDOCT system, which provided color-Doppler and velocity-variance images of mucosal and submucosal blood flow at one frame per second, simultaneously with high-spatial-resolution (10-25 mum) images of tissue microstructure. The images were acquired from normal GI tract and pathologic tissues. OBSERVATIONS: Subsurface microstructure and microcirculation images of normal and pathologic GI tissues, including Barrett's esophagus, esophageal varices, portal hypertensive gastropathy, gastric antral vascular ectasia, gastric lymphoma, and duodenal adenocarcinoma, were obtained from 72 individual sites in vivo. Differences in vessel diameter, distribution, density, and blood-flow velocity were observed among the GI tissue pathologies imaged. CONCLUSIONS: To our knowledge, this is the first study to demonstrate the feasibility of EDOCT imaging in the human GI tract during routine endoscopy procedures. EDOCT may detect the different microcirculation patterns exhibited by normal and diseased tissues, which may be useful for diagnostic imaging and treatment monitoring.

Adult↗

PubMed2005

Relaxin pretreatment decreases infarct size in male rats after middle cerebral artery occlusion.

We studied the possible neuroprotective action of relaxin in a rat stroke model. Relaxin (10 ng in 200 nL saline) or saline was injected into the secondary somatosensory cortex of anesthetized rats. Thirty minutes after treatment, the right middle cerebral artery was occluded, causing ischemic conditions. Brains were removed 4 hours after stroke, and 1-mm coronal sections were stained using 2-3-5-triphenoltetrazolium chloride. Digital photographs were taken of the sections, and the ratio of infarct area to ipsilateral hemispheric area was calculated. Relaxin treatment significantly (P < .05) reduced this ratio compared with that of saline-treated controls. Results suggest that relaxin may prevent ischemia-induced cell death.

Animals↗