[Safe prescribing in patients with liver cirrhosis; 5 pitfalls]. / Veilig voorschrijven bij levercirrose: 5 misvattingen.

The liver has a major role in the pharmacokinetics and pharmacodynamics of medicines and hepatic impairment could therefore lead to increased plasma levels and adverse drug reactions. Due to the large overcapacity of the liver, medication adjustments are only needed when a chronic liver disease has progressed to cirrhosis. Important pharmacokinetic alterations that could occur in cirrhosis are: (a) a decreased first-pass effect, (b) impaired metabolism by liver enzymes, and (c) in an advanced stage also impairment of renal elimination. Patients with cirrhosis could also be more sensitive to certain adverse drug reactions at normal drug levels, such as renal impairment due to NSAIDs or the sedative effect of morphinomimetics and psychotropic drugs. Prescribing in patients with cirrhosis is complex, which we illustrate by 5 common pitfalls. In practice, healthcare professionals could use a website with guidance for prescribing almost 300 medicines (www.geneesmiddelenbijlevercirrose.nl).

An improved treatment planning and quality assurance process for Collaborative Ocular Melanoma Study eye plaque brachytherapy.

PURPOSE: To develop a treatment planning platform for episcleral Collaborative Ocular Melanoma Study plaque therapy in an established treatment planning software and to improve an existing quality assurance (QA) process for nonuniformly loaded plaques that measures air kerma strengths (AKSs) and loading profile. MATERIALS AND METHODS: Treatment planning is performed in Pinnacle using scripts that let the planner choose plaque size and notching. Scripts load seed positions for each plaque and five source groups corresponding to available stock seeds that can be placed into each seed position. Contours are loaded that display the model eye and the plaque itself. Plaque QA is performed using a modification of our previous pinhole apparatus by replacing x-ray film exposure with an optical camera and scintillating film system. The captured image is processed to remove background and to correct the intensity of seeds on the plaque periphery. Measured total optical counts provide an estimate of total plaque AKS. RESULTS: Treatment planning of eye plaques using Pinnacle, in conjunction with our stock inventory of seeds, is established as standard practice at our center. Planned plaques can vary from uniformly loaded to asymmetrically loaded notched plaques. Using the optical camera system for assessment of the seed loadings has decreased QA time from 40 min/plaque to 10 min/plaque. Total AKS of each plaque can be measured using the optical camera with an accuracy of 10%. CONCLUSIONS: Treatment planning is performed on a Health Canada-approved software that accommodates nonuniform plaque loading. Optical imaging of the plaque provides absolute total AKS and the relative seed arrangement in the plaque.

Improving superficial target delineation in radiation therapy with endoscopic tracking and registration.

PURPOSE: Target delineation within volumetric imaging is a critical step in the planning process of intensity modulated radiation therapy. In endoluminal cancers, endoscopy often reveals superficial areas of visible disease beyond what is seen on volumetric imaging. Quantitatively relating these findings to the volumetric imaging is prone to human error during the recall and contouring of the target. We have developed a method to improve target delineation in the radiation therapy planning process by quantitatively registering endoscopic findings contours traced on endoscopic images to volumetric imaging. METHODS: Using electromagnetic sensors embedded in an endoscope, 2D endoscopic images were registered to computed tomography (CT) volumetric images by tracking the position and orientation of the endoscope relative to a CT image set. Regions-of-interest (ROI) in the 2D endoscopic view were delineated. A mesh created within the boundary of the ROI was projected onto the 3D image data, registering the ROI with the volumetric image. This 3D ROI was exported to clinical radiation treatment planning software. The precision and accuracy of the procedure was tested on two solid phantoms with superficial markings visible on both endoscopy and CT images. The first phantom was T-shaped tube with X-marks etched on the interior. The second phantom was an anatomically correct skull phantom with a phantom superficial lesion placed on the pharyngeal surface. Markings were contoured on the endoscope images and compared with contours delineated in the treatment planning system based on the CT images. Clinical feasibility was tested on three patients with early stage glottic cancer. Image-based rendering using manually identified landmarks was used to improve the registration. RESULTS: Using the T-shaped phantom with X-markings, the 2D to 3D registration accuracy was 1.5-3.5 mm, depending on the endoscope position relative to the markings. Intraobserver standard variation was 0.5 mm. Rotational accuracy was within 2°. Using the skull phantom, registration accuracy was assessed by calculating the average surface minimum distance between the endoscopy and treatment planning contours. The average surface distance was 0.92 mm with 93% of all points in the 2D-endoscopy ROI within 1.5 mm of any point within the ROI contoured in the treatment planning software. This accuracy is limited by the CT imaging resolution and the electromagnetic (EM) sensor accuracy. The clinical testing demonstrated that endoscopic contouring is feasible. With registration based on em tracking only, accuracy was 5.6-8.4 mm. Image-based registration reduced this error to less than 3.5 mm and enabled endoscopic contouring in all cases. CONCLUSIONS: Registration of contours generated on 2D endoscopic images to 3D planning space is feasible, with accuracy smaller than typical set-up margins. Used in addition to standard 3D contouring methods in radiation planning, the technology may improve gross tumour volume (GTV) delineation for superficial tumors in luminal sites that are only visible in endoscopy.

Image guided photothermal focal therapy for localized prostate cancer: phase I trial.

PURPOSE: We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. MATERIALS AND METHODS: Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. RESULTS: Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. CONCLUSIONS: Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response.

PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.

Accuracy of noninvasive in vivo measurements of photosensitizer uptake based on a diffusion model of reflectance spectroscopy.

This study compares the photosensitizer concentration measured noninvasively in vivo by diffuse reflectance spectroscopy with the results of postmortem tissue solubilization and fluorometric assay. The reflectance spectrometer consists of a fiber optic surface probe, spectrometer and charge-coupled device (CCD) array detector. The surface probe has eight detection fibers separated from the light source fiber by distances ranging from 0.85 to 10 mm. The imaging spectrometer disperses the light from each detector fiber onto the two-dimensional CCD array, while maintaining spatial separation of each individual spectrum. A single exposure of the CCD therefore captures the reflectance spectrum ar eight distances and over a range of 300 nm. From the spectra, the tissue's optical scattering and absorption coefficients are determined using a diffusion model of light propagation. Changes in the tissue absorption are used to estimate the photosensitizer concentration. Normal New Zealand White rabbits were injected with aluminum phthalocyanine tetrasulfonate (AlPcS4) and probe measurements made 24 h after injection on the dorsal skin, on muscle after surgically turning the skin back and on liver. For skin, the noninvasive estimate to proportional to the true concentration but low by a factor of 3. Based on Monte Carlo modeling of multilayered systems, this underestimate is attributed to the layered structure of the skin and nonuniform AlPcS4 distribution. A comparison of the noninvasive concentration estimates to the postmortem assay results finds good agreement for liver tissue even though application of the diffusion model is not strictly justified.