Search

Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence-surface histogram (FSH) was calculated for photofrin-mediated PDT to be able to cover 80% of pleural surface area to 50 J cm

Total skin electron therapy (TSET) has proven to be one of the most effective treatments for advanced-stage cutaneous T-cell lymphoma. Two most used techniques are the Stanford six-field and rotational techniques. This study compares patient skin dose distributions as a function of depth between these two techniques.The EGSnrc system was used to simulate electron beams and calculate patient dose distributions. The calculations assumed the same patient standing on a platform, and the patient's different postures were ignored for the Stanford technique in the comparison of dose distributions. The skin doses were analyzed as a function of skin depth-dose coverage and evaluated using dose-volume-histograms (DVH). The comparisons were performed in three realistic clinical settings in which dual-field were used for patients treated at extended distances of 316 and 500 cm, and a single field was used at 700 cm. In all cases the realistic patient treatment beam delivery geometry was simulated.Although small dose differences were observed in some local areas, no clinically significant differences were found in the patient 3D dose distributions between the Stanford and rotational techniques. Virtually the same DVH curves between two the techniques were observed for mean dose to skin depth of 0-5, 5-10, and 10-15 mm from the skin surface, respectively. It is found that the skin depth dose coverage is 2 mm shallower for patient treatment at 500 cm compared to at 316 cm due to the additional air attenuation. However, very similar dose coverage and uniformity can be achieved at these two different extended treatment distances by adjusting the thickness of acrylic scatter plate. Adequate thickness of a scattering plate improves the skin dose uniformity.Both the Stanford and rotational techniques deliver very similar skin dose coverage in DVH plots, and only small differences are seen in local areas. It is worth to emphasize that the DVH is a graphical representation of the distribution of dose within a structure, and it does not contain spatial information. Therefore, comparison of entire skin dose using DVH may mask some variations at different locations of the surface area. In addition, the comparison did not consider different patient postures of the Stanford technique. Including the different patient postures in the calculation may affect the result of doses to the limbs.

The emergence of the Halcyon linear accelerator has allowed for increased patient throughput and improved treatment times for common treatment sites in radiation oncology. However, it has been shown that this can lead to increased surface dose in sites like breast cancer compared with treatments on conventional machines with flattened radiation beams. Cherenkov imaging can be used to estimate surface dose by detection of Cherenkov photons emitted in proportion to energy deposition from high energy electrons in tissue. Phantom studies were performed with both square beams in reference conditions and with clinical treatments, and dosimeter readings and Cherenkov images report higher surface dose (25% for flat phantom entrance dose, 5.9% for breast phantom treatment) from Halcyon beam deliveries than for equivalent deliveries from a TrueBeam linac. Additionally, the first Cherenkov images of a patient treated with Halcyon were acquired, and superficial dose was estimated.

Photodynamic therapy (PDT) is an established modality for cancer treatment, and reactive oxygen species explicit dosimetry (ROSED), based on direct measurements of in-vivo light fluence (rate), in-vivo photofrin concentration, and tissue oxygenation concentration, has been proved to provide the best dosimetric quantity which can be used to predict non-fractionated PDT outcome. This study performed ROSED for Photofrin-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. As demonstrated by our previous study, fractionated PDT with a 2-hour time interval can significantly improve the long-term cure rate (from 15% to 65% at 90 days), and it tends to increase as the light dose for the first light fraction gets larger. This study focused on further improving the long-term cure rate without introducing apparent toxicity using combinations of different first light fraction lengths and total light fluences. Photofrin was injected through the mouse tail vein at a concentration of 5 mg/kg. After 18~24 hours, treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Mice were treated using two fractions of light fluences with a 2-hour dark interval. Different dose metrics were quantified, including light fluence, PDT dose, and [ROS]rx. In addition, the total reacted [ROS]rx and treatment outcomes were evaluated and compared to identify the optimal light fraction length and total light fluence.

We developed a simulation method for modeling the light fluence delivery in intracavity Photodynamic Therapy (icav-PDT) for pleural lung cancer using a moving light source. Due to the large surface area of the pleural lung cavity, the light source needs to be moved to deliver a uniform dose around the entire cavity. While multiple fixed detectors are used for dosimetry at a few locations, an accurate simulation of light fluence and fluence rate is still needed for the rest of the cavity. We extended an existing Monte Carlo (MC) based light propagation solver to support moving light sources by densely sampling the continuous light source trajectory and assigning the proper number of photon packages launched along the way. The performance of Simphotek GPU CUDA-based implementation of the method – PEDSy-MC – has been demonstrated on a life-size lung-shaped phantom, custom printed for testing icav-PDT navigation system at the Perlman School of Medicine (PSM) – calculations completed under a minute (for some cases) and within minutes have been achieved. We demonstrate results within a 5% error of the analytic solution for multiple detectors in the phantom. PEDSy-MC is accompanied by a dose-cavity visualization tool that allows real-time inspection of dose values of the treated cavity in 2D and 3D, which will be expanded to ongoing clinical trials at PSM. PSM has developed a technology to measure 8-detectors in a pleural cavity phantom using Photofrin-mediated PDT that has been used during validation.

Silicon phantom models have been utilized to calculate light fluence in patients being treated with Photodynamic Therapy (PDT). This application can be utilized for other non-ionizing wavelength therapies such as Photobiomodulation (PBM). We have developed a novel protocol to validate homogeneity for 3-dimensional silicon phantom models of the human maxilla. Accurately quantifying the light profiles of human tissue can accommodate for varying optical properties that occur between subjects. More importantly, this can help optimize light fluence dosimetry calculations to achieve intended results. Silicon models of identical composition were fabricated into two different shapes: 1 flat-planar cylindrical shaped model, 2) non-flat planar (3-dimensional) mold of the human maxilla. Fabricating homogenous silicon phantom models continues to be a challenge as micro-bubbles can contaminate the compound during the curing process. Integrating both proprietary CBCT and handheld surface acquisition imaging devices confirmed our results to be within 0.5mm of accuracy. This protocol was specifically used to cross-reference and validate homogeneity at various depths of penetration. These results present the first known successful validation of identical silicon tissue phantoms with a flat-planar surface vs. a non-flat 3D planar surface. This proof-of-concept phantom validation protocol is sensitive to the specific variations of 3-dimensional surfaces and can be applied to a workflow used to capture accurate light fluence calculations in the clinical setting.

Dosimetry for photodynamic therapy is dependent on multiple parameters. Critically, in vivo tissue optical properties and hemodynamics must be determined carefully to calculate the total delivered light dose.Spectroscopic analysis of diffuse reflectance measurements of tissues taken during a clinical trial of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a-mediated photodynamic therapy for pleural malignancies.Diffuse reflectance measurements were taken immediately before and after photodynamic therapy. Measurements were analyzed with a nonlinearly constrained multiwavelength, multi-distance algorithm to extract tissue optical properties, tissue oxygen saturation, StO2, and total hemoglobin concentration (THC).A total of 25 patients were measured, 23 of which produced reliable fits for optical property extraction. For all tissue types, StO2 ranged through [24, 100]% and [22, 97]% for pre-photodynamic therapy (PDT) and post-PDT conditions, respectively. Mean THC ranged through [ 69,152 ] μM and [ 48,111 ] μM, for pre-PDT and post-PDT, respectively. Absorption coefficients, μa, ranged through [ 0.024 , 3.5 ] cm - 1 and [ 0.039 , 3 ] cm - 1 for pre-PDT and post-PDT conditions, respectively. Reduced scattering coefficients, μs', ranged through [ 1.4 , 73.4 ] cm - 1 and [ 1.2 , 64 ] cm - 1 for pre-PDT and post-PDT conditions, respectively.There were similar pre- and post-PDT tissue optical properties and hemodynamics. The high variability in each parameter for all tissue types emphasizes the importance of these measurements for accurate PDT dosimetry.

PDT dose is the product of the photosensitizer concentration and the light fluence in the target tissue. For improved dosimetry during plural photodynamic therapy (PDT), an eight-channel PDT dose dosimeter was developed to measure both the light fluence and the photosensitizer concentration simultaneously from eight different sites in the pleural cavity during PDT. An isotropic detector with bifurcated fibers was used for each channel to ensure detected light was split equally to the photodiode and spectrometer. The light fluence rate distribution is monitored using an IR navigation system. The navigation system allows 2D light fluence mapping throughout the whole pleural cavity rather than just the selected points. The fluorescence signal is normalized by the light fluence measured at treatment wavelength. We have shown that the absolute photosensitizer concentration can be obtained by applying optical properties correction and linear spectral fitting to the measured fluorescence data. The detection limit and the optical property correction factor of each channel were determined and validated using tissue-simulating phantoms with known varying concentration of Photofrin. Tissue optical properties are determined using an absorption spectroscopy probe immediately before PDT at the same sites. The combination of 8-channel PDT dosimeter system and IR navigation system, which can calculate light fluence rate in the pleural cavity in real-time, providing a mean to determine the distribution of PDT dose on the entire pleural cavity to investigate the heterogeneity of PDT dose on the pleural cavity.

Photodynamic therapy (PDT) is an established modality for cancer treatment and reactive oxygen species explicit dosimetry (ROSED), based on direct measurements of in-vivo light fluence (rate), in-vivo photofrin concentration, and tissue oxygenation concentration, has been proved to be an effective dosimetric quantity which can be used to predict PDT outcome. In this study, ROSED was performed for photofrin-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. PDT treatments were performed using single or fractionated illumination to a same total fluence of 135 Jcm(−2). The effects of light fractionation on the total reacted [ROS](rx) and treatment outcomes were evaluated.

Accurate dosimetry is crucial for the ongoing development and clinical study of photodynamic therapy (PDT). Current dosimetry standards range from less accurate methods involving measurement of only light fluence and photosensitizer concentration during treatment, to significantly improved methods such as singlet oxygen explicit dosimetry (SOED), a macroscopic model that includes an additional important parameter in its dosimetric calculations: ground-state oxygen concentration ([(3)O(2)]). However, neither of these models is a method of direct dosimetry. Multispectral singlet oxygen luminescence dosimetry (MSOLD) shows promise in this regard but requires significant improvement in signal quality and remains to be validated in a clinical setting. In this study, we validate a linearly increasing MSOLD signal with an InGaAs photodiode detector for increasing concentration (0 mg/kg to 200 mg/kg) in tissue-simulating phantoms containing photofrin, calculating a calibration curve based on 1270 nm peak-intensity signal and area under the curve for background-subtracted singlet oxygen emission. Additionally, we validate MSOLD against the current clinical dosimetry standard, SOED, through simultaneous measurement of SOED parameters and MSOLD signal for varying concentrations (50 μM – 300 μM). Finally, we investigate the effects of using very high gain amplification on InGaAs photodiode detectors to amplify the MSOLD signal for use in clinical models. We show that a calibration curve relating photosensitizer concentration (PS) and MSOLD signal can be established. Additionally, we demonstrate good correlation between MSOLD signal and SOED-calculated [(1)O(2)](rx). However, we show that when using high amplification on InGaAs photodiodes for long illumination times, the inherent instability in these detectors becomes apparent.

The distributions of light and tissue oxygenation (St O2 ) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment-averaged fluence rate was similar among sites, ranging from a median of 40-61 mW cm-2 during periods of light exposure to a detector. St O2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median St O2 >90%; interquartile ranges ~85-95%). PDT effect on St O2 was characterized as the St O2 ratio (post-PDT St O2 /pre-PDT St O2 ). High St O2 pre-PDT was significantly associated with oxygen depletion (St O2 ratio < 1), although the extent of oxygen depletion was mild (median St O2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment-averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre-PDT St O2 , which may suggest the presence of a treatment effect.

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcomes. However, current practice when delivering intrapleural PDT uses a point source to deliver light that is monitored by seven isotropic detectors placed within the pleural cavity to assess its uniformity. We have developed a real-time infrared (IR) tracking camera to follow the movement of the light point source and the surface contour of the treatment area. The calculated light fluence rates were matched with isotropic detectors using a two-correction factor method and an empirical model that includes both direct and scattered light components. Our clinical trial demonstrated that we can successfully implement the IR navigation system in 75% (15/20) of the patients. Data were successfully analyzed in 80% (12/15) patients because detector locations were not available for three patients. We conclude that it is feasible to use an IR camera-based system to track the motion of the light source during PDT and demonstrate its use to quantify the uniformity of light distribution, which deviated by a standard deviation of 18% from the prescribed light dose. The navigation system will fail when insufficient percentage of light source positions is obtained (

Background Total skin electron therapy (TSET) utilizes high-energy electrons to treat malignancies on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interactions between the high-energy electron beam and tissue. Methods and materials With a time-gated intensified camera system, the Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real time. Fifteen patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. Each patient was monitored during TSET via in vivo detectors (IVD) in nine locations. For accurate Cherenkov imaging, a comparison between IVD and Cherenkov profiles was conducted using a polyvinyl chloride board to establish the perspective corrections. Results and discussion With proper corrections developed in this study including the perspective and inverse square corrections, the Cherenkov imaging provided two-dimensional maps proportional to dose and projected on patient skin. The results of ratio between chest and umbilicus points were in good agreement with in vivo point dose measurements, with a standard deviation of 2.4% compared to OSLD measurements. Conclusions Cherenkov imaging is a viable tool for validating patient-specific dose distributions during TSET.

Independent verification of the dose per monitor unit (MU) to deliver the prescribed dose to a patient has been a mainstay of radiation oncology quality assurance. We discuss the role of secondary dose/MU calculation programs as part of a comprehensive Quality Assurance (QA) program. This report provides guidelines on calculation-based dose/MU verification for intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) provided by various modalities. We provide a review of various algorithms for "independent/second check" of monitor unit calculations for IMRT/VMAT. The report makes recommendations on the clinical implementation of secondary dose/MU calculation programs; on commissioning and acceptance of various commercially available secondary dose/MU calculation programs; on benchmark QA and periodic quality assurance; and on clinically reasonable action levels for agreement of secondary dose/MU calculation programs.

Tissue optical properties are crucial for determining the light dose delivered to the tumor. Two probes are compared: the two-catheter probe is based on transmittance measurement between one point source and one isotropic detector inside parallel catheters spaced at 0.5 cm along a 1-inch diameter transparent cylinder; and a 1-inch trans-rectal diffuse optical tomography (DOT) probe designed for prostate measurements, using a multiple fiber-array with source-detector separations of 1.4–10 mm. The two-catheter probe uses an empirical model for primary and scatter light fluence rates in the cylindrical cavity condition for anal PDT to determine optical properties along the source catheter using dual motors to move the source and detector along the catheters. The DOT probe uses finite element method (FEM) to obtain distribution of optical properties in 3D. Validations for the two probes were performed in liquid and solid phantoms. For each method, validation was performed in tissue-mimicking liquid phantoms for a range of known optical properties (μ(a) between 0.05 and 0.9 cm(−1) and μ(s)’ between 5.5 and 16.5 cm(−1)). To cross-check the two methods, solid phantoms were created of known optical properties at the University of Pennsylvania and sent for measurement to Princess Margaret Cancer Centre (PMH) to mimic realistic patient simulating conditions. Measurements were taken and optical properties were then recovered without knowing the expected values to cross-validate each probe. The results show modest agreement between the measured μ(a) and μ(s)’values, but high degree of agreement between the measured μ(eff) performed independently using the two methods.

PDT efficacy depends on the availability and dynamic interactions of photosensitizer, light, and oxygen. Tissue optical properties influence the delivered light dose and impact PDT outcome. In-vivo measurements of tissue optical properties and photosensitizer concentration enable determination of explicit and implicit dose factors affecting PDT and helps to understand the underlying biophysical mechanism of PDT. In this study, we measure tissue optical properties (absorption μ(a) (λ) and scattering μ(s)’ (λ) coefficients) and PpIX concentration in tissue simulating liquid phantoms with a geometry that resembles anal canal. In-vivo light fluence rate and photosensitizer fluorescence of 405nm excitation light source were acquired using a dual-motor continuous wave transmittance spectroscopy system. We characterized the tissue optical properties correction factor of fluorescence signal using a series of tissue simulating phantoms with known PpIX concentrations and with absorption coefficient between 0.1 – 0.9 cm(−1) and reduced scattering coefficient between 5 – 40 cm(−1). The results demonstrated that our spectroscopy system could determine the distribution of tissue optical properties and PPIX concentration during anal PDT.

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real-time using a time-gated intensified camera system. Each patient was monitored during TSET by in-vivo detectors (IVD) as well as Scintillators. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. A rigorous methodology for converting Cherenkov intensity to surface dose as products of correction factors, including camera vignette correction factor, incident radiation correction factor, and tissue optical properties correction factor. A comprehensive study has been carried out by inspecting various positions on the patients such as vertex, chest, perineum, shins, and foot relative to the umbilicus point (the prescription point).

Photosensitizer fluorescence emission during photodynamic therapy (PDT) can be used to estimate for in vivo photosensitizer concentration. We built a surface contact probe with 405nm excitation light source to obtain Photofrin fluorescence signal during clinical PDT. The probe was equipped with multiple detector fibers that were located at distances between 0.14 to 0.87 cm laterally from the excitation source fiber. In this study, we investigated the probing depth of fluorescence in biological tissue with different source-detector separation using our contact probe setup. We used Monte Carlo method to simulate the 405nm excitation light and 630nm fluorescence probing depth at various source and detector (SD) separations. The results provided insight to the most probable depth of origin of detected fluorescence at each SD separation and help to understand the in vivo depth distribution of clinically measured Photofrin concentration.

Malignant tissues can be effectively treated by Total Skin Electron Therapy (TSET) over the entire body surface using 6 MeV electron beams. During the radiation treatment, Cherenkov photons are emitted from the patient's skin, and can potentially be used for in-vivo imaging of the radiation dose distribution. A Monte Carlo (MC) simulation toolkit TOPAS is used to study the generation and propagation of Cherenkov photons that are generated from the interaction of electron radiation with human tissues, and to understand the relationship between the dose distributions and the Cherenkov photon distributions. Validation of MC simulations with experiments are performed at 100 SSD and 500 SSD, and simulations of a patient phantom in realistic clinical treatment setups have been done. These simulations with TOPAS show that the emitted Cherenkov distributions at phantom surfaces closely follow their corresponding dose distributions.

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.

Reactive oxygen species explicit dosimetry (ROSED) has been recently developed and demonstrated to be able to better correlate with treatment outcome in both preclinical type I and type II PDT. ROSED involves direct measurements of in-vivo light fluence (rate), in-vivo photosensitizer concentration and tissue oxygenation to calculate for reacted ROS concentration ([ROS]rx) generated by PDT processes. In this study, we demonstrated ROSED in ALA-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. PDT treatments were performed using single or fractionated illumination to a same total fluence of 140Jcm-2. The effects of light fractionation on the total reacted [ROS]rx and treatment outcomes were evaluated.

Determination of in-vivo tissue optical properties for anal photodynamic therapy (PDT) is challenging due to the light integrating-sphere effect in an enclosed cylindrical cavity. We developed a model for optical properties determination for anal PDT from measurements of light fluence rate inside a cylindrical cavity submerged in tissue-mimicking liquid phantoms. Measurements are performed in a set of phantoms with known optical properties (μa = 0.1-0.9 cm-1) and (μs’ = 6.65-19.95 cm-1) and the primary and scatter light fluence rates are determined. We developed an analytical expression to relate scatter light fluence rate measured in an enclosed cylindrical geometry to the surrounding tissue optical properties in tissue-simulating liquid phantoms. In addition, the accuracy of determining tissue optical properties using the model was evaluated by comparing the recovered optical properties to the known optical properties of a series of independent test phantoms.

Pleural photodynamic therapy (PDT) is performed intraoperatively for the treatment of microscopic disease in patients with malignant pleural mesothelioma. Accurate delivery of light dose is critical to PDT efficiency. As a standard of care, light fluence is delivered to the prescribed fluence using eight isotropic detectors in pre-determined discrete locations inside the pleural cavity that is filled with a dilute Intralipid solution. An optical infrared (IR) navigation system was used to monitor reflective passive markers on a modified and improved treatment delivery wand to track the position of the light source within the treatment cavity during light delivery. This information was used to calculate the light dose, incorporating a constant scattered light dose and using a dual correction method. Calculation methods were extensively compared for eight detector locations and seven patient case studies. The light fluence uniformity was also quantified by representing the unraveled three-dimensional geometry on a two-dimensional plane. Calculated light fluence at the end of treatment delivery was compared to measured values from isotropic detectors. Using a constant scattered dose for all detector locations along with a dual correction method, the difference between calculated and measured values for each detector was within 15%. Primary light dose alone does not fully account for the light delivered inside the cavity. This is useful in determining the light dose delivered to areas of the pleural cavity between detector locations, and can serve to improve treatment delivery with implementation in real-time in the surgical setting. We concluded that the standard deviation of light fluence uniformity for this method of pleural PDT is 10%.

This chapter is intended to help make inroads to the role of Intralipid in photodynamic therapy (PDT). In addition to Intralipid's favorable property as a light scattering agent, we hypothesized that it will be unstable to photosensitized oxidation. To explore this, measurements of total quenching rate constants (kT) of singlet oxygen with Intralipid and its constituents are described. Furthermore, organic phosphines were tested to trap Intralipid peroxides formed in photosensitized oxidation reactions. Our findings indicate that the vulnerability of Intralipid to photooxidation might suggest limits of its use in PDT.

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (ϕ) effects, which impact the photochemical oxygen consumption rate, are not accounted for. In this preclinical study, reacted reactive oxygen species ([ROS]rx) was investigated as a dosimetric quantity for PDT outcome. The ability of [ROS]rx to predict the cure index (CI) of tumor growth, CI = 1 − k / k ctr, where k and k ctr are the growth rate of tumor under PDT study and the control tumor without PDT, respectively, for benzoporphyrin derivative (BPD)-mediated PDT, was examined. Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (Φ = 22.5 to 166.7 J / cm2) and in-air fluence rates (ϕair = 75 to 250 mW / cm2) with a BPD dose of 1 mg / kg and a drug-light interval (DLI) of 15 min. Treatment was delivered with a collimated laser beam of 1-cm-diameter at 690 nm. Explicit measurements of in-air light fluence rate, tissue oxygen concentration, and BPD concentration were used to calculate for [ROS]rx. Light fluence rate at 3-mm depth (ϕ3 mm), determined based on Monte-Carlo simulations, was used in the calculation of [ROS]rx at the base of tumor. CI was used as an endpoint for three dose metrics: light fluence, PDT dose, and [ROS]rx. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ3 mm. Preliminary studies show that [ROS]rx best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome. The threshold dose for [ROS]rx for vascular BPD-mediated PDT using DLI of 15 min is determined to be 0.26 mM and is about 3.8 times smaller than the corresponding value for conventional BPD-mediated PDT using DLI of 3 h.

Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intra-operatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5×10(9) μMs/cm(2) to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intra-patient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J/cm(2) was prescribed to all patients.

As part of a preclinical trial for the treatment of peritoneal carcinomatosis (PC) with photodynamic therapy (PDT), we have assessed changes in optical properties, tissue oxygenation and drug concentration as a result of benzoporphyrin derivative (BPD)-mediated PDT using diffuse reflectance and fluorescence measurements. PDT can effectively treat superficial disease spread, but treatment efficacy is influenced by physical properties of the treated tissue which can change over the treatment time. In this study, healthy canines were given BPD and irradiated with 690 nm light during a partial bowel resection, and spectroscopic and fluorescence measurements were made using an in-house built spectroscopic probe. Hemoglobin concentration, oxygenation and optical properties were determined to be highly heterogeneous between canines and at different anatomical locations within the same subject, so further development of PDT dosimetry systems will need to address this patient and location-specific dose optimization. Compared to other photosensitizers, we found no apparent BPD photobleaching after PDT.

The distributions of light and tissue oxygenation (S

Uniform delivery of light fluence is an important goal for photodynamic therapy. We present summary results for an infrared (IR) navigation system to deliver light dose uniformly during intracavitory PDT by tracking the movement of the light source and providing real-time feedback on the light fluence rate on the entire cavity surface area. In the current intrapleural PDT protocol, 8 detectors placed in selected locations in the pleural cavity monitor the light doses. To improve the delivery of light dose uniformity, an IR camera system is used to track the motion of the light source as well as the surface contour of the pleural cavity. A MATLAB-based GUI program is developed to display the light dose in real-time during PDT to guide the PDT treatment delivery to improve the uniformity of the light dose. We have developed an improved model for direct light calculation that accounts for the anisotropy of the light from the light sources. A comprehensive analysis of the distribution of light fluence during HPPH and Photofrin PDT is presented in clinical cases and the improvements between the two protocol are discussed.

Determination of in-vivo tissue optical properties for anal photodynamic therapy (PDT) is challenging due to the light integrating-sphere effect in an enclosed cylindrical cavity. We developed a model for optical properties determination for anal PDT from measurements of light fluence rate inside a cylindrical cavity submerged in tissue-mimicking liquid phantoms. Measurements are performed in a set of phantoms with known optical properties (μa = 0.1-0.9 cm-1) and (μs’ = 5.5-16.5 cm-1) and the primary and scatter light fluence rates are determined. We developed a forward empirical model to relate scatter light fluence rate measured in an enclosed cylindrical geometry to the surrounding tissue optical properties in tissue-simulating liquid phantoms.

Background We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (StO2) and blood volume (tHb) were studied for associations with patient outcomes. Methods PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion StO2 and tHb was measured. Results Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but StO2 was higher in patients with CR. In tongue/FOM lesions, baseline StO2 [mean(SE)] was 54(4)% in patients (n = 12) with CR versus 23(8)% in patients (n = 6) with local recurrence/persistence (p = 0.01). Similarly, for intact disease, baseline StO2 was 54(3)% in patients (n = 10) with CR versus 28(8)% in patients (n = 5) without CR (p = 0.03). In patients with intact disease, higher baseline StO2 associated with 24-month local control (p = 0.02). Conclusions Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT.

Intralipid is a lipid emulsion used in photodynamic therapy (PDT) for its light scattering and tissue-simulating properties. The purpose of this study is to determine whether or not Intralipid undergoes photooxidation, we have carried out an Intralipid peroxide trapping study using a series of phosphines [2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 3-(diphenylphosphino)benzenesulfonate, triphenylphosphine-3,3′,3′′-trisulfonate, and triphenylphosphine]. Our new findings are as follows: (i) An oxygen atom is transferred from Intralipid peroxide to the phosphine traps in the dark, after the photooxidation of Intralipid. 3-(Diphenylphosphino)benzenesulfonate is the most suitable trap in the series owing to a balance of nucleophilicity and water solubility. (ii) Phosphine trapping and monitoring by 31P NMR is effective in quantifying the peroxides in H2O. An advantage of the technique is that peroxides are detected in H2O; deuterated NMR solvents are not required. (iii) The percent yield of the peroxides increased linearly with the increase in fluence from 45 to 180 J cm−2 based on our trapping experiments. (iv) The photooxidation yields quantitated by the phosphines and 31P NMR are supported by the direct 1H NMR detection using deuterated NMR solvents. These data provide the first steps in the development of Intralipid peroxide quantitation after PDT using phosphine trapping and 31P NMR spectroscopy. This article is protected by copyright. All rights reserved.

Purpose Photodynamic therapy (PDT) is used after surgical resection to treat the microscopic disease for malignant pleural mesothelioma and to increase survival rates. As accurate light delivery is imperative to PDT efficacy, the deformation of the pleural volume during the surgery is studied on its impact on the delivered light fluence. In this study, a three-dimensional finite element-based (3D FEM) deformable image registration is proposed to directly match the volume of lung to the volume of pleural cavity obtained during PDT to have accurate representation of the light fluence accumulated in the lung, heart and liver (organs-at-risk) during treatment. Methods A wand, comprised of a modified endotrachial tube filled with Intralipid and an optical fiber inside the tube, is used to deliver the treatment light. The position of the treatment is tracked using an optical tracking system with an attachment comprised of nine reflective passive markers that are seen by an infrared camera-based navigation system. This information is used to obtain the surface contours of the plural cavity and the cumulative light fluence on every point of the cavity surface that is being treated. The lung, heart, and liver geometry are also reconstructed from a series of computed tomography (CT) scans of the organs acquired in the same patient before and after the surgery. The contours obtained with the optical tracking system and CTs are imported into COMSOL Multiphysics, where the 3D FEM-based deformable image registration is obtained. The delivered fluence values are assigned to the respective positions (x, y, and z) on the optical tracking contour. The optical tracking contour is considered as the reference, and the CT contours are used as the target, which will be deformed. The data from three patients formed the basis for this study. Results The physical correspondence between the CT and optical tracking geometries, taken at different times, from different imaging devices was established using the 3D FEM-based image deformable registration. The volume of lung was matched to the volume of pleural cavity and the distribution of light fluence on the surface of the heart, liver and deformed lung volumes was obtained. Conclusion The method used is appropriate for analyzing problems over complicated domains, such as when the domain changes (as in a solid-state reaction with a moving boundary), when the desired precision varies over the entire domain, or when the solution lacks smoothness. Implementing this method in real-time for clinical applications and in situ monitoring of the under- or over- exposed regions to light during PDT can significantly improve the treatment for mesothelioma.

Purpose The purpose of this study was to evaluate dose prescription and recording compliance to international standard (International Commission on Radiation Units & Measurements [ICRU]-83) in patients treated with intensity modulated radiation therapy (IMRT) among academic institutions. Methods and materials Ten institutions participated in this study to collect IMRT data to evaluate compliance to ICRU-83. Under institutional review board clearance, data from 5094 patients—including treatment site, technique, planner, physician, prescribed dose, target volume, monitor units, planning system, and dose calculation algorithm—were collected anonymously. The dose-volume histogram of each patient, as well as dose points, doses delivered to 100% (D100), 98% (D98), 95% (D95), 50% (D50), and 2% (D2), of sites was collected and sent to a central location for analysis. Homogeneity index (HI) as a measure of the steepness of target and is a measure of the shape of the dose-volume histogram was calculated for every patient and analyzed. Results In general, ICRU recommendations for naming the target, reporting dose prescription, and achieving desired levels of dose to target were relatively poor. The nomenclature for the target in the dose prescription had large variations, having every permutation of name and number contrary to ICRU recommendations. There was statistically significant variability in D95, D50, and HI among institutions, tumor site, and technique with P values Conclusions Nearly 95% of patient treatments deviated from the ICRU-83 recommended D50 prescription dose delivery. This variability is significant (P

Photodynamic therapy (PDT) is an effective non-ionizing treatment modality that is currently being used for various malignant and non-malignant diseases. In type II PDT with photosensitizers such as benzoporphyrin monoacid ring A (BPD), cell death is based on the creation of singlet oxygen ( 1 O 2 ). With a previously proposed empirical five-parameter macroscopic model, the threshold dose of singlet oxygen ([ 1 O 2 ] rx,sh ]) to cause tissue necrosis in tumors treated with PDT was determined along with a range of the magnitude of the relevant photochemical parameters: the photochemical oxygen consumption rate per light fluence rate and photosensitizer concentration ( ξ ), the probability ratio of 1 O 2 to react with ground state photosensitizer compared to a cellular target ( σ ), the ratio of the monomolecular decay rate of the triplet state photosensitizer ( β ), the low photosensitizer concentration correction factor ( δ ), and the macroscopic maximum oxygen supply rate ( g ). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated interstitially with a linear light source at 690 nm with total energy released per unit length of 22.5–135 J/cm and source power per unit length of 12–150 mW/cm to induce different radii of necrosis. A fitting algorithm was developed to determine the photochemical parameters by minimizing the error function involving the range between the calculated reacted singlet oxygen ([ 1 O 2 ] rx ) at necrosis radius and the [ 1 O 2 ] rx,sh . [ 1 O 2 ] rx was calculated based on explicit dosimetry of the light fluence distribution, the tissue optical properties, and the BPD concentration. The initial ground state oxygen concentration ([ 3 O 2 ] 0 ) was set to be 40 μM in this study. The photochemical parameters were found to be ξ = (55 ± 40) × 10 − 3 cm 2 mW − 1 s − 1 , σ = (1.8 ± 3) × 10 − 5 μM − 1 , and g = 1.7 ± 0.7 μM s − 1 . We have taken the literature values for δ = 33 μM, and β = 11.9 μM. [ 1 O 2 ] rx has shown promise to be a more effective dosimetry quantity for predicting necrosis than either light dose or PDT dose, where the latter is simplistically a temporal integral of the products of the photosensitizer concentration and light fluence rate.

Purpose Proton radiography (PR) and proton computed tomography (PCT) can be used to measure proton stopping power directly. However, practical and cost effective proton imaging detectors are not widely available. In this study, the authors investigated the feasibility of proton imaging using a silicon diode array. Methods A one-dimensional silicon diode detector array (1DSDA) was aligned with the central axis (CAX) of the proton beam. Polymethyl methacrylate (PMMA) slabs were used to find the correspondence between the water equivalent thickness (WET) and 1DSDA channel number. Two-dimensional proton radiographs were obtained by translation and rotation of a phantom relative to CAX while the proton nozzle and 1DSDA were kept stationary. A PCT image of one slice of the phantom was reconstructed using filtered backprojection. Results PR and PCT images of the PMMA cube were successfully acquired using the 1DSDA. The WET of the phantom was measured using PR data. The resolution and maximum error in WET measurement are 2.0 and 1.5 mm, respectively. Structures down to 2.0 mm in size could be resolved completely. Reconstruction of a PCT image showed very good agreement with simulation. Limitations in spatial resolution are attributed to limited spatial sampling, beam collimation, and proton scatter. Conclusions The results demonstrate the feasibility of using silicon diode arrays for proton imaging. Such a device can potentially offer fast image acquisition and high spatial and energy resolution for PR and PCT.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to calculate reactive oxygen species concentration ([ROS](rx)) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Singlet oxygen is the primary cytotoxic species for ROS, which is responsible for cell death in type II PDT, although other type I ROS is included in the parameters used in our model. Using a combination of fluences (50–250 J/cm(2)) and ϕ (50 – 150 mW/cm(2)), tumor regrowth rate, k, was determined for each condition by fitting the tumor volume vs. time to V(0)*exp(k*t). Treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and Photofrin concentration was used to calculate [ROS](rx,cal). ϕ was determined for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Tissue oxygenation is measured using an oxylite oxygen probe to throughout the treatment to calculate the measured [ROS](rx,mea). Cure index, CI = 1-k/k(ctr), for tumor gowth up to 14 days were determined as an endpoint using five dose metrics: light fluence, PDT dose, and [ROS](rx,cal), and [ROS](rx,mea). PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. Preliminary studies show that [ROS](rx,mea) best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome.

In this study, we use Monte Carlo modelling to investigate the effect of tissue optical properties on Cherenkov emission detected from tissue surface. MC simulations are performed for wavelength between 400-1000nm and the values of absorption coefficient at each wavelength are determined based on the molar extinction coefficients of oxy- and deoxy-hemoglobin, with varying total haemoglobin concentration and tissue oxygen saturation of 70%. Tissue reduced scattering coefficient is approximated using μ(s)’(λ) = Aλ(−0.838). A range of clinically relevant tissue optical properties was investigated, with absorption coefficient between 0.1 and 1 cm(−1) and reduced scattering coefficient between 5 and 40 cm(−1) at 665nm. The angular distribution, depth of origins and the effect of tissue optical properties on Cherenkov emission on tissue surface are evaluated.

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (ϕ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted reactive oxygen species ([ROS]rx) was investigated as a dosimetric quantity for PDT outcome. We studied the ability of [ROS]rx to predict the cure index (CI) after PDT of murine tumors; CI = 1 - k/kctr, where k and kctr are the growth rate of PDT-treated and control(untreated) tumor, respectively. Mice bearing radiation induced fibrosarcoma (RIF) tumors were treated with BPD-mediated PDT at different in-air fluences (22.5, 40, 45, 50, 70 and 100 J/cm2) and in-air ϕ (75 and 150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 15 mins. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [ 1 O 2 ] rx . ϕ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. CI was used as an endpoint for four dose metrics: light fluence, PDT dose, and [ROS]rx. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. Preliminary studies show that [ROS]rx best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome. The threshold dose for [ROS]rx is determined to be 0.23 mM and is about 4.3 times smaller than the corresponding value for conventional BPD-mediated PDT using DLI of 3 hrs.

We compare previously reported benzoporphyrin derivative (BPD)-mediated photodynamic therapy (PDT) results for reactive singlet oxygen concentration (also called singlet oxygen dose) on mice with simulations using a computational device, Dosie™, that calculates light transport and photokinetics for PDT in near real-time. The two sets of results are consistent and validate the use of the device in PDT treatment planning to predict BPD-mediated PDT outcomes in mice animal studies based on singlet oxygen dose, which showed a much better correlation with the cure index than the conventional light dose.