Category: Publications

Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):251-9. doi: 10.1016/j.ijrobp.2009.08.041.

ABSTRACT

PURPOSE: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed.

METHODS AND MATERIALS: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively.

RESULTS: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line.

CONCLUSIONS: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

PMID:20005458 | PMC:PMC2902770 | DOI:10.1016/j.ijrobp.2009.08.041

Acad Radiol. 2010 Jan;17(1):7-17. doi: 10.1016/j.acra.2009.07.027. Epub 2009 Sep 30.

ABSTRACT

RATIONALE AND OBJECTIVES: Noninvasive molecular imaging of glioma tumor receptor activity was assessed with diagnostic in vivo fluorescence monitoring during targeted therapy. The study goals were to assess the range of use for treatment monitoring and stratification of tumor types using epidermal growth factor (EGF) receptor (EGFR) status with administration of fluorescently labeled EGF and determine its utility for tumor detection compared to magnetic resonance imaging (MRI).

MATERIALS AND METHODS: EGFR+ and EGFR- glioma tumor lines (human glioma [U251-GFP] and rat gliosarcoma [9L-GFP], respectively) were used to assess these goals, having a 20-fold difference between their EGF uptakes.

RESULTS: Treatment with cetuximab in the EGFR+ tumor-bearing animals led to decreased EGF tumor uptake, whereas for the EGFR- tumors, no change in fluorescence signal followed treatment. This diagnostic difference in EGFR expression could be used to stratify the tumor-bearing animals into groups of potential responders and nonresponders, and receiver-operating characteristic curve analysis revealed an area under the curve (AUC) of 0.92 in separating these tumors. The nonlocalized growth pattern of U251-GFP tumors resulted in detection difficulty on standard MRI, but high EGFR expression made them detectable by fluorescence imaging (AUC = 1.0). The EGFR+ U251-GFP tumor-bearing animals could be noninvasively stratified into treated and untreated groups on the basis of fluorescence intensity difference (P = .035, AUC = 0.90).

CONCLUSIONS: EGFR expression was tracked in vivo with fluorescence and determined to be of use for the stratification of EGFR+ and EGFR- tumors, the detection of EGFR+ tumors, and monitoring of molecular therapy.

PMID:19796971 | PMC:PMC2790554 | DOI:10.1016/j.acra.2009.07.027

J Biomed Opt. 2009 May-Jun;14(3):034034. doi: 10.1117/1.3155512.

ABSTRACT

An automated algorithm and methodology is presented to identify tumor-tissue morphologies based on broadband scatter data measured by raster scan imaging of the samples. A quasi-confocal reflectance imaging system was used to directly measure the tissue scatter reflectance in situ, and the spectrum was used to identify the scattering power, amplitude, and total wavelength-integrated intensity. Pancreatic tumor and normal samples were characterized using the instrument, and subtle changes in the scatter signal were encountered within regions of each sample. Discrimination between normal versus tumor tissue was readily performed using a K-nearest neighbor classifier algorithm. A similar approach worked for regions of tumor morphology when statistical preprocessing of the scattering parameters was included to create additional data features. This type of automated interpretation methodology can provide a tool for guiding surgical resection in areas where microscopy imaging cannot be realized efficiently by the surgeon. In addition, the results indicate important design changes for future systems.

PMID:19566327 | PMC:PMC2857335 | DOI:10.1117/1.3155512

J Biomed Opt. 2009 Jan-Feb;14(1):014004. doi: 10.1117/1.3065540.

ABSTRACT

Highly localized reflectance measurements can be used to directly quantify scatter changes in tissues. We present a microsampling approach that is used to raster scan tumors to extract parameters believed to be related to the tissue ultrastructure. A confocal reflectance imager was developed to examine scatter changes across pathologically distinct regions within tumor tissues. Tissue sections from two murine tumors, AsPC-1 pancreas tumor and the Mat-LyLu Dunning prostate tumor, were imaged. After imaging, histopathology-guided region-of-interest studies of the images allowed analysis of the variations in scattering resulting from differences in tissue ultra-structure. On average, the median scatter power of tumor cells with high proliferation index (HPI) was about 26% less compared to tumor cells with low proliferation index (LPI). Necrosis exhibited the lowest scatter power signature across all the tissue types considered, with about 55% lower median scatter power than LPI tumor cells. Additionally, the level and maturity of the tumor’s fibroplastic response was found to influence the scatter signal. This approach to scatter visualization of tissue ultrastructure in situ could provide a unique tool for guiding surgical resection, but this kind of interpretation into what the signal means relative to the pathology is required before proceeding to clinical studies.

PMID:19256692 | PMC:PMC2813673 | DOI:10.1117/1.3065540

J Biomed Opt. 2007 May-Jun;12(3):034025. doi: 10.1117/1.2750663.

ABSTRACT

Complete blood vessel occlusion is required for the treatment of age-related macular degeneration (AMD). AMD is the leading cause of blindness in developed countries and current treatment regimes have potential to cause collateral damage, or do not remove pre-existing unwanted vasculature. It has been proposed that two-photon excitation (TPE) photodynamic therapy (PDT) can be applied to cause local blood vessel occlusion without damaging surrounding retinal tissues. The in ovo chicken chorioallantoic membrane (CAM) is used as the model for vascularization in the wet form of AMD; novel techniques for the utilization of the CAM are reported. Complete occlusion of CAM vessels approximately 15 microm in diameter is achieved using the clinically approved photosensitizer Verteporfin (Visudyne, QLT, Incorporated, Vancouver, British Columbia, Canada) and TPE activation. The average and peak irradiances used for treatment are 3.3×10(6) Wcm(2) and 3.7×10(11) Wcm(2), respectively. A total fluence of 1.1×10(8) Jcm(2) is the dosage required for successful occlusion, and it is expected that for optimal conditions it will be much less. These results are the first proof-of-principle evidence in the literature that indicate TPE-PDT can be used to occlude small blood vessels. Further investigation will help determine the utility of TPE-PDT for treating wet AMD, perhaps through targeting feeder vessels.

PMID:17614733 | DOI:10.1117/1.2750663

Photochem Photobiol. 2006 Jan-Feb;82(1):152-7. doi: 10.1562/2005-05-28-RA-549.

ABSTRACT

Two-photon excitation photodynamic therapy (TPE-PDT) is being developed as an improved treatment for retinal diseases. TPE-PDT has advantages over one-photon PDT, including lower collateral damage to healthy tissue and more precise delivery of PDT. As with one-photon PDT, there can be local photochemical depletion of oxygen during TPE-PDT. Here, we investigate model systems and live cells to measure local photosensitizer photobleaching and through it, infer local oxygen consumption in therapeutic volumes of the order 1 microm3. Multilamellar vesicles (MLV) and African green monkey kidney (CV-1) cells were used to study the TPE photobleaching dynamics of the photosensitizer, Verteporfin. It was found that in an oxygen-rich environment, photobleaching kinetics could not be modeled using a mono-exponential function, whereas in hypoxic conditions a mono-exponential decay was adequate to represent photobleaching. A biexponential was found to adequately model the oxygen-rich conditions and it is hypothesized that the fast part of the decay is oxygen-dependent, whereas the slower rate constant is largely oxygen-independent. Photobleaching recovery studies in the CV-1 cells support this hypothesis.

PMID:16149861 | DOI:10.1562/2005-05-28-RA-549

J Biomed Opt. 2003 Jul;8(3):410-7. doi: 10.1117/1.1577117.

ABSTRACT

Two-photon excitation photodynamic therapy (TPE-PDT) is being investigated as a clinical treatment for age-related macular degeneration (AMD). TPE-PDT has the potential to provide a more specific and therefore advantageous therapy regime than traditional one-photon excitation PDT. The highly vascularized 8 to 9-day-old chicken chorioallantoic membrane (CAM) is used to model the rapid growth of blood vessels in the wet form of AMD. Using an ex ovo model system for the CAM, ablation studies were successful in mimicking the leaky vessels found in AMD. In addition, the distribution and localization of liposomal Verteporfin were investigated in order to characterize the photosensitizing drug in vivo. Localization of the photosensitizer appears to be greatest on the upper vessel wall, which indicates a potentially strong treatment locale for TPE-PDT.

PMID:12880346 | DOI:10.1117/1.1577117