Publications by authors named "Gal Shafirstein"

50 Publications

Photodynamic Therapy of Polymicrobial Biofilms Commonly Associated With Otitis Media.

Front Microbiol 2020 31;11:558482. Epub 2020 Aug 31.

Department of Microbiology and Immunology, Jacobs School of Medicine, University at Buffalo, State University of New York, Buffalo, NY, United States.

Otitis media (OM) is a prevalent pediatric infection characterized by painful inflammation of the middle ear. There are more than 700 million cases of OM diagnosed globally each year, with 50% of affected children under 5 years of age. Further, OM is the most common reason for children to receive antibiotic treatment in developed countries. The most recent work on this dynamic disease indicates that biofilms and polymicrobial infections play a role in recurrent OM and chronic OM, which are difficult to eradicate using standard antibiotic protocols. Antimicrobial photodynamic therapy (aPDT) is a promising new strategy for the treatment of resistant bacteria and persistent biofilms which lead to chronic infections. While PDT continues to be successfully used for oncological, dermatological, and dental applications, our work focuses on the efficacy of aPDT as it relates to otopathogens responsible for OM. Previous studies from our laboratory and others have shown that non-typeable and , the three most common otopathogens, are susceptible to different forms of aPDT. However, many cases of OM involve multiple bacteria and to date no one has investigated the efficacy of this technology on these complex polymicrobial biofilms. We treated polymicrobial biofilms of the three most common otopathogens with the photosensitizer Chlorin e6 (Ce6) and a continuous wave 405 ± 10 nm light emitted diode. Our data show significant bactericidal activity on polymicrobial biofilms associated with OM. These studies indicate that aPDT warrants further analysis as a possible treatment for OM and our results provide the foundation for future studies designed to identify the optimal aPDT parameters for polymicrobial biofilm-associated infections of the middle ear.
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http://dx.doi.org/10.3389/fmicb.2020.558482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487423PMC
August 2020

Antimicrobial Photodynamic Therapy with Chlorin e6 Is Bactericidal against Biofilms of the Primary Human Otopathogens.

mSphere 2020 07 15;5(4). Epub 2020 Jul 15.

Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York, USA

, , and nontypeable (NTHi) are ubiquitous upper respiratory opportunistic pathogens. Together, these three microbes are the most common causative bacterial agents of pediatric otitis media (OM) and have therefore been characterized as the primary human otopathogens. OM is the most prevalent bacterial infection in children and the primary reason for antibiotic administration in this population. Moreover, biofilm formation has been confirmed as a primary mechanism of chronic and recurrent OM disease. As bacterial biofilms are inherently metabolically recalcitrant to most antibiotics and these complex structures also present a significant challenge to the immune system, there is a clear need to identify novel antimicrobial approaches to treat OM infections. In this study, we evaluated the potential efficacy of antibacterial photodynamic therapy (aPDT) with the photosensitizer chlorin e6 (Ce6) against planktonic as well as biofilm-associated , , and NTHi. Our data indicate aPDT with Ce6 elicits significant bactericidal activity against both planktonic cultures and established biofilms formed by the three major otopathogens (with an efficacy of ≥99.9% loss of viability). Notably, the implementation of a novel, dual-treatment aPDT protocol resulted in this disinfectant effect on biofilm-associated bacteria and, importantly, inhibited bacterial regrowth 24 h posttreatment. Taken together, these data suggest this novel Ce6-aPDT treatment may be a powerful and innovative therapeutic strategy to effectively treat and eradicate bacterial OM infections and, significantly, prevent the development of recurrent disease. Otitis media (OM), or middle ear disease, is the most prevalent bacterial infection in children and the primary reason for antibiotic use and surgical intervention in the pediatric population. Biofilm formation by the major bacterial otopathogens, , , and nontypeable , has been shown to occur within the middle ears of OM patients and is a key factor in the development of recurrent disease, which may result in hearing impairment and developmental delays. Bacterial biofilms are inherently impervious to most antibiotics and present a significant challenge to the immune system. In this study, we demonstrate that antimicrobial photodynamic therapy (aPDT) using the photosensitizer chlorin e6 elicits significant bactericidal activity versus planktonic and biofilm-associated otopathogens and supports further analyses of this novel, efficacious, and promising technology as an adjunctive treatment for acute and recurrent OM.
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http://dx.doi.org/10.1128/mSphere.00492-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364218PMC
July 2020

TLD1433-Mediated Photodynamic Therapy with an Optical Surface Applicator in the Treatment of Lung Cancer Cells In Vitro.

Pharmaceuticals (Basel) 2020 Jun 28;13(7). Epub 2020 Jun 28.

Department of Cell Stress Biology, Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.

Intra-operative photodynamic therapy (IO-PDT) in combination with surgery for the treatment of non-small cell lung cancer and malignant pleural mesothelioma has shown promise in improving overall survival in patients. Here, we developed a PDT platform consisting of a ruthenium-based photosensitizer (TLD1433) activated by an optical surface applicator (OSA) for the management of residual disease. Human lung adenocarcinoma (A549) cell viability was assessed after treatment with TLD1433-mediated PDT illuminated with either 532- or 630-nm light with a micro-lens laser fiber. This TLD1433-mediated PDT induced an EC of 1.98 μM (J/cm) and 4807 μM (J/cm) for green and red light, respectively. Cells were then treated with 10 µM TLD1433 in a 96-well plate with the OSA using two 2-cm radial diffusers, each transmitted 532 nm light at 50 mW/cm for 278 s. Monte Carlo simulations of the surface light propagation from the OSA computed light fluence (J/cm) and irradiance (mW/cm) distribution. In regions where 100% loss in cell viability was measured, the simulations suggest that >20 J/cm of 532 nm was delivered. Our studies indicate that TLD1433-mediated PDT with the OSA and light simulations have the potential to become a platform for treatment planning for IO-PDT.
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http://dx.doi.org/10.3390/ph13070137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407920PMC
June 2020

Irradiance, Photofrin Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.

Photochem Photobiol 2020 03 18;96(2):397-404. Epub 2020 Feb 18.

Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center (Roswell Park), Buffalo, NY.

The objective of the present study was to develop a predictive model for Photofrin -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin at 5.0 or 6.6 mg kg , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm . In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm and fluence was 45 J cm . No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm .
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http://dx.doi.org/10.1111/php.13207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138700PMC
March 2020

An Optical Surface Applicator for Intraoperative Photodynamic Therapy.

Lasers Surg Med 2020 07 6;52(6):523-529. Epub 2019 Oct 6.

Department of Cell Stress Biology, Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center (Roswell Park), 665 Elm St., Buffalo, New York, 14203.

Background And Objectives: Intraoperative photodynamic therapy (IO-PDT) is typically administered by a handheld light source. This can result in uncontrolled distribution of light irradiance that impacts tissue and tumor response to photodynamic therapy. The objective of this work was to characterize a novel optical surface applicator (OSA) designed to administer controlled light irradiance in IO-PDT.

Study Design/materials And Methods: An OSA was constructed from a flexible silicone mesh applicator with multiple cylindrically diffusing optical fibers (CDF) placed into channels of the silicone. Light irradiance distribution, at 665 nm, was evaluated on the OSA surface and after passage through solid tissue-mimicking optical phantoms by measurements from a multi-channel dosimetry system. As a proof of concept, the light administration of the OSA was tested in a pilot study by conducting a feasibility and performance test with 665-nm laser light to activate 2-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) in the thoracic cavity of adult swine.

Results: At the OSA surface, the irradiance distribution was non-uniform, ranging from 128 to 346 mW/cm . However, in the tissue-mimicking phantoms, beam uniformity improved markedly, with irradiance ranges of 39-153, 33-87, and 12-28 mW/cm measured at phantom thicknesses of 3, 5, and 10 mm, respectively. The OSA safely delivered the prescribed light dose to the thoracic cavities of four swine.

Conclusions: The OSA can provide predictable light irradiances for administering a well-defined and potentially effective therapeutic light in IO-PDT. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131890PMC
July 2020

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer.

Br J Cancer 2018 11 24;119(10):1191-1199. Epub 2018 Oct 24.

Photodynamic Therapy Center, Roswell Park Comprehensive Cancer Center (Roswell Park), Buffalo, NY, USA.

Background: Currently delivered light dose (J/cm) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm) and associated heating on tumour response and cure.

Methods: Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry.

Results: In the mouse model, cure rates of 70-90% were obtained with I-PDT using 8.4-245 mW/cm and ≥45 J/cm in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin resulted in significantly (p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5-398 mW/cm and ≥45 J/cm in 100% of the tumour.

Conclusion: In Photofrin-mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.
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http://dx.doi.org/10.1038/s41416-018-0210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251027PMC
November 2018

A three-dimensional transient computational study of 532-nm laser thermal ablation in a geometrical model representing prostate tissue.

Int J Hyperthermia 2018 10;35(1):568-577. Epub 2018 Oct 10.

e Biomedical Engineering Department , University of Minnesota , Minneapolis , Minnesota, MN , USA.

Objective: Laser with 532-nm wavelength (GreenLight) is clinically approved to treat benign prostatic hyperplasia (BPH). However, low rate of tissue ablation and excessive thermal coagulation are shortcomings of this therapy. The goal of this study was to use a mathematical model to identify clinically viable laser settings that have the potential to improve treatment time and outcomes.

Methods: A three-dimensional transient computational model was developed, validated against analytical and experimental results, and utilized to investigate the response of tissues subjected to continuous-wave and pulsed lasers emitting 532-nm light (GreenLight laser). The impact of laser power (10-125 W), pulse duration (100 ns and 100 µs) and pulse frequency (10 and 100 Hz) on tissue ablation and coagulation rates and sizes was explored.

Results: Good agreement between the computational model and analytical and experimental results was found. Continuous-wave laser results in 13% less coagulation zone thickness and 10% higher ablation rate than the low frequency pulsed laser. With increasing laser power; ablation rate is expected to increase linearly, while coagulation zone thickness is expected to increase asymptotically. Pulse frequency influence on tissue ablation and coagulation is relevant at high power, but pulse duration is found to have minimal effect at all powers.

Conclusions: Laser thermal tissue ablation employing continuous wave mode lasers outperforms that employing pulsed mode lasers. Laser power settings should be carefully selected to maximize the rate of tissue ablation and minimize tissue coagulation.
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http://dx.doi.org/10.1080/02656736.2018.1512162DOI Listing
August 2019

Photodynamic therapy does not induce cyclobutane pyrimidine dimers in the presence of melanin.

Photodiagnosis Photodyn Ther 2018 Jun 24;22:241-244. Epub 2018 Apr 24.

Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, United States; Department of Dermatology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, United States. Electronic address:

Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive oxygen species (ROS). Cyclobutane pyrimidine dimers (CPDs) are the most important DNA changes responsible for ultraviolet (UV) carcinogenesis. Recently ROS induced by UVA were shown to generate CPDs via activating melanin. This raised the possibility that PDT induced ROS may also induce CPDs and mutagenesis in melanin containing cells. Previously the effect of PDT on CPDs in melanin containing cells has not been assessed. Our current work aimed to compare the generation of CPDs in melanin containing cells subjected to UVA treatment and porfimer sodium red light PDT. We used ELISA to detect CPDs. After UVA we found a dose dependent increase in CPDs in melanoma cells (B16-F10, MNT-1) with CPD levels peaking hours after discontinuation of UVA treatment. This indicated the generation of UVA induced dark-CPDs in the model. Nevertheless, PDT in biologically relevant doses was unable to induce CPDs. Our work provides evidence for the lack of CPD generation by PDT in melanin containing cells.
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http://dx.doi.org/10.1016/j.pdpdt.2018.04.018DOI Listing
June 2018

Reconstruction of a Deformed Tumor Based on Fiducial Marker Registration: A Computational Feasibility Study.

Technol Cancer Res Treat 2018 01;17:1533034618766792

1 Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.

Interstitial photodynamic therapy has shown promising results in the treatment of locally advanced head and neck cancer. In this therapy, systemic administration of a light-sensitive drug is followed by insertion of multiple laser fibers to illuminate the tumor and its margins. Image-based pretreatment planning is employed in order to deliver a sufficient light dose to the complex locally advanced head-and-neck cancer anatomy, in order to meet clinical requirements. Unfortunately, the tumor may deform between pretreatment imaging for the purpose of planning and intraoperative imaging when the plan is executed. Tumor deformation may result from the mechanical forces applied by the light fibers and variation of the patient's posture. Pretreatment planning is frequently done with the assistance of computed tomography or magnetic resonance imaging in an outpatient suite, while treatment monitoring and control typically uses ultrasound imaging due to considerations of costs and availability in the operation room. This article presents a computational method designed to bridge the gap between the 2 imaging events by taking a tumor geometry, reconstructed during preplanning, and by following the displacement of fiducial markers, which are initially placed during the preplanning procedure. The deformed tumor shape is predicted by solving an inverse problem, seeking for the forces that would have resulted in the corresponding fiducial marker displacements. The computational method is studied on spheres of variable sizes and demonstrated on computed tomography reconstructed locally advanced head and neck cancer model. Results of this study demonstrate an average error of less than 1 mm in predicting the deformed tumor shape, where 1 mm is typically the order of uncertainty in distance measurements using magnetic resonance imaging or computed tomography imaging and high-quality ultrasound imaging. This study further demonstrates that the deformed shape can be calculated in a few seconds, making the proposed method clinically relevant.
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http://dx.doi.org/10.1177/1533034618766792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909864PMC
January 2018

FOXQ1 controls the induced differentiation of melanocytic cells.

Cell Death Differ 2018 06 20;25(6):1040-1049. Epub 2018 Feb 20.

Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.

Oncogenic transcription factor FOXQ1 has been implicated in promotion of multiple transformed phenotypes in carcinoma cells. Recently, we have characterized FOXQ1 as a melanoma tumor suppressor that acts via repression of N-cadherin gene, and invasion and metastasis. Here we report that FOXQ1 induces differentiation in normal and transformed melanocytic cells at least partially via direct transcriptional activation of MITF gene, melanocytic lineage-specific regulator of differentiation. Importantly, we demonstrate that pigmentation induced in cultured melanocytic cells and in mice by activation of cAMP/CREB1 pathway depends in large part on FOXQ1. Moreover, our data reveal that FOXQ1 acts as a critical mediator of BRAF-dependent regulation of MITF levels, thus providing a novel link between two major signal transduction pathways controlling MITF and differentiation in melanocytic cells.
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http://dx.doi.org/10.1038/s41418-018-0066-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988681PMC
June 2018

Endobronchial ultrasound-guidance for interstitial photodynamic therapy of locally advanced lung cancer-a new interventional concept.

J Thorac Dis 2017 Aug;9(8):2613-2618

Department of Cell Stress Biology, Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, NY, USA.

Recent advances in interventional pulmonology led to a significant expansion of the diagnostic and therapeutic role of endobronchial ultrasound. In this paper, we describe a new concept for using endobronchial ultrasound to guide interstitial photodynamic therapy (PDT). For this purpose, we conducted in vitro and in vivo experiments using a phantom and animal models, respectively. A new 0.5 mm optical fiber, with cylindrical diffuser end, was used to deliver the therapeutic light through the 21-gauge endobronchial ultrasound needle. The animal experiments were performed under real-time ultrasonography guidance in mice and rabbits' tumor models. Safe and effective fiber placements and tumor illumination was accomplished. In addition, computer simulation of light propagation suggests that locally advanced lung cancer tumor can be illuminated. This study demonstrates the potential feasibility of this new therapeutic modality approach, justifying further investigation in the treatment of locally advanced lung cancers.
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http://dx.doi.org/10.21037/jtd.2017.07.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594182PMC
August 2017

Quantum dot light emitting devices for photomedical applications.

J Soc Inf Disp 2017 Mar 10;25(3):177-184. Epub 2017 Apr 10.

College of Optics and Photonics, University of Central Florida, Orlando, FL, USA., Nanoscience Technology Center, University of Central Florida, Orlando, FL, USA; Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, USA.

While OLEDs have struggled to find a niche lighting application that can fully take advantage of their unique form factors as thin, flexible, lightweight and uniformly large-area luminaire, photomedical researchers have been in search of low-cost, effective illumination devices with such form factors that could facilitate widespread clinical applications of photodynamic therapy (PDT) or photobiomodulation (PBM). Although existing OLEDs with either fluorescent or phosphorescent emitters cannot achieve the required high power density at the right wavelength windows for photomedicine, the recently developed ultrabright and efficient deep red quantum dot light emitting devices (QLEDs) can nicely fit into this niche. Here, we report for the first time the in-vitro study to demonstrate that this QLED-based photomedical approach could increase cell metabolism over control systems for PBM and kill cancerous cells efficiently for PDT. The perspective of developing wavelength-specific, flexible QLEDs for two critical photomedical fields (wound repair and cancer treatment) will be presented with their potential impacts summarized. The work promises to generate flexible QLED-based light sources that could enable the widespread use and clinical acceptance of photomedical strategies including PDT and PBM.
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http://dx.doi.org/10.1002/jsid.543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576728PMC
March 2017

Current state and future of photodynamic therapy for the treatment of head and neck squamous cell carcinoma.

World J Otorhinolaryngol Head Neck Surg 2016 Jun 1;2(2):126-129. Epub 2016 Jul 1.

Department of Head and Neck Surgery/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY, United States.

Photodynamic therapy has shown promise in the treatment of early head and neck squamous cell carcinoma (SCC). In photodynamic therapy (PDT), a light sensitive drug (photosensitizer) and visible light cause cancer cell death by the creation of singlet oxygen and free radicals, inciting an immune response, and vascular collapse. In this paper, we review several studies that demonstrate the effectiveness of PDT in the treatment of early stage SCC of the head and neck, with some showing a similar response rate to surgery. Two cases are presented to illustrate the effectiveness of PDT. Then, new advances are discussed including the discovery of STAT3 crosslinking as a potential biomarker for PDT response and interstitial PDT for locally advanced cancers.
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http://dx.doi.org/10.1016/j.wjorl.2016.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376070PMC
June 2016

Surface markers for guiding cylindrical diffuser fiber insertion in interstitial photodynamic therapy of head and neck cancer.

Lasers Surg Med 2017 08 10;49(6):599-608. Epub 2017 Feb 10.

Photodynamic Therapy Center, Roswell Park Cancer Institute (RPCI), Buffalo, New York.

Background And Objectives: Image-based treatment planning can be used to compute the delivered light dose during interstitial photodynamic therapy (I-PDT) of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The objectives of this work were to evaluate the use of surface fiducial markers and flexible adhesive grids in guiding interstitial placement of laser fibers, and to quantify the impact of discrepancies in fiber location on the expected light dose volume histograms (DVHs).

Methods: Seven gel-based phantoms were made to mimic geometries of LA-HNSCC. Clinical flexible grids and fiducial markers were used to guide the insertion of optically transparent catheters, which are used to place cylindrical diffuser fibers within the phantoms. A computed tomography (CT) was used to image the markers and phantoms before and after catheter insertion and to determine the difference between the planned and actual location of the catheters. A finite element method was utilized to compute the light DVHs. Statistical analysis was employed to evaluate the accuracy of fiber placement and to investigate the correlation between the location of the fibers and the calculated DVHs.

Results: There was a statistically significant difference (P = 0.018) between all seven phantoms in terms of the mean displacement. There was also statistically significant correlation between DVHs and depth of insertion (P = 0.0027), but not with the lateral displacement (P = 0.3043). The maximum difference between actual and planned DVH was related to the number of fibers (P = 0.0025) and the treatment time.

Conclusions: Surface markers and a flexible grid can be used to assist in the administration of a prescribed DVH within 15% of the target dose provided that the treatment fibers are placed within 1.3 cm of the planned depth of insertion in anatomies mimicking LA-HNSCC. The results suggest that the number of cylindrical diffuser fibers and treatment time can impact the delivered DVHs. Lasers Surg. Med. 49:599-608, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.22644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513772PMC
August 2017

Interstitial Photodynamic Therapy-A Focused Review.

Cancers (Basel) 2017 Jan 24;9(2). Epub 2017 Jan 24.

Simphotek, Inc., 211 Warren St, Newark, NJ 07103, USA.

Multiple clinical studies have shown that interstitial photodynamic therapy (I-PDT) is a promising modality in the treatment of locally-advanced cancerous tumors. However, the utilization of I-PDT has been limited to several centers. The objective of this focused review is to highlight the different approaches employed to administer I-PDT with photosensitizers that are either approved or in clinical studies for the treatment of prostate cancer, pancreatic cancer, head and neck cancer, and brain cancer. Our review suggests that I-PDT is a promising treatment in patients with large-volume or thick tumors. Image-based treatment planning and real-time dosimetry are required to optimize and further advance the utilization of I-PDT. In addition, pre- and post-imaging using computed tomography (CT) with contrast may be utilized to assess the response.
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http://dx.doi.org/10.3390/cancers9020012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332935PMC
January 2017

Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma.

J Biomed Opt 2016 Jan;21(1):18002

Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United StatesbWright State University, Department of Biomedical, Industrial and Human Factors Engineering, 207 Russ Center, Dayton, Ohio 45.

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http://dx.doi.org/10.1117/1.JBO.21.1.018002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996863PMC
January 2016

Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions.

Ann Am Thorac Soc 2016 Feb;13(2):265-75

3 Department of Thoracic Surgery.

Photodynamic therapy (PDT) is an established treatment modality for non-small cell lung cancer. Phototoxicity, the primary adverse event, is expected to be minimized with the introduction of new photosensitizers that have shown promising results in phase I and II clinical studies. Early-stage and superficial endobronchial lesions less than 1 cm in thickness can be effectively treated with external light sources. Thicker lesions and peripheral lesions may be amenable to interstitial PDT, where the light is delivered intratumorally. The addition of PDT to standard-of-care surgery and chemotherapy can improve survival and outcomes in patients with pleural disease. Intraoperative PDT has shown promise in the treatment of non-small cell lung cancer with pleural spread. Recent preclinical and clinical data suggest that PDT can increase antitumor immunity. Crosslinking of signal transducer and activator of transcription-3 molecules is a reliable biomarker to quantify the photoreaction induced by PDT. Randomized studies are required to test the prognosis value of this biomarker, obtain approval for the new photosensitizers, and test the potential efficacy of interstitial and intraoperative PDT in the treatment of patients with non-small cell lung cancer.
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http://dx.doi.org/10.1513/AnnalsATS.201509-650FRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015713PMC
February 2016

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

Head Neck 2016 04 29;38 Suppl 1:E377-83. Epub 2015 Jun 29.

Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York.

Background: The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses.

Methods: A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response.

Results: Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD.

Conclusion: HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016.
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http://dx.doi.org/10.1002/hed.24003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499022PMC
April 2016

A new finite element approach for near real-time simulation of light propagation in locally advanced head and neck tumors.

Lasers Surg Med 2015 Jan 5;47(1):60-7. Epub 2015 Jan 5.

Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York.

Background And Objectives: Several clinical studies suggest that interstitial photodynamic therapy (I-PDT) may benefit patients with locally advanced head and neck cancer (LAHNC). For I-PDT, the therapeutic light is delivered through optical fibers inserted into the target tumor. The complex anatomy of the head and neck requires careful planning of fiber insertions. Often the fibers' location and tumor optical properties may vary from the original plan therefore pretreatment planning needs near real-time updating to account for any changes. The purpose of this work was to develop a finite element analysis (FEA) approach for near real-time simulation of light propagation in LAHNC.

Methods: Our previously developed FEA for modeling light propagation in skin tissue was modified to simulate light propagation from interstitial optical fibers. The modified model was validated by comparing the calculations with measurements in a phantom mimicking tumor optical properties. We investigated the impact of mesh element size and growth rate on the computation time, and defined optimal settings for the FEA. We demonstrated how the optimized FEA can be used for simulating light propagation in two cases of LAHNC amenable to I-PDT, as proof-of-concept.

Results: The modified FEA was in agreement with the measurements (P = 0.0271). The optimal maximum mesh size and growth rate were 0.005-0.02 m and 2-2.5 m/m, respectively. Using these settings the computation time for simulating light propagation in LAHNC was reduced from 25.9 to 3.7 minutes in one case, and 10.1 to 4 minutes in another case. There were minor differences (1.62%, 1.13%) between the radiant exposures calculated with either mesh in both cases.

Conclusions: Our FEA approach can be used to model light propagation from diffused optical fibers in complex heterogeneous geometries representing LAHNC. There is a range of maximum element size (MES) and maximum element growth rate (MEGR) that can be used to minimize the computation time of the FEA to 4 minutes.
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http://dx.doi.org/10.1002/lsm.22313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304874PMC
January 2015

Molecular changes in bone marrow, tumor and serum after conductive ablation of murine 4T1 breast carcinoma.

Int J Oncol 2014 Feb 21;44(2):600-8. Epub 2013 Nov 21.

Department of Radiation Oncology, University of Arkansas for Medical Science, Little Rock, AR, USA.

Thermal ablation of solid tumors using conductive interstitial thermal therapy (CITT) produces coagulative necrosis in the center of ablation. Local changes in homeostasis for surviving tumor and systemic changes in circulation and distant organs must be understood and monitored in order to prevent tumor re-growth and metastasis. The purpose of this study was to use a mouse carcinoma model to evaluate molecular changes in the bone marrow and surviving tumor after CITT treatment by quantification of transcripts associated with cancer progression and hyperthermia, serum cytokines, stress proteins and the marrow/tumor cross-talk regulator stromal-derived factor 1. Analysis of 27 genes and 22 proteins with quantitative PCR, ELISA, immunoblotting and multiplex antibody assays revealed that the gene and protein expression in tissue and serum was significantly different between ablated and control mice. The transcripts of four genes (Cxcl12, Sele, Fgf2, Lifr) were significantly higher in the bone marrow of treated mice. Tumors surviving ablation showed significantly lower levels of the Lifr and Sele transcripts. Similarly, the majority of transcripts measured in tumors decreased with treatment. Surviving tumors also contained lower levels of SDF-1α and HIF-1α proteins whereas HSP27 and HSP70 were higher. Of 16 serum chemokines, IFNγ and GM-CSF levels were lower with treatment. These results indicate that CITT ablation causes molecular changes which may slow cancer cell proliferation. However, inhibition of HSP27 may be necessary to control aggressiveness of surviving cancer stem cells. The changes in bone marrow are suggestive of possible increased recruitment of circulatory cancer cells. Therefore, the possibility of heightened bone metastasis after thermal ablation needs to be further investigated and inhibition strategies developed, if warranted.
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http://dx.doi.org/10.3892/ijo.2013.2185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898720PMC
February 2014

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity.

Clin Cancer Res 2013 Dec 2;19(23):6605-13. Epub 2013 Oct 2.

Authors' Affiliations: Photodynamic Therapy Center at the Department of Cell Stress Biology, Departments of Head and Neck Surgery, Molecular and Cellular Biology, Biostatistics and Bioinformatics, Dentistry, and Pathology, Roswell Park Cancer Institute (RPCI), Buffalo, New York.

Purpose: The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction.

Experimental Design: Patients with histologically proven oral dysplasia, carcinoma in situ, or early-stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies used an HPPH dose of 4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of STAT3 were assessed as potential indicators of PDT effective reaction.

Results: Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and carcinoma in situ and 82% for squamous cell carcinomas (SCC) lesions at 140 J/cm(2). The responses in the carcinoma in situ/dysplasia cohort are not durable. The PDT-induced STAT3 cross-links is significantly higher (P = 0.0033) in SCC than in carcinoma in situ/dysplasia for all light doses.

Conclusion: HPPH-PDT is safe for the treatment of carcinoma in situ/dysplasia and early-stage cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to HPPH-PDT in comparison with premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT-mediated photoreaction.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911775PMC
December 2013

Hyperthermia-enhanced indocyanine green delivery for laser-induced thermal ablation of carcinomas.

Int J Hyperthermia 2013 Aug;29(5):474-9

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Purpose: Intravenous administration of indocyanine green (ICG) dye can effectively convert near-infrared (NIR) laser light into heat and enhance thermal injury of blood vessels; however, there is no selective uptake of ICG by the tumour compared to the other tissues, which impacts the therapeutic ratio of this strategy unless uptake can be selectively increased in tumour tissue. Here we investigated the use of local hyperthermia prior to intravenous ICG administration to enhance ICG uptake in tumour tissue, thereby enhancing laser thermal ablation of solid tumours.

Methods: Murine SCK breast or SCCVII head and neck tumours were treated with a 755-nm laser light either alone or with prior intravenous administration of 4 mg/kg ICG and/or local tumour hyperthermia at 42.5 °C for 60 min. Retention of ICG was quantified using a NIR animal imaging system. Treatment effects were assessed by growth delay and histology.

Results: ICG accumulation in the heated tumours was 1.23-fold greater on average compared to non-heated tumours, in both models. In SCK tumours, animals receiving either laser irradiation alone or in conjunction with ICG had a 1.86- or 3.91-fold increase in tumour growth delay, respectively. The addition of local hyperthermia before ICG injection resulted in complete regression of SCK tumours. Uptake of ICG increased in SCCVII tumours; however, little change in tumour growth delay was observed.

Conclusion: Using local hyperthermia may improve the delivery of ICG to the tumour and thereby increase the extent of laser thermal ablation of smaller superficial malignancies that can be effectively exposed to laser therapy.
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http://dx.doi.org/10.3109/02656736.2013.817615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901080PMC
August 2013

Adjuvant intraoperative photodynamic therapy in head and neck cancer.

JAMA Otolaryngol Head Neck Surg 2013 Jul;139(7):706-11

Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York, USA.

Importance: There is an immediate need to develop local intraoperative adjuvant treatment strategies to improve outcomes in patients with cancer who undergo head and neck surgery.

Objectives: To determine the safety of photodynamic therapy with 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) in combination with surgery in patients with head and neck squamous cell carcinoma.

Design, Setting, And Participants: Nonrandomized, single-arm, single-site, phase 1 study at a comprehensive cancer center among 16 adult patients (median age, 65 years) with biopsy-proved primary or recurrent resectable head and neck squamous cell carcinoma.

Interventions: Intravenous injection of HPPH (4.0 mg/m2), followed by activation with 665-nm laser light in the surgical bed immediately after tumor resection.

Main Outcomes And Measures: Adverse events and highest laser light dose.

Results: Fifteen patients received the full course of treatment, and 1 patient received HPPH without intraoperative laser light because of an unrelated myocardial infarction. Disease sites included larynx (7 patients), oral cavity (6 patients), skin (1 patient), ear canal (1 patient), and oropharynx (1 patient, who received HPPH only). The most frequent adverse events related to photodynamic therapy were mild to moderate edema (9 patients) and pain (3 patients). One patient developed a grade 3 fistula after salvage laryngectomy, and another patient developed a grade 3 wound infection and mandibular fracture. Phototoxicity reactions included 1 moderate photophobia and 2 mild to moderate skin burns (2 due to operating room spotlights and 1 due to the pulse oximeter). The highest laser light dose was 75 J/cm2.

Conclusions And Relevance: The adjuvant use of HPPH-photodynamic therapy and surgery for head and neck squamous cell carcinoma seems safe and deserves further study.

Trial Registration: clinicaltrials.gov Identifier: NCT00470496.
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http://dx.doi.org/10.1001/jamaoto.2013.3387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302749PMC
July 2013

The role of mathematical modelling in thermal medicine.

Int J Hyperthermia 2013 Jun;29(4):259-61

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http://dx.doi.org/10.3109/02656736.2013.800999DOI Listing
June 2013

Orthotopic VX rabbit tongue cancer model with FDG-PET and histologic characterization.

Head Neck 2013 Aug 18;35(8):1119-23. Epub 2012 Sep 18.

Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Background: We present our experience with the use of an immunocompetent medium-sized animal model of tongue cancer that may be suitable for imaging and surgical studies.

Methods: A New Zealand white rabbit model of tongue cancer was created by injecting a VX tumor cell suspension grown in culture into the tongue of our model. The tumor was examined 7 days following implantation by physical examination, photography, and (18) fluoro 2-deoxyglucose-positron emission tomography (FDG-PET). At 12 days postimplantation, the model was again studied as described above prior to euthanization, and then tongue excision and bilateral neck dissections were performed. All tissue was examined by histology.

Results: We confirmed a successful orthotopic tongue cancer model that resulted in cervical nodal metastases.

Conclusion: This model may be a useful model of orthotopic head and neck cancer for future surgical or imaging research.
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http://dx.doi.org/10.1002/hed.23105DOI Listing
August 2013

SonoKnife for ablation of neck tissue: in vivo verification of a computer layered medium model.

Int J Hyperthermia 2012 5;28(7):698-705. Epub 2012 Sep 5.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Purpose: This study aimed to determine which treatment parameters of the SonoKnife device can be used to safely and effectively perform non-invasive thermal ablation of subcutaneous tissue.

Methods: A three-dimensional computational layered medium model was constructed to simulate thermal ablation treatment of the SonoKnife device. The acoustic and thermal fields were calculated with the Fast Object-Oriented C++ Ultrasound-Simulator software and a finite difference code, respectively. Subcutaneous tissue was represented as layers of skin, fat and muscle. The simulations were conducted for ultrasound frequencies of 1 or 3.5 MHz. The thermal dose model was used to predict the size and location of the ablated regions. The computer simulations were verified by using the SonoKnife to perform subcutaneous ablations in the neck area of healthy pigs, in vivo. Triphenyltetrazolium chloride viability stain was used to differentiate viable tissue from ablated regions ex vivo.

Results: The simulations for the layered medium model suggest that operating the SonoKnife at frequency of 1 MHz is more effective and safer than 3.5 MHz providing skin cooling is applied prior to ablation. These predictions were in agreement with the results observed in the animal studies. The required sonication time for ablation increased from 50 to 300 s by using 1 MHz.

Conclusion: Our modelling and animal studies suggest that 1 MHz with pretreatment skin cooling are the optimal settings to operate the SonoKnife to safely and effectively perform subcutaneous thermal ablation of porcine skin. More work is needed to optimise skin cooling and define the optimal sonication time.
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http://dx.doi.org/10.3109/02656736.2012.706730DOI Listing
March 2013

Indocyanine green-augmented diode laser therapy of telangiectatic leg veins: a randomized controlled proof-of-concept trial.

Lasers Surg Med 2012 Jul 5;44(5):369-76. Epub 2012 Apr 5.

Department of Dermatology, University Hospital Regensburg, 93042 Regensburg, Germany.

Background: Telangiectatic leg veins, which affect about 40-50% of adults, represent a frequent cosmetic rather than a medical problem. Besides sclerotherapy, various laser devices are common treatment options. However, complete clearance rates can only be achieved in a small number of patients.

Objective: In this proof-of-concept study, the safety and efficacy of indocyanine green (ICG)-augmented diode laser therapy (808 nm) was evaluated for the treatment of telangiectatic leg veins.

Methods: ICG (2 mg/kg body weight) was intravenously administered in 15 female patients (skin type II to III) with telangiectatic leg veins (measuring between 0.25 and 3 mm in diameter). Immediately after ICG injection, diode laser pulses with different radiant exposures (50-110 J/cm(2)) were applied as one single treatment. Safety and efficacy were assessed 1 and 3 months after treatment by a blinded investigator and the patient. Treatments with the pulsed dye laser (PDL) and the diode laser without ICG served as reference therapies.

Results: The safety of ICG application and diode laser treatment was excellent in all patients with no persisting side effects. Vessel clearance was dose-dependent. Diode laser treatment at radiant exposures between 100 and 110 J/cm(2) resulted in good vessel clearance, which even improved to excellent after the application of double pulses. Diode laser therapy without ICG and PDL treatment induced poor to moderate clearance of telangiectatic leg veins.

Conclusion: ICG-augmented diode laser therapy has proved to be a safe and effective treatment option for telangiectatic leg veins.
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http://dx.doi.org/10.1002/lsm.22022DOI Listing
July 2012

Conductive thermal ablation of 4T1 murine breast carcinoma reduces severe hypoxia in surviving tumour.

Int J Hyperthermia 2012 ;28(2):156-62

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Purpose: The purpose of this study was to quantify hypoxia changes in viable tumour volumes after thermal ablation of a murine breast carcinoma.

Methods: Murine breast 4T1 tumours were grown in the rear leg of BALB/c mice to an average diameter of 10-12 mm. Tumours were treated with conductive interstitial thermal therapy (CITT) at a peak temperature of 80-90°C for 10 min. The animals were euthanised 72 h later, and the tumours were removed for immunohistochemical staining with pimonidazole - a marker of partial pressure of oxygen. The levels of pimonidazole staining intensity were used to quantify changes in hypoxia gradients in terms of strong, medium and weak positive pixel fractions.

Results: The pimonidazole staining ratio of viable control tumour tissue to viable tissue in tumours that were ablated was 0.7 for weak staining, 2.7 for medium staining and 8.0 (p < 0.03) for strong pimonidazole staining.

Conclusion: This shift of pimonidazole staining toward lower intensity pixels in the remaining tumour indicates that tumour ablation with CITT may increase radiosensitivity of the remaining tumour tissue and presents a rationale for combination therapy.
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http://dx.doi.org/10.3109/02656736.2011.636783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324855PMC
June 2012

A pilot in vivo model of human microcystic lymphatic malformations.

Arch Otolaryngol Head Neck Surg 2011 Dec;137(12):1280-5

Division of Pediatric Otolaryngology, Arkansas Children's Hospital, 1 Children's Way, Little Rock, AR 72202, USA.

Objective: To develop an in vivo mouse model of human microcystic lymphatic malformations (LMs) and provide a tool for investigating the biological mechanisms and treatment of microcystic disease.

Design: Animal model and histologic analysis.

Setting: Tertiary referral center.

Subjects: Fresh microcystic LM from human subjects were harvested and xenografted in the immunologically naïve nude mice (Athymic Nude- Foxn1(nu)).

Main Outcome Measures: Specimens were divided (5 × 5 × 5 mm) and secured in 4 quadrants subcutaneously along the dorsum of 4 nude mice. Weekly observations for volume, color, and texture of the grafts were performed with sequential harvesting from each quadrant at 30-day intervals. All grafts (n = 16) were sectioned and stained with hematoxylin-eosin. Comparative pathologic evaluation of the grafts and native LM was performed by 2 blinded pathologists. Immunohistochemical analysis for D2-40 (a known lymphatic endothelial cell marker), Ki-67, and human-specific nuclear antigen was performed.

Results: Near complete microcystic LM xenograft survival (n = 13 [81%]) was achieved in the mouse irrespective of the period of implantation. Xenografts underwent a brief growth phase to day 20 to 30 and were quiescent until approximately day 65 but ultimately had a gradual loss of volume following transplant. Histologic analysis revealed structural characteristics matching the native LM tissue. Immunohistochemical analysis found that 10 (77%) of the surviving xenografts (77%) were positive for D2-40, 9 (69%) were positive for human-specific nuclear antigen, and 8 (62%) were positive for Ki-67.

Conclusions: This preliminary in vivo model suggests that microcystic LM can survive in the athymic nude mouse. The presence of markers for human antibodies, lymphatic endothelium, and cellular proliferation demonstrates the stability of native tissue qualities within the xenografts.
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http://dx.doi.org/10.1001/archoto.2011.203DOI Listing
December 2011

Using 5-aminolevulinic acid and pulsed dye laser for photodynamic treatment of oral leukoplakia.

Arch Otolaryngol Head Neck Surg 2011 Nov;137(11):1117-23

Department of Otolaryngology, Jackson T. Stephens Spine Center, University of Arkansas for Medical Sciences, 501 Jack Stephens Drive, Little Rock, AR 72205, USA.

Objective: To determine the safety and efficacy of photodynamic therapy in the treatment of oral leukoplakia with 5-aminolevulinic acid and pulsed dye laser.

Design: Nonrandomized, single-arm, single-site phase 1/2 pilot study.

Setting: Academic referral center.

Patients: A total of 23 patients, aged 37 to 79 years, having a confirmed diagnosis of leukoplakia with or without dysplasia measuring at least 10 mm in diameter.

Interventions: Application of 5-aminolevulinic acid to lesions followed by activation with high-power 585-nm pulsed dye laser.

Main Outcome Measures: Maximum tolerated dose of laser, postprocedure complications, objective response to treatment, and immunohistochemical changes in treated tissue.

Results: No significant adverse events occurred; minor local adverse effects were observed during and following photodynamic therapy in the safety phase of the study. The maximum tolerated dose was 8 J/cm(2). Of 17 patients, 7 (41%) had more than 75% regression (significant response) and 9 (53%) had more than 25% regression (partial response), for an overall response rate of 94% at 90 days. This response rate was far higher than the null-hypothesis 20% rate (P < 10(-10)) and the alternative-hypothesis 50% rate (P = .0001) for which the study was powered. When compared with baseline levels immunohistochemically, p53 expression was increased in 8 of 11 available samples (73%) and Ki-67 expression was decreased in 7 of 12 available samples (58%).

Conclusions: Photodynamic therapy with 5-aminolevulinic acid and pulsed dye laser could be used to achieve regression of oral leukoplakia. The treatment is safe and well tolerated. An application time of 1.5 hours and laser radiant exposure of 8 J/cm(2) with 1.5-ms pulse time were found to be the optimal settings in this study. The high-power laser used in this study allows completion of laser therapy within 1 to 3 minutes. Further studies are necessary to determine the optimal laser radiant exposure and drug application to maximize the response rate.
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http://dx.doi.org/10.1001/archoto.2011.178DOI Listing
November 2011