bluuebunny/crossref_metadata_2025 huggingface dataset:
High Intensity Focused Ultrasound for Prostate Cancer: A Review of the Scientific Foundation, Technology and Clinical Outcomes
Authors: Rewcastle John C.
Published: October 2014

High Intensity Focused Ultrasound (HIFU) is a definitive treatment for localized prostate cancer that is currently utilized most in Europe and Japan but it not yet approved by the FDA for this indication. Within the armamentarium of definitive prostate cancer therapies it is unique as it is truly non-invasive and does not involve incision or excision. The purpose of this paper is to review the scientific foundation of the technology as well as the clinical outcomes of commercially available devices. The scientific foundation of HIFU is reviewed in terms of how it has resulted in the development of commercially available equipment. MEDLINE was used to search the medical literature for publications pertaining to HIFU for prostate cancer as a primary therapy in terms of clinical outcomes. Biochemical disease free rates as well as negative biopsy rates are reviewed. Different engineering optimization strategies in the face of technicalities inherent to HIFU for prostate cancer have led to the development of two distinct commercially available devices. Each has their own merits and limitations. HIFU provides excellent biochemical and local control and results appear to be durable. Clinical outcomes are similar for the two technologies developed but are difficult to compare due to different lengths of follow-up and varying patient populations. HIFU is a technically advanced definitive local therapy for prostate cancer. Short and medium term results are encouraging and its role as a primary therapy for prostate cancer continues to be defined as more results become available.
Influence of Intensity-Modulated Radiotherapy on Acute Genitourinary and Gastrointestinal Toxicity in the Treatment of Localized Prostate Cancer
Authors: Jani Ashesh B. , Gratzle John , Correa David
Published: October 2014

The objective of this investigation is to compare acute genitourinary (GU) and gastrointestinal (GI) toxicity results of radiotherapy to localized fields delivered using intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy (ConvRT). The records of 481 consecutive prostate cancer patients receiving RT to localized fields at a single institution were reviewed; 108 received IMRT and 373 received ConvRT. Acute GU and GI toxicity, as defined by the Radiation Therapy Oncology Group (RTOG) grading system, were compared using the chi-square test. Ordered logit regression analyses were performed using all major disease and treatment factors as covariates. Acute GU grade 0, 1, 2, 3, and 4 toxicity rates were 23%, 40%, 34%, 3%, and 0%, respectively, in the IMRT cohort and 31%, 37%, 30%, 1%, and 1%, respectively, in the ConvRT cohort - these rates were not significantly different (p=0.118). Acute GI grade 0, 1, 2, 3, and 4 toxicity rates were 42%, 37%, 22%, 0%, and 0%, respectively, in the IMRT cohort and 33%, 32%, 35%, 0%, and 0%, respectively, in the ConvRT cohort - this lower toxicity in the IMRT group was significant (p=0.013). The regression analyses showed that only IMRT use (p=0.046) predicted reduction in acute GI toxicity but no factors correlated with acute GU toxicity rate. In conclusion, in our retrospective single-institution analysis, IMRT was not associated with reduction of acute GU toxicity but was associated with a reduction of acute GI toxicity over ConvRT in the treatment of prostate cancer to localized fields.
Modeling and Sensitivity Analysis of Acoustic Release of Doxorubicin from Unstabilized Pluronic P105 Using an Artificial Neural Network Model
Authors: Husseini Ghaleb A. , Abdel-Jabbar Nabil M. , Mjalli Farouq S. , Pitt William G.
Published: October 2014

This paper models steady state acoustic release of Doxorubicin (Dox) from Pluronic P105 micelles using Artificial Neural Networks (ANN). Previously collected release data were compiled and used to train, validate, and test an ANN model. Sensitivity analysis was then performed on the following operating conditions: ultrasonic frequency, power density, Pluronic P105 concentration, and temperature. The model showed that drug release was most efficient at lower frequencies. The analysis also demonstrated that release increases as the power density increases. Sensitivity plots of ultrasound intensity revealed a drug release threshold of 0.015 W/cm2 and 0.38 W/cm2 at 20 and 70 kHz, respectively. The presence of a power density threshold provides strong evidence that cavitation plays an important role in acoustically activated drug release from polymeric micelles. Based on the developed model, Dox release is not a strong function of temperature, suggesting that thermal effects do not play a major role in the physical mechanism involved. Finally, sensitivity plots of P105 concentration indicated that higher release was observed at lower copolymer concentrations.
Cryosurgery: Ultrastructural Changes in Pancreas Tissue after Low Temperature Exposure
Authors: Korpan Nikolai N.
Published: October 2014

A number of theoretical and experimental studies, both in vitro and in vivo, have been performed to explain the action of low temperatures on tissue. It is now evident that the thermal parameters used in the past for freezing during cryosurgery were not precise; this may have resulted in the failure of treatment. For the first time, this report describes the early ultrastructural features of pancreatic parenchyma after low temperature exposure, i.e., cryosurgery, in vivo. We demonstrate the effect of freeze-thawing processes using temperatures of various intensities. The cryosurgical response of pancreas parenchyma, i.e., ultrastructural cellular changes in pancreas tissue, was investigated. The electronic microscopic analysis showed that, after local cryodestruction at temperatures of −80°C and −180°C, similar processes occurred within the pancreas tissue in the early postcryosurgical phase - immediately and up to 24 hours after low temperature exposure on tissue. The exocrine pancreatic cells in the center of the cryozone changed upon thawing. Ultrastructural changes in the exocrine pancreatic cells, where the first signs of dystrophic processes had been noticed, were increased. These ultrastructural changes in the pancreatic cells provide a platform to better understand the mechanisms of damage and the pathogenesis of frostbite after cryosurgery. The properties of the pancreas parenchyma response after low temperature exposure provide important insights into the mechanisms of damage and the cryogenic lesion immediately after thawing in cryosurgery. Our new insights prove on the cell level that suddenly and progressively damaged pancreatic cells in the postcryosurgical zone lead to aseptic cryonecrosis and then to aseptic cryoapoptosis of vital normal tissue. The vascular capillary changes and circulatory stagnation demonstrate the anti-angiogenesis mechanism, which, together with cryoaponecrosis and cryoapoptosis, are some of the main mechanisms of biological tissue injury following the low temperature exposure.
Cryoablation of Renal Cancer: Variables Involved in Freezing-Induced Cell Death
Authors: Clarke Dominic M. , Robilotto Anthony T. , Rhee Elisa , VanBuskirk Robert G. , Baust John G. , Gage Andrew A. , Baust John M.
Published: October 2014

The detection of renal tumors has increased significantly over recent years resulting in a greater demand for novel, minimally invasive techniques. Cryoablation has emerged as a valuable treatment modality for the management of renal cancer. In an effort to detail the effects of freezing in renal cancer, the human renal cancer (RCC) cell line, 786-O, was evaluated in vitro. 786-O cells were exposed to a range of freezing temperatures from −5 to −40°C and compared to non-frozen controls. The data show that freezing to −5°C did not affect 786-O cell viability, while −10°C, −15°C, and −20°C results in a significant loss of viability (23, 70, and 91%, respectively). A complete loss of cell viability was evident at temperatures of −25°C and colder. Following this analysis, variables involved in the success of cryoablation were investigated. For each of the temperatures tested, extended freeze hold times and passive thawing rates resulted in more extensive cell damage. Additionally, a double freeze-thaw cycle significantly increased cell death compared to a single cycle (62% vs. 22% at −10°C; 89% vs. 63% at −15°C, respectively). While these variables play an important part in the effective application of cryoablation, a molecular understanding of the cell death involved is critical to improving efficacy. Apoptotic inhibition afforded 12% (−10°C), 25% (−15°C), and 11% (−20°C) protection following freezing. Using fluorescence microscopy analysis, the results demonstrated that apoptosis peaked at six hours post-thaw. Next, apoptotic initiating agents including 5-FU and resveratrol (RVT) applied prior to freezing exposure resulted in a significant increase in cell death compared to either application alone. Importantly, the combination of RVT and freezing was noticeably less effective when applied to normal renal cells. The results herein demonstrate the efficacy of freezing and describe a novel therapeutic model for the treatment of renal cancer that may distinguish between cancer and normal cells.
Analysis of Laterality and Percentage of Tumor Involvement in 1386 Prostatectomized Specimens for Selection of Unilateral Focal Cryotherapy
Authors: Mouraviev Vladimir , Mayes Janice M. , Madden John F. , Sun Leon , Polascik Thomas J.
Published: October 2014

In total, 1386 paraffin embedded radical prostatectomy specimens from patients with clinically localized prostate cancer (PCa) excised between 2002–06 were analyzed. Pathologic assessment paid particular attention to laterality and percentage of tumor involvement (PTI) along with pathologic Gleason Score (pGS). Completely unilateral cancers were identified in 254 (18.3%) patients, and in 39% cases of them the signs of clinically significant PCa were revealed. The majority of unilateral tumors (72%) were low volume with a PTI of ≤5. This study suggests that only a select group of men diagnosed with PCa have completely unilateral cancers that would be amenable to focal ablation therapy targeting 1 lobe. Further study is needed to develop predictive models for those patients likely to have small, unilateral cancers that may be amenable to focal therapy.
RT_Image: An Open-Source Tool for Investigating PET in Radiation Oncology
Authors: Graves Edward E. , Quon Andrew , Loo Billy W.
Published: October 2014

Positron emission tomography (PET) has emerged as a valuable imaging modality for the diagnosis and staging of cancer. However, despite evidence that PET may be useful for defining target volumes for radiation therapy, no standardized methodology for accomplishing this task exists. To facilitate the investigation of the utility of PET imaging in radiotherapy treatment planning and accelerate its integration into clinical radiation oncology, we have developed software for exploratory analysis and segmentation of functional imaging datasets.

The application, RT_Image, allows display of multiple imaging datasets and associated three-dimensional regions-of-interest (ROIs) at arbitrary view angles and fields of view. It also includes semi-automated image segmentation tools for defining metabolically active tumor volumes that may aid creation of target volumes for treatment planning. RT_Image is DICOM compliant, permitting the transfer of imaging data and DICOM-RT structure sets between the application and treatment planning software.

RT_Image has been used by radiation oncologists, nuclear medicine physicians, and radiation physicists to analyze over 200 PET datasets. Novel segmentation techniques have been implemented within this programming framework for therapy planning and for evaluation of molecular imaging-derived parameters as prognostic indicators.

RT_Image represents a freely-available software base on which further investigations of the utlity of PET and molecular imaging in radiation oncology may be built. The development of tools such as this is critical in order to realize the potential of molecular imagingguided radiation therapy.
Optically Guided Linac Radiosurgery with a Leksell Head Frame as an Adjunct to Gamma Knife™ Treatment
Authors: Ekstrand Kenneth E. , Hinson William H. , Kearns William , Bourland J. Daniel , deGuzman Allan F. , McMullen Kevin P. , Stieber Volker W.
Published: October 2014

Because of geometrical limitations in the helmet of the Leksell Gamma Knife™ (Elekta Corp., Atlanta, GA, USA) certain regions within the cranium cannot be targeted for treatment. We describe a method by which lesions in these regions can be treated with the Varian-Zmed stereotactic radiosurgery system utilizing an infrared optical positioning system attached to a Leksell head frame. We have measured the accuracy of the optical tracking system using a phantom attached to a Leksell frame and have determined that the system can target a linear accelerator radiosurgery beam to an accuracy of within 1 millimeter.
The Effect of Beam Energy on the Quality of IMRT Plans for Prostate Conformal Radiotherapy
Authors: de Boer Steven F. , Kumek Yunus , Jaggernauth Wainwright , Podgorsak Matthew B.
Published: October 2014

Three dimensional conformal radiation therapy (3DCRT) for prostate cancer is most commonly delivered with high-energy photons, typically in the range of 10–21 MV. With the advent of Intensity Modulated Radiation Therapy (IMRT), an increase in the number of monitor units (MU) relative to 3DCRT has lead to a concern about secondary malignancies. This risk becomes more relevant at higher photon energies where there is a greater neutron contribution. Subsequently, the majority of IMRT prostate treatments being delivered today are with 6–10 MV photons where neutron production is negligible. However, the absolute risk is small [Hall, E. J. Intensity Modulated Radiation Therapy, Protons, and the Risk of Second Cancers. Int J Radiat Oncol Bio Phys 65, 1–7 (2006); Kry, F. S., Salehpour, M., Followill, D. S., Stovall, M., Kuban, D. A., White, R. A., and Rosen, I. I. The Calculated Risk of Fatal Secondary Malignancies From Intensity Modulated Radiation Therapy. Int J Radiat Oncol Bio Phys 62, 1195–1203 (2005).] and therefore it has been suggested that the use of an 18MV IMRT may achieve better target coverage and normal tissue sparing such that this benefit outweighs the risks. This paper investigates whether 18MV IMRT offer better target coverage and normal tissue sparing. Computed Tomography (CT) image sets of ten prostate cancer patients were acquired and two separate IMRT plans were created for each patient. One plan used 6 MV beams, and the other used 18 MV, both in a coplanar, non-opposed beam geometry. Beam arrangements and optimization constraints were the same for all plans. This work includes a comparison and discussion of the total integral dose, neutron dose conformity index, and total number of MU for plans generated with both energies.
Irreversible Electroporation in Medicine
Authors: Rubinsky Boris
Published: October 2014

This is a brief introduction to the emerging field of irreversible electroporation in medicine. Certain electrical fields when applied across a cell can have as a sole effect the permeabilization of the cell membrane, presumable through the formation of nanoscale defects in the cell membrane. Sometimes this process leads to cell death, primarily when the electrical fields cause permanent permeabilization of the membrane and the consequent loss of cell homeostasis, in a process known as irreversible electroporation. This is an unusual mode of cell death that is not understood yet. While the phenomenon of irreversible electroporation may have been known for centuries it has become only recently rigorously considered in medicine for various applications of tissue ablation. A brief historical perspective of irreversible electroporation is presented and recent studies in the field are discussed.
Technical Description, Phantom Accuracy, and Clinical Feasibility for Single-Session Lung Radiosurgery Using Robotic Image-Guided Real-time Respiratory Tumor Tracking
Authors: Muacevic A. , Drexler C. , Wowra B. , Schweikard A. , Schlaefer A. , Hoffmann R. T. , Wilkowski R. , Winter H. , Reiser M.
Published: October 2014

To describe the technological background, the accuracy, and clinical feasibility for single session lung radiosurgery using a real-time robotic system with respiratory tracking. The latest version of image-guided real-time respiratory tracking software (Synchrony®, Accuray Incorporated, Sunnyvale, CA) was applied and is described. Accuracy measurements were performed using a newly designed moving phantom model. We treated 15 patients with 19 lung tumors with robotic radiosurgery (CyberKnife®, Accuray) using the same treatment parameters for all patients. Ten patients had primary tumors and five had metastatic tumors. All patients underwent computed tomography-guided percutaneous placement of one fiducial directly into the tumor, and were all treated with single session radiosurgery to a dose of 24 Gy. Follow up CT scanning was performed every two months.

All patients could be treated with the automated robotic technique. The respiratory tracking error was less than 1 mm and the overall shape of the dose profile was not affected by target motion and/or phase shift between fiducial and optical marker motion. Two patients required a chest tube insertion after fiducial implantation because of pneumothorax. One patient experienced nausea after treatment. No other short-term adverse reactions were found. One patient showed imaging signs of pneumonitis without a clinical correlation.

Single-session radiosurgery for lung tumor tracking using the described technology is a stable, safe, and feasible concept for respiratory tracking of tumors during robotic lung radiosurgery in selected patients. Longer follow-up is needed for definitive clinical results.
Comparison of Similarity Measures for Rigid-body CT/Dual X-ray Image Registrations
Authors: Kim Jinkoo , Li Shidong , Pradhan Deepak , Hammoud Rabih , Chen Qing , Yin Fang-Fang , Zhao Yang , Kim Jae Ho , Movsas Benjamin
Published: October 2014

A set of experiments were conducted to evaluate six similarity measures for intensity-based rigid-body 3D/2D image registration. Similarity measure is an index that measures the similarity between a digitally reconstructed radiograph (DRR) and an x-ray planar image. The registration is accomplished by maximizing the sum of the similarity measures between biplane x-ray images and the corresponding DRRs in an iterative fashion. We have evaluated the accuracy and attraction ranges of the registrations using six different similarity measures on phantom experiments for head, thorax, and pelvis. The images were acquired using Varian Medial System On-Board Imager. Our results indicated that normalized cross correlation and entropy of difference showed a wide attraction range (62 deg and 83 mm mean attraction range, ωmean), but the worst accuracy (4.2 mm maximum error, emax). The gradient-based similarity measures, gradient correlation and gradient difference, and the pattern intensity showed sub-millimeter accuracy, but narrow attraction ranges ( ωmean=29 deg, 31 mm). Mutual information was in-between of these two groups ( emax=2.5 mm, ωmean= 48 deg, 52 mm). On the data of 120 x-ray pairs from eight IRB approved prostate patients, the gradient difference showed the best accuracy. In the clinical applications, registrations starting with the mutual information followed by the gradient difference may provide the best accuracy and the most robustness.
Retrospective Evaluation of Pediatric Cranio-Spinal Axis Irradiation Plans with the Hi-ART Tomotherapy System
Authors: Peñagarícano José A. , Yan Yulong , Corry Peter , Moros Eduardo , Ratanatharathorn Vaneerat
Published: October 2014

Helical tomotherapy (HT) can be used for the delivery of cranio-spinal axis irradiation (CSAI) without the need for beam matching of conventional linac-based external beam irradiation. The aim of this study is to retrospectively evaluate HT plans used for treatment in nine patients treated with CSAI.

Helical tomotherapy cranio-spinal axis irradiation (HT-CSAI) plans were created for each patient. Average length along the cranio-spinal axis of the PTV was 65.6 cm with a range between 53 and 74 cm. Treatment planning optimization and plan evaluation parameters were obtained from the HT planning station for each of the nine patients. PTV coverage by the 95% isodose surface ranged between 98.0 to 100.0% for all nine patients. The clinically acceptable dose variation within the PTV or tolerance range was between 0.7 and 2.5% for all nine patients. Doses to the organs at risk were clinically acceptable.

An increasing length along the longitudinal axis of the PTV did not consistently increase the beam-on time indicating that using a larger jaw width had a greater impact on treatment time. With a larger jaw width it is possible to substantially reduce the normalized beam-on treatment time without compromising plan quality and sparing of organs at risk. By using a larger jaw width or lower modulation factor or both, normalized beam-on times were decreased by up to 61% as compared to the other evaluated treatment plans. From the nine cases reported in this study the minimum beam-on time was achieved with a jaw width of 5.0 cm, pitch of 0.287 and a modulation factor of 2.0. Large and long cylindrical volumes can be effectively treated with helical tomotherapy with both clinically acceptable dose distribution and beam-on time.
Effects of N-Methyl Pyrrolidone on the Uptake of Hypericin in Human Bladder Carcinoma and Co-staining with DAPI Investigated by Confocal Microscopy
Authors: Saw Constance Lay Lay , Olivo Malini , Wohland Thorsten , Fu Chit Yaw , Kho Kiang Wei , Soo Khee Chee , Heng Paul Wan Sia
Published: October 2014

Photodynamic diagnosis (PDD) using hypericin (HY), a natural photosensitizer, detects bladder cancer significantly better than white light endoscopy. However, the lipophilicity of HY complicates its administration for clinical applications. Currently, pharmaceutical preparations for HY without plasma protein are being developed. Formulations containing a biocompatible solvent, N-methyl pyrrolidone (NMP) have been shown to enhance the photodynamic therapeutic effects of HY. It was recently reported that, NMP formulations of HY were able to produce significantly higher contrast for fluorescence detection of tumors than albumin-containing HY formulations. This present work hypothesizes that NMP acts both as a solvent and penetration enhancer to improve the delivery of HY into cells by increasing the permeability of cell membranes. This paper reports the use of 3-D confocal microscopy to monitor real-time uptake of HY in human carcinoma. 3-D confocal microscopy was used to investigate the possibility of nuclear localization of HY in MGH cells. The fluorescence of HY was confirmed to be emitted from HY containing cells using spectrometry. The localization of a DNA fluorescent probe 4′, 6-diamidino-2-phenylindole dihydrochloride (DAPI) was used to confirm the possibility of colocalization of DAPI and HY. The colocalization analysis in the present study suggests that it was very unlikely that HY colocalized in the nucleus that was stained by DAPI. Fluorescein leakage tests showed that 1% NMP changes the permeability of cell membranes, and enhanced the delivery of HY into cells resulting in lower cell survival ratios. Thus, NMP was able to enhance the photodynamic therapeutic effects of HY on cancer cells.
Effect of Plasmonic Gold Nanoparticles on Benign and Malignant Cellular Autofluorescence: A Novel Probe for Fluorescence Based Detection of Cancer
Authors: El-Sayed Ivan , Huang Xiaohua , Macheret Fima , Humstoe Joseph Oren , Kramer Randall , El-Sayed Mostafa
Published: October 2014

Due to the strong surface fields of noble metal nanoparticles, absorption and scattering of electromagnetic radiation is greatly enhanced. Noble metallic nanoparticles represent potential novel optical probes for simultaneous molecular imaging and photothermal cancer therapy using the enhanced scattering and absorption of light. Further, gold nanoparticles can affect molecular fluorescence via chemical, electronic, or photonic interactions. Live cells generate fluorescence due to intracellular and extracellular molecules. Differences in the biochemical composition between healthy and malignant cells can be exploited in vivo to help identify cancer spectroscopically. The interaction of gold nanoparticles with cellular autofluorescence has not yet been characterized. We hypothesized that gold nanoparticles delivered to live cells in vitro would alter cellular autofluorescence and may be useful as a novel class of contrast agent for fluorescence based detection of cancer. The fluorescence of two fluorophores that are responsible for tissue autofluorescence, NADH and collagen, and of two oral squamous carcinoma cell lines and one immortalized benign epithelial cell line were measured in vitro. Gold nanoparticles of different shapes, both spheres and rods, quenched the fluorescence of the soluble NADH and collagen. Reduction of NADH fluorescence was due to oxidation of NADH to NAD+ catalyzed by gold nanoparticles (results we previously published). Reduction of collagen fluorescence appears due to photonic absorption of light. Furthermore, a mean quenching of 12/8% (p<0.00050) of the tissue autofluorescence of cell suspensions was achieved in this model when nanospheres were incubated with the live cells. Gold nanospheres significantly decrease cellular autofluorescence of live cells under physiological conditions when excited at 280nm. This is the first report to our knowledge to suggest the potential of developing targeted gold nanoparticles optical probes as contrast agents for fluorescence based diagnoses of cancer.
Stereotactic Radiotherapy for Ocular Melanoma: Initial Experience Using Closed Eyes for Ocular Target Immobilization
Authors: Miralbell Raymond , Caro Monica , Weber Damien C. , Elizalde Javier , Perez-Ochoa Agata , Villà Salvador , IgnacioToscas José , Martinez Pedro , Linero Dolors , Nouet Philippe , Escudé Lluís
Published: October 2014

To assess the reliability and target positioning reproducibility with eyes closed in uveal melanoma patients treated with a micromultileaf-based linear accelerator dedicated for stereotactic radiotherapy. Five consecutive patients treated with curative radiotherapy for uveal melanoma were monitored for positioning reproducibility with resimulation CT scans performed every two days while on treatment (23 resimulation CTs available). All patients underwent MRIs of the orbits before simulation to help to define the target and organs at risk ( e.g., lenses, optic nerves, ciliary bodies, and lacrimal glands) in the simulation CT (MRI-to-CT bone registration). Patients were simulated, resimulated, and treated with eyes closed. Patient #1 was treated with 5 daily fractions while patients #2 to #5, were treated with 10 daily fractions. We chose the lens of the tumor-bearing eye as the structure to be controlled, assuming that correct repositioning of the lens should be a valid surrogate for correctness of target repositioning. Displacements (mean and standard deviations, SD) of the lens in the three axes were measured for each patient. Systematic and standard errors were calculated. Planning target volume (PTV) margins were estimated according to McKenzie et al. [ Phys Med Biol 45, 3331-3342 (2000)].

For both AP-PA and left-right shifts calculated SD were always below 1 mm, except for patient #4, who was treated with a non-customized bolus that pushed the globe backwards in a random fashion. In ideal set-up conditions PTV margins around the target were estimated to be 3 mm. Asking patients to close their eyes is a simple and reliable immobilization procedure when treating ocular tumors with stereotactic radiotherapy. Margins of 3 mm around the target may be necessary to safely treat these tumors under ideal set-up conditions.
Pulmonary Hilar Stereotactic Body Radiation Therapy in the Rat
Authors: Tinnel B. , Mendonca M. S. , Henderson M. , Cummings O. , Chin-Sinex H. , Timmerman R. , McGarry R. C.
Published: October 2014

Stereotactic Body Radiation therapy (SBRT) is an emerging modality of treatment for early stage non-small cell lung carcinoma. Concerns have arisen related to increased toxicities for medial tumors. We have developed a model of high dose, hypofractionated radiotherapy to the pulmonary hilum using the Leksell Gamma-Knife™. Sprague-Dawley rats received hypofractionated SBRT to the unilateral lung hilum using a custom immobilization device on the Gamma Knife. Each animal was individually scanned, treatment planned, and treated with either two 4 mm or one 8 mm collimated shots at escalating doses of 20, 40, and 80 Gy to the 50% isodose volume, encompassing the right mainstem bronchus. All animals were carefully followed post-treatment and imaged by plain film and CT. In addition, histopathological analysis of all rats was performed at selected time points. Animals treated with 4 mm collimated shots demonstrated no appreciable changes on plain films or sequential, follow-up CT scans, or histopathologically. Animals irradiated with the 8 mm collimator were less active, gained weight at a reduced rate, and demonstrated histopathological changes in 7/34 animals six months post-irradiation. Cellular atypia and interstitial pneumonitis were found, three of the seven of the animals showed clear bronchial damage and two showed vascular damage. Significant volume and time effects were found. Utilizing a novel Gamma Knife based animal model to study SBRT toxicity, it was found that the bronchus will tolerate small volumes of very high dose radiotherapy. It was postulated that radiation of the surrounding support stroma and normal tissue are important in the etiology of bronchial or hilar damage.
Ultrasound-Enhanced Chemotherapy and Gene Delivery for Glioma Cells
Authors: Zarnitsyn Vladimir G. , Kamaev Pavel P. , Prausnitz Mark R.
Published: October 2014

Treatment of brain cancer is limited in part by inefficient intracellular delivery of drugs and DNA for chemotherapy and gene therapy, respectively. This study tested the hypothesis that ultrasound may be used to enhance intracellular delivery and efficacy of chemotherapeutics and genes in glioma cells in vitro. First, suitable ultrasound conditions were identified by measuring intracellular uptake of calcein and viability of GS 9L rat gliosarcoma cells after a range of different ultrasound exposures. We selected sonication at 10 J/cm2, which achieved intracellular delivery of ν106 molecules/cell. Next, glial cells were sonicated with varying concentrations of model chemotherapeutics: BCNU and bleomycin. For both drugs, cytotoxicity was increased in a synergistic manner when accompanied by ultrasound exposure. Finally, expression of a plasmid DNA encoding a GFP reporter was increased up to 30-fold when exposed to ultrasound. Altogether, these findings suggest that ultrasound may be useful to increase the efficacy of chemotherapy and gene therapy of glioma cells.
Curative Stereotactic Robotic Radiotherapy Treatment for Extracranial, Extrapulmonary, Extrahepatic, and Extraspinal Tumors: Technique, Early Results, and Toxicity
Authors: Nuyttens J. J. , Prévost J-B. , Van der Voort van Zijp N. C. , Hoogeman M. , Levendag P. C.
Published: October 2014

We investigated the technique, early results and toxicity of curative stereotactic radiotherapy with the CyberKnife® (Accuray Incorporated, Sunnyvale, California, USA) in 15 extracranial, extrapulmonary, extrahepatic, and extraspinal tumors. Fourteen tumors were located close to the bowel or esophagus. The PTV = GTV + 2–5 mm. The dose to the tumors varied from 10 fractions of 4 Gy up to 3 fractions of 20 Gy (median dose/fraction: 7 Gy; median number of fractions: 6), and depended on the proximity of the bowel. A small volume of the bowel was allowed to receive a dose of 6 Gy/fraction. The dose to the PTV was prescribed to the 75–85% isodose line. With a median follow up of 18 months, the 2-year local control and overall survival was 100%. Due to our flexible fractionation schedules, we were able to prescribe the dose to at least 90% of the PTV (median 95%) without increasing the dose to the bowel > 6 Gy/fraction. Five acute side effects were seen in four patients: two patients had transient grade 1 lymph edema in the leg, one patient complained of grade 1 pain in the abdomen and diarrhea, and one patient complained of grade 1 radiation dermatitis. Late toxicity such as grade 1 rectal bleeding, grade 1 diarrhea, grade 2 painful subcutaneous fibrosis, grade 2 pain in a surgical scar on the abdominal wall and an asymptomatic occlusion of the ureter was observed. Curative stereotactic radiotherapy treatment with the CyberKnife for extracranial, extrapulmonary, extrahepatic, and extraspinal, locally recurrent or solitary metastatic tumors is feasible and results in excellent local control and survival with low acute and late toxicity. A small volume of the bowel is able to tolerate a dose of 6 Gy per fraction for a maximum of 6 fractions.
Short Term Clinical Outcome after Laparoscopic Cryoablation of the Renal Tumor ≤ 3.5 cm
Authors: Polascik Thomas J. , Nosnik Israel , Mayes Janice M. , Mouraviev Vladimir
Published: October 2014

Between September 2000 and September 2006, 26 patients underwent primary laparoscopic cryosurgical procedures (28) for an organ-confined renal tumor(s). In one case, cryosurgery was done sequentially on both kidneys. All patients had been carefully selected based on the following criteria: tumor size ≤ 3.5 cm, the absence of local and systemic spread on cross-sectional computed tomography (CT) or magnetic resonance imaging (MRI), and the ability to tolerate general anesthesia. A pure laparoscopic approach was employed using third generation cryotechnology (Galil Medical Inc., Plymouth Meeting, USA). Patients were followed by serial CT or MRI scan, creatinine level, and physical examination at least every six months after cryotherapy. The mean patient age was 64 years (range: 44–79) and the mean follow-up was 20.9 +/- 17.2 months. The median tumor size was 2.0 cm (range: 1–3.5 cm). Only one patient required a blood transfusion and one patient developed a transient ileus. The median length of stay was 2.0 days (range: 0–9 days). The median change in creatinine was 0.1 mg/dl (range:-0.4 to 1.8). No patient was converted to open surgery. No evidence of recurrence or progression was found in all patients, and overall survival rate was 100%. Laparoscopic renal cryoablation of the small renal tumor is a safe procedure with minimal complications. Although there were no recurrences with short term follow-up, further long term study is needed to verify its efficacy.
Developing and Understanding a Hospital-Based Proton Facility: Bringing Physics into Medicine
Authors: Slater James M.
Published: October 2014

From October 18 to 20, 2006, a symposium, Developing and Understanding a Hospital-based Proton Facility: Bringing Physics Into Medicine, was held at the Renaissance Esmeralda Resort and Spa, Indian Wells, California. The event was offered by the Department of Radiation Medicine at Loma Linda University (LLU), supported by the Telemedicine and Advanced Technology Research Center (TATRC) and the United States Army Medical Research and Materiel Command (USAMRMC). The meeting was intended to discuss factors involved in planning, developing, and operating a hospital-based proton treatment center. It brought together some of the most distinguished physicists, radiation biologists, and radiation oncologists in the world, and more than 100 individuals participated in the three-day educational offering. This overview reports on the event and introduces several papers written by many of the speakers from their presentations, for publication in this issue of Technology in Cancer Research and Treatment. Both the symposium and the papers are appropriate for this journal: exploitation of technology was one of the underlying themes of the symposium.
Selecting the Optimum Particle for Radiation Therapy
Authors: Slater James M.
Published: October 2014

Ionizing radiation therapy is one of the primary modalities for treating cancers. Ideally, the particle selected to deliver ionizing radiation for routine therapy should control the disease, cause minimal side effects, and be affordable. Two major properties for judging the utility of a particle, physical controllability and selective cell destruction, influence the decision for selection. The proton, at present, has the best combination of capabilities for routine radiation therapy. Heavier ions require further study to determine their role in patient treatment.
Facility Overview for a Proton Beam Treatment Center
Authors: Lesyna David
Published: October 2014

Proton beam therapy is now widely recognized as the most precise form of radiation treatment available for certain types of diseases. As such, there is an ever-increasing demand for efficient hospital-based systems capable of providing proton therapy on a routine basis. A hospital-based proton-beam treatment center consists of many systems that must be integrated to form a single simple-to-operate and maintain medical device. The system must be capable of accelerating the proton beam to the needed energies safely and effectively, transporting the beam successfully to the appropriate treatment room, and shaping the proton beam to the desired target volume within the patient.

This paper overviews the major systems needed to meet these objectives as part of a complete proton-beam treatment system. This paper focuses on the areas of beam acceleration, beam transport, and beam delivery methods, including an introduction to both passive and active beam delivery methods. Additionally, it introduces and provides examples of the required simplicity and types of automation needed to achieve a high-capacity proton-beam treatment system, with specific examples based on use at the system at Loma Linda University Medical Center.
Clinical Proton Radiation Therapy Research at the Francis H. Burr Proton Therapy Center
Authors: DeLaney Thomas F.
Published: October 2014

The Francis H. Burr Proton Therapy Center has a 230 MeV cyclotron from which proton beams are directed to two isocentric gantries, a stereotactic intracranial beam line, and an eye line. Because of improved physical dose distribution, proton radiotherapy allows dose escalation to improve local tumor control in anatomic sites and histologies where local control is suboptimal with photons. The improved dose localization also reduces normal-tissue doses with an anticipated reduction in acute and late toxicity. Clinical treatment protocols, developed to exploit the dosimetric advantages of protons over photons, have been grouped into two broad categories. In the first, dose is escalated for anatomic sites where local control with conventional radiation doses has been suboptimal. In the second, normal-tissue sparing with protons is designed to minimize acute and late toxicity. Treatment of patients on clinical research protocols has been encouraged. Patient treatments began on the first gantry in November 2001; on the eye line in April 2002; on the second gantry in May 2002; and on the stereotactic intracranial line in August 2006. The facility currently treats 60 patients per day, including up to six children daily under anesthesia. Dose-escalation studies have been completed for early stage prostate cancer (in conjunction with Loma Linda University) and sarcomas of the cervical spine/base of skull and thoracolumbosacral spine. Protocols are in progress or development for carcinoma of the nasopharynx, paranasal sinus carcinoma, non-small-cell lung carcinoma, locally advanced carcinoma of the prostate, hepatocellular carcinoma, and pancreatic cancer. Studies evaluating the use of protons for morbidity reduction include protocols for craniospinal irradiation in conjunction with systemic chemotherapy for medulloblastoma, retinoblastoma, pediatric rhabdomyosarcoma, other pediatric sarcomas, and accelerated, hypofractionated partial breast irradiation for T1N0 breast carcinomas. For pediatric patients, protons have also been accepted as an alternative to photons for children enrolled in Children's Oncology Group (COG) protocols. Treatment of patients on these studies has often required the development of new treatment techniques ( i.e., matching abutting fields for craniospinal irradiation), respiratory gating, and development of appropriate clinical infrastructure support ( i.e., increase in availability of pediatric anesthesia) to allow appropriate treatment. In addition, a clinical research infrastructure for protocol development and data management is required. Results to date indicate that proton radiation therapy offers several potential treatment advantages to patients that can be studied in the setting of clinical trials. Patients' willingness to enter these clinical trials seems to be quite high; accrual to selected studies has been favorable.
Development and Operation of the Loma Linda University Medical Center Proton Facility
Authors: Slater Jerry D.
Published: October 2014

The Proton Treatment Center at Loma Linda University Medical Center, the world's first hospital-based proton facility, opened in 1990 after two decades of development. Its early years were marked by a deliberately cautious approach in clinical utilization of protons, with intent to establish hospital-based proton therapy on a scientific basis. The facility was designed to be upgradeable, and development since 1990 has proceeded in three distinct phases of upgrades, both in technology and clinical applications. Upgrades continue, all of them based on an underlying program of basic and clinical research; future new applications of proton radiation therapy are expected to follow.
Recent Advances in Nanooncology
Authors: Jain K. K.
Published: October 2014

Nanobiotechnology is playing an important role in advances in oncology and currently nanooncology is the most important chapter of nanomedicine. Nanobiotechnologies have refined molecular diagnostics and enabled early detection of tumors and discovery of biomarkers of cancer. Various nanoparticles are the basis of diagnostic assays for cancer as well as contrast materials for MRI. Nanobiotechnology is facilitating the discovery and development of drugs for cancer. Several nanobiotechnologies, mostly based on nanoparticles, have been described to facilitate drug delivery in cancer, which is important for optimizing the effect of drugs and reducing toxic side effects. Nanoparticles for targeted drug delivery in cancer enable combination of diagnostics and therapeutics and act as adjuncts to hyperthermia and photodynamic therapy. Several applications of nanobiotechnology in cancer surgery include use of nanoparticles to visualize tumor during surgery as aid to proper removal, and nanorobotics for remotely controlled diagnostics combined with therapeutics. Selected new developments in nanooncology have been highlighted in this review and these point to an important role in development of personalized oncology.
Cardioprotective Effects of Fullerenol C60(Oh)24 on a Single Dose Doxorubicin-induced Cardiotoxicity in Rats with Malignant Neoplasm
Authors: Injac Rade , Perse Martina , Boskovic Marija , Djordjevic-Milic Vukosava , Djordjevic Aleksandar , Hvala Anastazija , Cerar Anton , Strukelj Borut
Published: October 2014

The therapeutic utility of the anthracycline antibiotic doxorubicin is limited due to its cardiotoxicity. Our aim was to investigate the efficacy of fullerenol C60(OH)24 in preventing single, high-dose doxorubicin-induced cardiotoxicity in rats with malignant neoplasm. Experiment was performed on adult female Sprague Dawley rats with chemically induced mammary carcinomas. The animals were sacrificed two days after the application of doxorubicin and/or fullerenol, and the serum activities of CK, LDH and α-HBDH, as well as the levels of MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS in the heart, were determined. The results obtained from the enzymatic activity in the serum show that the administration of a single dose of 8 mg/kg in all treated groups induces statistically significant damage. There are significant changes in the enzymes of LDH and CK (p < 0.05), after an i.p. administration of doxorubicin/fullerenol and fullerenol. Comparing all groups with untreated control group, point to the conclusion that in the case of a lower α-HBDH/LDH ratio, results in more serious the liver parenchymal damage. The results revealed that doxorubicin induced oxidative damage and that the fullerenol antioxidative influence caused significant changes in MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS level in the heart (p < 0.05). Therefore, it is suggested that fullerenol might be a potential cardioprotector in doxorubicin-treated individuals.
Assessment of Bevacizumab Conjugated to Cy5.5 for Detection of Head and Neck Cancer Xenografts
Authors: Withrow Kirk P. , Newman J. Robert , Skipper Joni B. , Gleysteen John P. , Magnuson J. Scott , Zinn Kurt , Rosenthal Eben L.
Published: October 2014

Optical fluorescent technology has the potential to deliver real time imaging of cancer into the operating room and the clinic. To determine the efficacy of fluorescently labeled anti-vascular endothelial growth factor (VEGF) antibody to be used as a cancer specific optical contrast agent to guide surgical resections, we evaluated the sensitivity and specificity of this agent to detect microscopic residual disease in a preclinical model of head and neck squamous cell carcinoma (HNSCC). Using a flank murine model, mice were xenografted with SCC-1 tumor cells and injected with anti-VEGF antibody (bevacizumab) conjugated to an optically active fluorophore (Cy5.5). Tumors underwent sub-total resections and were assessed for the presence of residual disease by fluorescent stereomicroscopy. Expected positive and negative biopsies were taken according to the presence or absence of fluorescence, respectively. Histology was used to confirm the presence or absence of disease. Biopsies taken from areas of fluorescence within the wound bed (n=18) were found to be histologically malignant in all but one biopsy. Samples taken from a non-fluorescing tumor bed (n=15) were found to be histologically benign in 11 of 15. These findings correlated with a sensitivity and specificity of 80.9% and 91.7%, respectively. This data supports previous data presented by this group and supports further investigation of fluorescently labeled anti-tumor antibodies to detect disease in the surgical setting.
A Monte-Carlo Derived Dual-Source Model for Helical Tomotherapy Treatment Planning
Authors: Hsiao Yayun , Stewart Robert D. , Li X. Allen
Published: October 2014

Full Monte Carlo radiation transport simulations of accelerator heads are impractical for routine treatment planning because of the excessive computational burden and memory requirements. To improve the accuracy and efficiency of treatment plans for helical tomotherapy, we have developed a dual-source model to characterize the radiation emitted from the head of a commercial helical tomotherapy accelerator. Percentage depth dose (PDD) and beam profiles computed using the dual-source model with the EGS/BEAMnrc Monte Carlo package agree within 2% of measurements for a wide range of field sizes, which suggests that the proposed dual-source model provides an adequate representation of the tomotherapy head for dose calculations in routine treatment planning.