bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment Planning for Conformal Proton Radiation Therapy
Authors: Bussière Marc R. , Adams Judith A.
Published: October 2014

Clinical results from various trials have demonstrated the viability of protons in radiation therapy and radiosurgery. This has motivated a few large medical centers to design and build expensive hospital based proton facilities based proton facilities (current cost estimates for a proton facility is around $100 million). Until this development proton therapy was done using retrofitted equipment originally designed for nuclear experiments. There are presently only three active proton therapy centers in the United States, 22 worldwide. However, more centers are under construction and being proposed in the US and abroad.

The important difference between proton and x-ray therapy is in the dose distribution. X-rays deposit most of their dose at shallow depths of a few centimeters with a gradual decay with depth in the patient. Protons deliver most of their dose in the Bragg peak, which can be delivered at most clinically required depths followed by a sharp fall-off. This sharp falloff makes protons sensitive to variations in treatment depths within patients.

Treatment planning incorporates all the knowledge of protons into a process, which allows patients to be treated accurately and reliably. This process includes patient immobilization, imaging, targeting, and modeling of planned dose distributions. Although the principles are similar to x-ray therapy some significant differences exist in the planning process, which described in this paper.

Target dose conformality has recently taken on much momentum with the advent of intensity modulated radiation therapy (IMRT) with photon beams. Proton treatments provide a viable alternative to IMRT because they are inherently conformal avoiding normal tissue while irradiating the intended targets.

Proton therapy will soon bring conformality to a new high with the development of intensity modulated proton therapy (IMPT). Future challenges include keeping the cost down, increasing access to conventional proton therapy as well as the clinical implementation of IMPT. Computing advances are making Monte Carlo techniques more accessible to treatment planning for all modalities including proton therapy. This technique will allow complex delivery configurations to be properly modeled in a clinical setting.
Use of the Leksell Gamma Knife for Localized Small Field Lens Irradiation in Rodents
Authors: DesRosiers Colleen , Mendonca Marc S. , Tyree Craig , Moskvin Vadim , Bank Morris , Massaro Leo , Bigsby Robert M. , Caperell-Grant Andrea , Valluri Shailaja , Dynlacht Joseph R. , Timmerman Robert
Published: October 2014

For most basic radiobiological research applications involving irradiation of small animals, it is difficult to achieve the same high precision dose distribution realized with human radiotherapy. The precision for irradiations performed with standard radiotherapy equipment is ±2 mm in each dimension, and is adequate for most human treatment applications. For small animals such as rodents, whose organs and tissue structures may be an order of magnitude smaller than those of humans, the corresponding precision required is closer to ±0.2 mm, if comparisons or extrapolations are to be made to human data. The Leksell Gamma Knife is a high precision radiosurgery irradiator, with precision in each dimension not exceeding 0.5 mm, and overall precision of 0.7 mm. It has recently been utilized to treat ocular melanoma and induce targeted lesions in the brains of small animals. This paper describes the dosimetry and a technique for performing irradiation of a single rat eye and lens with the Gamma Knife while allowing the contralateral eye and lens of the same rat to serve as the “control”. The dosimetry was performed with a phantom in vitro utilizing a pinpoint ion chamber and thermoluminescent dosimeters, and verified by Monte Carlo simulations. We found that the contralateral eye received less than 5% of the administered dose for a 15 Gy exposure to the targeted eye. In addition, after 15 Gy irradiation 15 out of 16 animals developed cataracts in the irradiated target eyes, while 0 out of 16 contralateral eyes developed cataracts over a 6-month period of observation. Experiments at 5 and 10 Gy also confirmed the lack of cataractogenesis in the contralateral eye. Our results validate the use of the Gamma Knife for cataract studies in rodents, and confirmed the precision and utility of the instrument as a small animal irradiator for translational radiobiology experiments.
Foreword: Potential of Optical Imaging for Early Cancer Detection, Screening, Diagnosis and Image Guided Treatment
Authors: Clarke Laurence P. , Baker Houston , Kelloff Gary
Published: October 2014

This issue of the journal is dedicated to outline emerging optical technologies that have the potential to improve early cancer detection, screening, diagnosis, and treatment. The authors have briefly reviewed the progress of emerging technologies, described some of the emerging optical systems or methods in their laboratories, and then discuss the barriers for their translation to clinical applications. The scope of the manuscripts includes both endogenous and exogenous contrast agents, including molecular probes. The first four papers address early cancer detection, the remaining four papers address cancer diagnosis or image guided therapy, including either molecular or multi-modality imaging methods.
Development of a Fluorescence Detection System Using Optical Parametric Oscillator (OPO) Laser Excitation for in Vivo Diagnosis
Authors: Song Joon Myong , Jagannathan Ramesh , Stokes David L. , Kasili Paul M. , Panjehpour Masoud , Phan Mary N. , Overholt Bergein F. , DeNovo Robert C. , Pan Xiaogang , Lee Robert J. , Vo-Dinh Tuan
Published: October 2014

In this work, the development and applications of a fluorescence detection system using optical parametric oscillator (OPO) laser excitation for in vivo disease diagnosis including oral carcinoma are described. The optical diagnosis system was based on an OPO laser for multi-wavelength excitation and time-resolved detection. The pulsed Nd-YAG-pumped OPO laser system (6 ns, 20 Hz) is compact and has a rapid, broad, and uniform tuning range. Time-gated detection of intensified charge-coupled device (ICCD) making use of external triggering was used to effectively eliminate the laser scattering and contribute to the highly sensitive in vivo measurements. Artificial tissue-simulating phantoms consisting of polystyrene microspheres and tissue fluorophores were tested to optimize the gating parameters. 51-ns gate width and 39-ns gate delays were determined to be the optimal parameters for sensitive detection. in vivo measurements with the optical diagnosis system were applied to esophagus, stomach, and small intestine using an endoscope in canine animal studies. The rapid tuning capability of the optical diagnosis system contributed greatly to the optimization of wavelength for the observation of porphyrin in the small intestine. When the small intestine was thoroughly washed with water, the emission band which corresponds to porphyrin disappeared. Based on this observation, it was concluded that the detected signal was yielded by porphyrin-containing bile secretion. Also, multispectral analyses using multiple excitations from 415 to 480 nm at 5 nm intervals confirmed the porphyrin detection in the small intestine. The optical diagnosis system was also applied to the detection of human xenograft of oral carcinoma in mice using 5-aminolevulinic acid (5-ALA) which is a photodynamic therapy (PDT) drug. Significant differences in protoporphyrin IX fluorescence intensity between normal and tumor tissue could be obtained 2 hours after the injection of 5-ALA into mice due to the preferential accumulation of 5-ALA in tumors. Results reported herein demonstrate potential capabilities of the LIF-OPO system for in vivo disease diagnosis.
Tissue Characterization by Quantitative Optical Imaging Methods
Authors: Gandjbakhche Amir H. , Chernomordik Victor , Hattery David , Hassan Moinuddin , Gannot Israel
Published: October 2014

Optical methods have a long history in the field of medical diagnosis. The biomolecular specificity possible with optical methods has been particularly valuable in microscopy and histopathology while in vivo imaging of deep structures has traditionally been the domain of X-ray and MRI. The use of optical methods in deep tissue has been limited by multiple-scattering which blurs or distorts the optical signal. New stochastic methods which account for multiple scattering have been developed that are extending the usefulness of optical methods deep into tissue. In optical mammography, photons may travel through 10cm of tissue before arriving at the detector. We have developed a method for quantifying parameters of anomalous sites in breast tissue that may be used for functional characterization of tumors. In other work presented here, we are developing fluorescence based methods to detect and monitor tumor status. The immune response to a tumor is a target for fluorescently labeled specific antibodies. We have developed a method to localize the tumor site using CW fluorescence. Additionally, we have developed a method which uses time-resolved data and capitalizes on probe lifetime sensitivity to metabolic parameters such as pH and temperature to obtain functional information from the tumor site.
Effect of Alanine Energy Response and Phantom Material on Depth Dose Measurements in Ocular Proton Beams
Authors: Palmans Hugo
Published: October 2014

The usefulness of the alanine dosimeter for proton beams has been demonstrated before. In this paper a literature overview is given of the application of alanine in proton beam dosimetry. The energy dependence of the dosimeter has been investigated and Monte Carlo calculations were performed to investigate the influence of this energy dependence on a Bragg curve as well as to explain some phenomena related to the use of alanine in a solid phantom that were reported in the literature.
Quantitative Analysis of Three-dimensional Conformal Radiotherapy Techniques for Posterior Fossa Treatment in Children
Authors: Timmerman Robert D. , Ewing Marveen , Donges Merideth , Wilson Julie , Jakacki Regina , Randall Marcus E.
Published: October 2014

Numerous beam directions using 3-D conformal techniques can be employed in treating tumors in the posterior fossa, each with characteristic normal tissue exposure along the entrance and exit trajectory. A representative variety of beam configurations were modeled in a modern computer planning system initially with the entire posterior fossa as the target. These beams were quantitatively scored using criteria based on integral doses for both low dose and high dose effects encompassing a variety of critical normal structures, thus identifying strengths and weaknesses of each beam. By blocking portions of a particular beam accounting for unfavorable scores, a map of “zones” within the posterior fossa ideally treated by a certain beam or beams could be constructed. No universally ideal photon beam arrangement for the entire posterior fossa target could be identified. However, using single beam analysis, the strengths and weaknesses of particular strategies could be quantified. For example, vertex beams treating the cerebellar hemispheres allow the greatest sparing of cochlea and hypothalamus but at the cost of increased low to moderate dose to the supratentorial brain. Using the constructed maps identifying “zones” appropriately treated by a given beam or beams, three-dimensional conformal treatment plans with favorable dose-volume statistics can be designed based on previously defined normal tissue tolerance considerations. It is shown how this approach can be individualized based on specific patient characteristics (e.g., age). We conclude that radiotherapy directed to the posterior fossa can be optimized based on systematic assessment of individual beam contributions to normal tissues. This technique allows fast selection of treatment beams based on known normal tissue anatomical and tolerance information. Further studies will be required regarding long term effects of various radiation doses on specific volumes of normal tissue in order to individualize beam selection. When treating children, knowledgeable consideration of these beam characteristics can help avoid late effects.
Fluorescence Imaging in Vivo: Raster Scanned Point-Source Imaging Provides More Accurate Quantification than Broad Beam Geometries
Authors: Pogue Brian W. , Gibbs Summer L. , Chen Bin , Savellano Mark
Published: October 2014

Two fluorescence imaging systems were compared for their ability to quantify mean fluorescence intensity from surface-weighted imaging of tissue. A broad beam CCD camera system was compared to a point sampling system that raster scans to create the image. The effects of absorption and scattering in the background tissue volume were shown to be similar in their effect upon the signal, but the effect of the three-dimensional shape of the tissue was shown to be a significant distortion upon the signal. Spherical phantoms with Intralipid and blood for absorber and scatterer were used with a fixed concentration of aluminum phthalocyanine fluorophore to illustrate that the mean intensity observed with the broad beam system increased with size, while the mean intensity observed with the raster scanned system was not as significantly affected. Similar results were observed in vivo with mice injected with the fluorophore and imaged multiple times to observe the pharmacokinetics of the drug. The fluorescence in the tumor observed with the broad beam system was higher than that observed with the raster scanned system. Based upon the phantom and animal observations in this study, it should be concluded that using broad beam fluorescence imaging systems to quantify fluorescence in vivo may be problematic when comparing tissues with different three dimensional characteristics. In particular, the ratio of fluorescence from tumor to normal tissue can yield inaccurate results when the tumor is large. However, similar measurements with a narrow beam system that is raster scanned to create the images are not as significantly affected by the three dimensional shape of the tissue. Raster scanned imaging appears to provide a more uniform and accurate way to quantify fluorescence signals from distributed tissues in vivo.
Inversely Planned Intensity Modulated Radiotherapy of the Breast Including the Internal Mammary Chain: A Plan Comparison Study
Authors: Thilmann Christoph , Sroka-Perez Gabriele , Krempien Robert , Hoess Angelika , Wannenmacher Michael , Debus Jürgen
Published: October 2014

The aim of this paper is to evaluate the benefit of inversely planned intensity modulated radiotherapy (IMRT) in the adjuvant irradiation of breast cancer when internal mammary lymph nodes are included in the treatment volume. 20 patients treated with 3D-planned conventional radiotherapy (CRT) following breast conserving surgery were included in the study. We chose 10 patients with left-sided and 10 patients with right-sided tumors. All treatment volumes included the internal mammary chain. For plan comparison to the applied CRT plan an inverse IMRT-plan in ‘step-and-shoot’-technique was calculated.

For all patients IMRT resulted in an improved conformity of dose distribution to the target volume compared to CRT (mean COIN95: 0.798 vs. 0.514 with COIN95 = C1* C2 (C1= fraction of CTV that is covered by > 95% of the prescribed dose and C2 = volume of CTV that is covered by > 95% of the prescribed dose/total volume that is covered by > 95% of the prescribed dose). In all cases with matching adjacent beams, the homogeneity in the target volume was improved. The volume of the ipsilateral lung irradiated with a dose higher than 20 Gy was reduced with IMRT from 24.6% to 13.1% compared to CRT. For left-sided target volume the heart volume with a dose higher than 30 Gy was reduced from 6.2% to 0.2%.

The presented plan comparison study for irradiation of the breast and the parasternal lymph nodes showed a substantial improvement of the dose distribution by inversely planned IMRT compared to CRT. This is visible for the target volume, the ipsilateral lung and, in case of left-sided target volume, the heart. Despite an increase in integral dose to the entire normal tissue, the application of IMRT might be clinically advantageous in cases where no satisfying dose distribution can be obtained by CRT.
Liver Tumor Cryoablation: A Commentary on the Need of Improved Procedural Monitoring
Authors: Mala Tom , Aurdal Lars , Frich Lars , Samset Eigil , Hol Per Kristian , Edwin Bjørn , Søreide Odd , Gladhaug Ivar
Published: October 2014

Cryoablation is a method used for in situ destruction of liver tumors not eligible for surgical resection. Local recurrences following such treatment have been reported at rates of 5–44%. Insufficient procedural monitoring of the ablation is one plausible explanation for these recurrences. The cryoablative procedure is usually monitored by ultrasonography, but acoustic shadowing and loss of signals, compromise visualisation of the cryolesion circumference. Other monitoring modalities such as computer tomography and invasive methods like the use of thermocouples and impedance measurements have also been studied, but are not in common clinical use as single monitoring modalities. Thermodynamic conditions assumed adequate for tumor eradication are likely to occur only in parts of the cryolesion. This tumoricidal part of the cryolesion is not adequately depicted using any of these modalities.

Magnetic resonance imaging (MRI) provides a clear delineation of the cryolesion circumference. Noninvasive temperature measurements assisted by MRI indicate which parts of the cryolesion that may be subject to complete necrosis. In this article MRI monitored cryoablation of liver tumors is discussed. Improved peroperative monitoring as offered by MRI may reduce the rates of local recurrences after treatment, but further technological improvements are required.
Improved Cryosurgery by Use of Thermophysical and Inflammatory Adjuvants
Authors: Han Bumsoo , Iftekhar Arif , Bischof John C.
Published: October 2014

In the present article, recent research efforts in our laboratory to improve cryosurgery by use of mechanistically derived adjuvants are reviewed. Our research has been focused on enhancing two freezing induced injury mechanisms - i) direct cell injury by use of thermophysical adjuvants, and ii) vascular injury by use of an inflammatory adjuvant. The thermophysical adjuvants are chemicals, usually salts, which can induce secondary crystallization, called eutectic solidification, in a cryolesion; thereby enhancing direct cell injury. The inflammatory adjuvant is a cytokine, tumor necrosis factor-alpha (TNF-α), which upregulates inflammation of microvasculature in tumors prior to freezing to promote vascular injury in the cryolesion. Even though the individual mechanism of injury enhancement within the cryolesion of each adjuvant requires further study, both adjuvants are envisioned to enlarge the complete killing zone so that the boundary of the cryolesion matches more closely with the edge of ice-ball. By bringing the edge of the cryolesion closer to the edge of iceball, the adjuvants hold promise for improvement of image guidance and outcome of cryosurgery.
Parametric Analysis of Intercellular Ice Propagation during Cryosurgery, Simulated Using Monte Carlo Techniques
Authors: Stott Shannon L. , Irimia Daniel , Karlsson Jens O.M.
Published: October 2014

A microscale theoretical model of intracellular ice formation (IIF) in a heterogeneous tissue volume comprising a tumor mass and surrounding normal tissue is presented. Intracellular ice was assumed to form either by intercellular ice propagation or by processes that are not affected by the presence of ice in neighboring cells (e.g., nucleation or mechanical rupture). The effects of cryosurgery on a 2D tissue consisting of 104 cells were simulated using a lattice Monte Carlo technique. A parametric analysis was performed to assess the specificity of IIF-related cell damage and to identify criteria for minimization of collateral damage to the healthy tissue peripheral to the tumor. Among the parameters investigated were the rates of interaction-independent IIF and intercellular ice propagation in the tumor and in the normal tissue, as well as the characteristic length scale of thermal gradients in the vicinity of the cryosurgical probe. Model predictions suggest gap junctional intercellular communication as a potential new target for adjuvant therapies complementing the cryosurgical procedure.
Cryotherapy for Liver Tumors: Current Status, Perspectives, Clinical Results, and Review of Literature
Authors: Seifert J. K. , Junginger T.
Published: October 2014

Cryotherapy has gained importance as a locally ablative treatment option for patients with non-resectable liver tumors, especially metastases from colorectal cancer. We have used this technique since 1996 for the treatment of 77 patients with malignant liver tumors. Patient data was prospectively recorded and follow-up was until September 2002 or death. Fifty-five patients had colorectal cancer liver metastases, 16 metastases from other primaries and 6 had hepatoma. Forty patients had cryotherapy only and 37 had an additional liver resection. Morbidity and mortality were 22% and 1.3%, respectively.

In 68% of patients with colorectal liver metastases and an elevated serum carcinoembryonic antigen-level preoperatively, it returned to the normal range following cryosurgery. For all 77 patients, median survival was 28 months with a 3- and 5-year-survival rate of 39% and 26%, respectively, and median survival was 29 months with a 3- and 5-year-survival rate of 44% and 26%, respectively, for the 55 patients with colorectal liver metastases.

Local recurrence at the cryosite was observed in 13 of 65 patients (20%) with initially complete treatment. For cryotherapy to further establish as a treatment for malignant liver tumors in a time where many new local ablative techniques are developing, different goals need to be achieved.

The trauma of the procedure and local treatment failure need to be minimized and survival results need to be optimized. Published studies and new possible fields of research regarding these goals are discussed.
Cryosurgery for Breast Cancer
Authors: Kaufman Cary S. , Rewcastle John C.
Published: October 2014

As the majority of breast cancers present as small non-palpable lesions, alternatives for surgical lumpectomy come into consideration. Breast tumor ablation without surgical excision may be a less morbid procedure without sacrificing cancer control. Cryosurgery is one of several ablative options for the treatment of small unifocal breast cancer. The potential advantages include avoidance of a surgical procedure, less overall discomfort, improved cosmesis, quicker recovery and the prospect of overall cost benefits. Clinical experience in 29 patients is reviewed demonstrating effectiveness in properly chosen patients. A comparison of ablation methods is discussed. Finally, future research of the role of cryosurgery in the management of breast cancer is described.
Computerized Planning of Cryosurgery Using Cryoprobes and Cryoheaters
Authors: Rabin Yoed , Lung David C. , Stahovich Thomas F.
Published: October 2014

In a typical minimally invasive cryoprocedure, multiple cryoprobes are inserted into the tissue with the goal of maximizing cryoinjury within a predefined target region, while minimizing cryoinjury to the surrounding tissues. A temperature-controlled electrical heater has been developed recently by this research team, in order to assist in limiting the cryoinjury to the target region. The new device has been termed a ‘cryoheater,’ and it can work with any cryosurgical cooling technique. A prototype computerized planning tool has been presented recently by this research team, which helps to determine the best locations in which to insert the cryoprobes. This prototype was designed for cryoprobes only. The planning procedure utilized a novel iterative optimization technique, based on a force-field analogy. The combination of cryoheaters with computerized planning is the subject matter of this report. The current report includes a review of cryoheater development, and presents an improved cryosurgery planning tool which incorporates cryoheaters.
In Treating Localized Prostate Cancer the Efficacy of Cryoablation is Independent of DNA Ploidy Type
Authors: Bahn Duke K. , Silverman Paul , Lee Fred , Badalament Robert , Bahn Eric D , Rewcastle John C.
Published: October 2014

While the prognostic value of DNA ploidy has been well established for radical prostatectomy, external beam radiation, brachytherapy and androgen deprivation therapy its role as a survival outcome predictor for prostate cancer patients treated with cryoablation has not yet been examined. Anecdotal evidence suggesting that cryoablation may be independent of DNA ploidy type led to the implementation of the current study. Retrospective analysis of data including flow digital cytometry was performed on 447 archival specimens taken from patients who had undergone cryosurgical ablation of primary prostate cancer. Five-year biochemical disease free survivals (bDFS) (defined as PSA thresholds of 0.5 and 1.0 ng/ml) were determined with Kaplan-Meier analysis. Patients were grouped according to DNA ploidy types then stratified by Gleason grade, risk group, pre-surgical PSA level, and disease stage.

Mean and median age of the cohort was 65 and 64.6 years. Mean follow-up was 65.7 months. The DNA ploidy status of the population was found to be 59% diploid, 13% tetraploid, and 28% aneuploid. Using PSA < 1.0 ng/ml criterion, the bDFS rates for diploid, tetraploid, and aneuploid were 78%, 75%, and 79% respectively. The bDFS rates using a PSA < 0.5 ng/ml criterion were 67%, 59%, and 69% for diploid, tetraploid, and aneuploid groups. No significant outcome differences were found in stratified analysis. This investigation demonstrates that the efficacy of cryoablation is independent of DNA ploidy type.
Radiation Dosimetry of a Conformal Heat-brachytherapy Applicator
Authors: Taschereau Richard , Stauffer Paul R. , Hsu I-Chow , Schlorff Jaime L. , Milligan Andrew J. , Pouliot Jean
Published: October 2014

The purpose of this paper is to report the radiation dosimetric characteristics of a new combination applicator for delivering heat and radiation simultaneously to large area superficial disease <1.5 cm deep. The applicator combines an array of brachytherapy catheters (for radiation delivery) with a conformal printed circuit board microwave antenna array (for heat generation), and a body-conforming 5–10 mm thick temperature-controlled water bolus. The rationale for applying both modalities simultaneously includes the potential for significantly higher response rate due to enhanced synergism of modalities, and lower peak toxicity due to temporal extension of heat and radiation induced toxicities. Treatment plans and radiation dosimetry are calculated with IPSA (an optimization tool developed at UCSF) for 15 × 15 cm2 and 35 × 24 cm2 applicators, lesion thicknesses of 5 to 15 mm, flat and curved surfaces, and catheter separation of 5 and 10 mm. The effect on skin dose of bolus thickness and presence of thin copper antenna structures between radiation source and tissue are also evaluated. Results demonstrate the ability of the applicator to provide conformal radiation dose coverage for up to 15 mm deep target volumes under the applicator. For clinically acceptable plans, tumor coverage is > 98%, homogeneity index > 0.95 and the percentage of normal tissue irradiated is < 20%. The dose gradient at the skin surface varies from 3 to 5 cGy/mm depending on bolus thickness and lesion depth. Attenuation of the photon beam by the printed circuit antenna array is of the order 0.25% and secondary electron emissions are absorbed completely within 5 mm of water bolus and plastic layers. Both phenomena can then be neglected in dose calculations allowing commercial software to be used for treatment planning. This novel applicator should prove useful for the treatment of diffuse chestwall disease located over contoured anatomy that may be difficult to treat with single field external beam therapy. By delivering heat and radiation simultaneously, increased synergism is expected with a TER in the range of 2–5. Lowering radiation dose by an equivalent factor may produce lower radiation toxicity with similar efficacy, while preserving the option of subsequent retreatment(s) with thermoradiotherapy in order to further extend patient survival.
Fiducial Markers Implanted during Prostate Brachytherapy for Guiding Conformal External Beam Radiation Therapy
Authors: Welsh James S. , Berta Christine , Borzillary Scott , Sam Celis , Shickell Derek , Nobile Lisa , Greenberg Marsha , Weiss Stephanie , Detorie Nicholas
Published: October 2014

Prostate movement imposes limits on safe dose-escalation with external beam radiation therapy. If the precise daily location of the prostate is known, dose escalation becomes more feasible. We have developed an approach to dose escalation using a combination of prostate brachytherapy followed by external beam radiation therapy in which fiducial markers are placed along with125 I seeds during transperineal interstitial permanent prostate brachytherapy. These markers serve to verify daily prostate location during the subsequent external beam radiotherapy. Prior to implementing this approach, preliminary studies were performed to test visibility of the markers. Three different125 I seed models, as well as gold and silver marker seeds were placed within tissue-equivalent phantoms. Images were obtained with conventional x-rays (75–85 kV) and 6 MV photons from a linear accelerator. All125 I seed models were clearly visible on conventional x-rays but none were seen with 6 MV photons. The gold markers were visible with both energies. The silver markers were visible with conventional x-rays and 6 MV x-rays, but not as clearly as the gold seeds at 6 MV. Subsequently, conventional x-rays, CT scans, and 6 MV port films were obtained in 29 patients in whom fiducial gold marker seeds were implanted into the prostate during125 I prostate brachytherapy. To address the possibility of “seed migration” within the prostate, CT scans were repeated 5 weeks apart in 14 patients and relative positions of the gold seeds were evaluated. The repeated CT scans showed no change in intraprostatic gold marker location, suggesting minimal migration. The gold seeds were visible with conventional x-rays, CT, and 6 MV port films in all patients. During the course of external beam radiation therapy, the gold markers were visible on routine 6 MV port films and were seen in different locations from film to film suggesting prostate motion. Mean daily displacement was 4–5 mm in the anterior-posterior, and 4–5 mm in superior-inferior dimensions. Left-right displacement appeared less, averaging 2–3 mm. We conclude that implantation of gold marker seeds during prostate brachytherapy represents an easily implemented and practical means of prostate localization during subsequent image-guided external beam radiotherapy. With such markers, conformality of the external beam component can be confidently improved without expensive new equipment.
Cryotherapy of Musculoskeletal Tumors — From Basic Science to Clinical Results
Authors: Robinson Dror , Yassin Mustafa , Nevo Zvi
Published: October 2014

Combined modality treatment of musculoskeletal tumors led to improved patient survival. As survival improves, more consideration is given to the functional outcome of treatment, and interest is focused on the development of less mutilating and extensive surgery. One modality that can reduce patient disability significantly is cryosurgery, as it allows minimally invasive surgery based on marginal resection and tumor interface sterilization instead of wide resection of certain neoplasms. Classical cryosurgery as developed by Marcove involves pouring of liquid nitrogen into the tumor bed. This approach revolutionized the treatment of some tumors such as giant cell tumor of bone, allowing intra-lesional resection to substitute the wide-resection method used up to that time. However, complications of this method of treatment are common, including nitrogen emboli, fractures of the bone due to extensive necrosis and damage to neurovascular elements. A recent development in the field of cryosurgery has been the argon-based system allowing controlled formation of an ice-ball surrounding a metallic probe. The system is computer controlled and allows precise evaluation of the tumor bed interface as well as surrounding structures that need to be protected. Prior to application of this method in humans it is important to ensure that interface sterilization is indeed achieved using cryosurgery. To evaluate this question, a Swarm rat chondrosarcoma was used. Cell viability was assessed following ice-ball formation. Histological evaluation indicated that cell death occurs up to 5 millimeters from the ice-ball if temperatures of −40° Celsius at the metallic probe are achieved. A further evaluation was performed on samples obtained from patients during surgery. A minimum of two freezing cycles was shown to be necessary to achieve tissue viability similar to that of boiled tissue. Twenty-seven patients were operated to date using an argon-based cryosurgery system. The patients included 7 cases of grade I chondrosarcoma, 5 cases of giant cell tumor of bone, 14 cases of a metastatic lytic bone lesion and a single case of osseous-fibrous dysplasia. None of the patients suffered nerve injury during the operation. After a minimal follow-up period of 2 years only two of the surviving patients had a recurrence (a giant cell tumor of the proximal fibula, and the patient with the osseous-fibrous dysplasia whose tumor recurred as a frankly malignant adamantimoma). There were no pathological fractures. This method appears practical and allows close monitoring of the surrounding tissue to reduce the chances of recurrence.
Modifications of Cellular Autofluorescence Emission Spectra under Oxidative Stress Induced by 1 α,25dihydroxyvitamin D3 and its Analog EB1089
Authors: Bondza-Kibangou Patrick , Millot Christine , Dufer Jean , Millot Jean-Marc
Published: October 2014

We attempted to characterize the cellular autofluorescence phenomenon of living HL-60 cells and to appraise its modifications under oxidative stress conditions induced by 1α,25(OH)2D3 (VD3) and its analog EB1089. Autofluorescence emission spectra of human promyelocytic HL-60 leukemic cells were monitored using laser scanning confocal microspectrofluorometry under UV excitation. Evaluation of reactive oxygen species (ROS) release was performed using the 2′,7′-dichlorodihydrofluorescein diacetate (H2-DCFDA) staining and fluorescence emission measurement. VD3 (1, 10, 100 nM) or EB1089 (0.1, 1 and 10 nM) induces a decrease in autofluorescence emission intensity that can be attributed to the oxidation of the coenzyme nicotinamide adenine dinucleotide (phosphate) NAD(P)H into NAD(P)+. A dose-dependent increase (p<0.05) in ROS release is observed in VD3- and EB1089-treated cells. As compared with VD3- or EB1089-treated cells, doxorubicin-VD3 or doxorubicin-EB1089 treatments strongly decrease the autofluorescence intensity and induce a higher release of ROS (p<0.05). The association of antioxidants (N-acetyl cysteine, superoxide dismutase, catalase) with VD3 or EB1089 induce a more limited autofluorescence decrease and a weaker ROS generation, as compared with VD3 and EB1089 treated cells. In conclusion, the free radicals release, generated by VD3 and EB1089, was associated with the decrease in autofluorescence emission and can be modulated by doxorubicin and antioxidants.
Cassette-based Digital Mammography
Authors: Seibert J. Anthony , Boone John M. , Cooper Virgil N. , Lindfors Karen K.
Published: October 2014

Over the past several years, digital mammography systems have been installed clinically across North America in small but growing numbers. A photostimulable phosphor-based full-field digital mammography image was evaluated in this investigation. Commonly known as computed radiography (CR), its use closely mimics the screen-film mammography paradigm. System performance using modulation transfer function (MTF) and detective quantum efficiency (DQE) metrics show MTF(2.5 mm−1) = 0.5, DQE(2.5 mm−1) = 0.3, and MTF(5.0 mm−1) = 0.2, DQE(5.0 mm−1) = 0.05, for a 26 kVp beam, 0.03 mm molybdenum tube filtration, 4.5 cm tissue attenuation, and 15 mR incident exposure to the detector. Slightly higher DQE values were measured at 32 kVp with 0.025 mm rhodium tube filtration. CR mammography advantages include the ability to use existing mammography machines, where multiple rooms can be converted to “digital” operation, which allows overall cost savings compared to integrated digital mammography systems. Chief disadvantages include the labor-intensive handling of the cassettes prior to and after the imaging exam, lack of a direct interface to the x-ray system for recording technique parameters, and relatively slow processing time. Clinical experience in an IRB-approved research trial has suggested that digital mammography with photostimulable storage phosphors and a dedicated CR reader is a viable alternative to conventional screen-film mammography.
Gene Therapy Applications of Viral Vectors
Authors: Lundstrom Kenneth
Published: October 2014

Viral vectors have frequently been applied in gene therapy with the final goal of treating various diseases in the areas of neurology, neurodegeneration, metabolic disease, and cancer. Vectors have been engineered based on AAV, adenoviruses, alphaviruses, herpes simplex viruses, lentiviruses, and retroviruses. Some vectors are suitable for short-term episomal transgene expression, whereas others are integrated into the host cell genome to provide long-term expression. Additionally, hybrid vectors with favorable features from different viruses have been developed. Therapeutic genes of choice have typically been toxic genes such as thymidine kinase, pro-apoptotic genes like Bax, and immunostimulatory genes (for instance, interleukin-12). A large number of animal studies have demonstrated proof of concept of viral gene therapy. Many types of viral vectors have been employed in more than 700 clinical trials that have been carried out or are currently in progress.
Effects of High Intensity Focused Ultrasound on Vascular Endothelial Growth Factor in Melanoma Bearing Mice
Authors: Yang Xueqin , Bai Jin , Yu Tinghe , Wang Zhibiao , Li Qingfeng
Published: October 2014

This study was to investigate the effects of high intensity focused ultrasound on vascular endothelial growth factor. A B16 melanoma model was adopted in our study. Melanoma bearing mice were randomly divided into two groups: HIFU group and surgery group. While the control group was only injected with isovolumetric normal saline solution and treated as the surgery group. We detected VEGF both in tissues and sera through immunohistochemical method and ELISA respectively. Tissues were sampled pre- and at the 3rd day post-operation in HIFU group and blood samples were taken pre- and at the 1st, 3rd, and 7th day post-operation in all the groups. As a result, in the tissues, VEGF was expressed in 80% melanomas, but none was detected in the targeted area after HIFU treatment. In the sera, there was a decreasing tendency of serum-VEGF concentrations in group HIFU and surgery after operation, while that in the control group increased after operation. The levels in the HIFU group on day 1, 3, and 7 postoperatively were all lower than that in the surgery group respectively (79.16 pg/ml vs 91.59 pg/ml; 33.64 pg/ml vs 49.39 pg/ml; 30.37 pg/ml vs 46.68 pg/ml), but there wasn't any significant difference (P > 0.05). So HIFU can destroy VEGF in the targeted area and maybe have less of an effect on serum-VEGF than surgery.
Differentiating Surgical from Non-Surgical Lesions using Perfusion MR Imaging and Proton MR Spectroscopic Imaging
Authors: Law Meng , Hamburger Micole , Johnson Glyn , Inglese Matilde , Londono Ana , Golfinos John , Zagzag David , Knopp Edmond A.
Published: October 2014

Advanced MRI techniques, such as MR spectroscopy, diffusion and perfusion MR imaging can give important in vivo physiological and metabolic information, complementing morphologic findings from conventional MRI in the clinical setting. Combining perfusion MRI and MR spectroscopy can help in patients with brain masses in who the pre-operative differential diagnosis is unclear. This review demonstrates the use of dynamic, susceptibility weighted, contrast-enhanced MR imaging (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI) to distinguish surgical from non-surgical lesions in the brain. There is overlap in the MRI appearance of many enhancing and ring-enhancing lesions such as gliomas, metastases, inflammatory lesions, demyelinating lesions, subacute ischemia, abscess and some AIDS related lesions. We review examples of histopathologically confirmed high-grade glioma, a middle cerebral artery territory infarct, a tumefactive demyelinating lesion and a metastasis for which conventional MR imaging (MRI) was non-specific and potentially misleading and demonstrate how DSC MRI and MRSI features were used to increase the specificity of neurodiagnosis. At several institutions, many patients routinely undergo MRI as well as MRSI and DSC MRI. Cerebral blood flow (CBF), mean transit time (MTT), and relative cerebral blood volume (rCBV) measurements are obtained from regions of maximal perfusion as determined from perfusion color overlay maps. Metabolite levels and ratios are determined for Choline (Cho), N-Acetyl Aspartate (NAA), Lactate and Lipids (LL). Metabolite levels are obtained by measuring the peak heights of each metabolite and the ratios are obtained from these measurements for Cho/Cr, Cho/NAA and NAA/Cr. Neurosurgical intervention carries substantial morbidity, mortality, financial and potential emotional cost to the patient and family. Making a pre-operative diagnosis allows the neurosurgeon to be confident in the choice of treatment plan for the patient and allays considerable patient anxiety. The utility of combining clinical findings with multi-parametric information from perfusion and spectroscopic MR imaging in differentiating surgical lesions from those which do not require surgical intervention is discussed.
Resolution and Contrast in Magnetic Resonance Electrical Impedance Tomography (MREIT) and its Application to Cancer Imaging
Authors: Muftuler L. Tugan , Hamamura Mark , Birgul Ozlem , Nalcioglu Orhan
Published: October 2014

It has been reported that the electrical impedance of malignancies could be 20–40 times lower than healthy tissues and benign formations. Therefore, in vivo impedance imaging of suspicious lesions may prove to be helpful in improving the sensitivity and specificity of detecting malignant tumors. Several systems have been developed to map the conductivity distribution inside a volume of tissue, however they suffer from poor spatial resolution because the measurements are taken only from surface electrodes. MRI based impedance imaging (MREIT) is a novel method, in which weak electrical currents are injected into the tissue and the resulting perturbations in the magnetic field are measured using MRI. This method has been shown to provide better resolution compared to previous techniques of impedance imaging because the measurements are taken from inside the object on a uniform grid. Thus, it has the potential to be a useful modality that may detect malignancies earlier. Several phantom imaging experiments were performed to investigate the spatial resolution and dynamic range of contrast of this technique. The method was also applied to a live rat bearing a R3230 AC tumor. Tumor location was identified by contrast enhanced imaging.
Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy
Authors: Sahu R. K. , Argov S. , Salman A. , Huleihel M. , Grossman N. , Hammody Z. , Kapelushnik J. , Mordechai S.
Published: October 2014

FTIR spectroscopy has been extensively used to understand the differences between normal and malignant cells and tissues. In the present study, FTIR microspectroscopy was performed on biopsies to evaluate parameters deduced from changes in nucleic acid absorbance monitored at various characteristic wavenumbers in the Mid-IR region. The data showed that there were differences in the spectra of normal and malignant tissues from several organs such as colon, cervix, skin and blood with respect to absorbance due to nucleic acids. Similar results were observed in the case of cell lines that were transformed to induce carcinogenesis. Of the several ratios examined for consistency in differentiating cancer and normal tissues, the I(996 cm−1)/I(966 cm−1) showed promise as a distinguishing parameter and was comparable to the I(1121 cm−1)/I(1020 cm−1) ratio reported in many earlier studies. The absorbance of nucleic acids is presented with an emphasis on the application of FTIR microspectroscopy for diagnosis of malignancy. Our results indicate that usage of nucleic acid absorbance yield statistically significant parameters, which could differentiate normal and cancerous tissues.
Nanoparticle Based Systemic Gene Therapy for Lung Cancer: Molecular Mechanisms and Strategies to Suppress Nanoparticle-Mediated Inflammatory Response
Authors: Gopalan Began , Ito Isao , Branch Cynthia D. , Stephens Clifton , Roth Jack A. , Ramesh Rajagopal
Published: October 2014

Cancer gene therapy for the treatment of lung cancer has shown promise in the laboratory and in Phase I/II clinical trials. However, it is currently limited to treating localized tumors due to host-immunity against the gene delivery vector and the transgene. Therefore, there is a tremendous effort to develop and test alternate gene delivery vectors that are efficient, non-immunogenic, and applicable for systemic therapy. One such gene delivery vehicle is the non-viral vector, DOTAP: cholesterol (DOTAP:Chol) nanoparticle. Preclinical studies from our laboratory has shown that DOTAP:Chol. nanoparticles are effective systemic gene delivery vectors that efficiently deliver tumor-suppressor genes to disseminated lung tumors. Based on our findings we have recently initiated a Phase-I trial for systemic treatment of lung cancer using a novel tumor suppressor gene, FUS1. Although DOTAP:Chol. nanoparticles complexed to DNA (DNA-nanoparticles) are efficient vectors for systemic therapy, induction of an inflammatory response in a dose-dependent fashion has also been observed thereby limiting its use. A better understanding of the underlying mechanism for DNA-nanoparticles-mediated inflammatory response will allow us to develop strategies to suppress inflammation and expand the therapeutic window in treating human cancer. In the present study we conducted experiments examining the mechanism of nanoparticle-mediated inflammatory response in vitro and in vivo. We demonstrate that systemic administration of DNA-nanoparticles induced multiple signaling molecules both in vitro and in vivo that are associated with inflammation. Use of small molecule inhibitors against the signaling molecules resulted in their suppression and thereby reduced inflammation without affecting transgene expression. Our results provide a rationale to use small molecule inhibitors to suppress nanoparticle-mediated inflammation when administered systemically. Further development and testing will allow us to incorporate this strategy into future clinical trials that is based on systemic non-viral vector gene therapy.