bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic IMRT Treatments of Sinus Region Tumors: Comparison of Monte Carlo Calculations with Treatment Planning System Calculations and Ion Chamber Measurements
Authors: Court Laurence E. , Jahnke Lennart , Chin David , Song Jun , Cormack Robert , Zygmanski Piotr , Tishler Roy B. , Chin Lee
Published: October 2014

Results are presented comparing Monte Carlo (MC) calculations for dynamic IMRT treatments of tumors in the sinus region with Eclipse treatment planning system dose calculations, and ion chamber measurements. The EGS4nrc MC code, BEAMnrc, was commissioned to simulate a Varian 21Ex Linac for both open and IMRT fields. The accuracy of the simulation for IMRT plans was evaluated using a head phantom by comparing MC, Eclipse, TLD results, and ion chamber in solid water phantom measurements. The MC code was then used to simulate dose distributions for five patients who were treated using dynamic IMRT for tumors in the sinus region. The results were compared with absolute and relative dose distributions calculated using Eclipse (pencil beam, modified-Batho inhomogeneity correction). Absolute dose differences were also compared with ion chamber results. Comparison of the doses calculated on the head phantom using MC, compared with Eclipse, ion chamber, and TLD measurements showed differences of −3.9%, −1.4%, and −2.0%, respectively (MC is colder). Relative dose distributions for the patient plans calculated using MC agreed well with those calculated using Eclipse with respect to targets and critical organs, indicating the modified-Batho correction is adequate. Average agreement for mean absolute target doses between MC and Eclipse was −3.0 ± 2.3% (1 s.d.). Agreement between ion chamber and Eclipse for these patients was −2.2 ± 1.9%, compared with 0.2 ± 2.0% for all head and neck IMRT patients. When Eclipse doses were corrected based on ion chamber results, agreement between MC and Eclipse was −0.7 ± 2.0%, indicating a small systematic uncertainty in the doses calculated using the treatment planning system for this subset of patients.
Single Course IMRT Plan to Deliver 45 Gy to Seminal Vesicles and 81 Gy to Prostate in 45 Fractions
Authors: Reddy Nandanuri M. S. , Sood Brij Mohan , Sampath Seshadri , Mazur Andrej , Osian Adrian , Ravi Akkamma , Poli Jaganmohan , Nori Dattatreyudu
Published: October 2014

We treat prostate and seminal vesicles (SV) to 45 Gy in 25 fractions (course 1) and boost prostate to 81 Gy in 20 more fractions (course 2) with Intensity Modulated Radiation Therapy (IMRT). This two-course IMRT with 45 fractions delivered a non-uniform dose to SV and required two plans and two QA procedures. We used Linear Quadratic (LQ) model to develop a single course IMRT plan to treat SV to a uniform dose, which has the same biological effective dose (BED) as that of 45 Gy in 25 fractions and prostate to 81 Gy, in 45 fractions. Single course IMRT plans were compared with two-course IMRT plans, retrospectively for 14 patients. With two-course IMRT, prescription to prostate and SV was 45 Gy in 25 fractions and to prostate only was 36 Gy in 20 fractions, at 1.8 Gy/fraction. With 45-fraction single course IMRT plan, prescription to prostate was 81 Gy and to SV was 52 or 56 Gy for a α/β of 1 and 3, respectively. 52 Gy delivered in 45 fractions has the same BED of 72 Gy3 as that of delivering 45 Gy in 25 fractions, and is called Matched Effective Dose (MED). LQ model was used to calculate the BED and MED to SV for α/β values of 1–10. Comparison between two-course and single course IMRT plans was in terms of MUs, dose-max, and dose volume constraints (DVC). DVC were: 95% PTV to be covered by at least 95% of prescription dose; and 70, 50, and 30% of bladder and rectum should not receive more than 40, 60, and 70% of 81 Gy. SV Volumes ranged from 2.9–30 cc. With two-course IMRT plans, mean dose to SV was non-uniform and varied between patients by 48% (54 to 80 Gy). With single-course IMRT plan, mean dose to SV was more uniform and varied between patients by only 9.6% (58.2 to 63.8 Gy), to deliver MED of 56 Gy for α/β − 1. Single course IMRT plan MUs were slightly larger than those for two-course IMRT plans, but within the range seen for two-course plans (549–959 MUs, n=51). Dose max for single-course plans were similar to two-course plans. Doses to PTV, rectum and bladder with single course plans were as per DVC and comparable to two-course plans. Single course IMRT plan reduces IMRT planning and QA time to half.
Linac-Based Intensity Modulated Total Marrow Irradiation (IM-TMI)
Authors: Aydogan Bulent , Mundt Arno J. , Roeske John C.
Published: October 2014

Total body irradiation (TBI) has been used as a form of systemic therapy for the treatment of hematological malignancies and as a pre-conditioning regimen prior to bone marrow transplant. However, standard techniques are associated with both acute and chronic toxicities due to the large volumes of normal tissue irradiated. Intensity modulated radiation therapy (IMRT), with its ability to conform the high dose region to the shape of the target, offers a method to reduce radiation related sequelae and potentially allow for the delivery of higher than conventional doses. The goal of this study is to investigate the feasibility of a linac-based approach to intensity modulated total marrow irradiation (IM-TMI) and to discuss the challenges associated with its clinical implementation. The successful development of linac-based IM-TMI would represent advancement in the field of radiotherapy and potentially reduce the incidence and severity of complications associated with current TBI techniques.
In Vivo Tumor Imaging in Mice Using a State-of-the-Art Clinical PET/CT in Comparison with a Small Animal PET and a Small Animal CT
Authors: Seemann Marcus D. , Beck Roswitha , Ziegler Sibylle
Published: October 2014

The aim of this prospective study was to assess the feasibility of a state-of-the-art clinical PET/CT scanner for in vivo tumor imaging in mice in comparison to a small animal PET scanner and a small animal CT scanner.

Seventeen female NMRI nude mice bearing a subcutaneous transplanted murine mammary carcinoma (EMT6) on the right hind limb were examined using a clinical PET/CT scanner (biograph Sensation 16®), a dedicated small animal PET scanner (MOSAIC® system), and a dedicated small animal CT scanner (MicroCAT® II). 18F-fluoroazomycin arabinoside (18F-FAZA) was used as PET tracer for imaging of regional tumor hypoxia.

The examination of tumor-bearing mice using a state-of-the-art clinical PET/CT scanner, a dedicated small animal PET scanner and a dedicated small animal CT scanner revealed good image quality and allowed the evaluation and correlation of molecular/metabolic alterations of cancers with anatomical/morphological findings. The tumor lesions showed a 1.89 ± 0.6 higher mean tumor-to-background ratio ± SD for the dedicated small animal PET scanner than the PET from the clinical PET/CT scanner (P<0.001). The mean tumor-to-background ratio of the PET of the clinical PET/CT scanner showed a high correlation with the mean tumor-to-background ratio of the dedicated small animal PET scanner (r2 = 0.92). The tissue hypoxia in the subcutaneous transplanted EMT6 tumors did not correlate with the tumor volume.

Clinical PET/CT scanners are widely available and could contribute not only to human clinical routine examinations, but also to tumor research in animals. The molecular/metabolic information is reduced when imaging small tumors of mice with clinical PET/CT scanners due to the low spatial resolution and sensitivity of the PET scanners. The examination of small tumors in mice should be resevered to research centers with small animal PET/CT scanners because they provide promising hope to achieve accurate measurement of activity concentration. For tumor research in humans and animals using clinical PET/CT scanners, PET scanners with a higher spatial resolution and a higher sensitivity will be highly promising, but will be in competition to PET/MRI.
Dissection of Signaling Pathways in Fourteen Breast Cancer Cell Lines Using Reverse-Phase Protein Lysate Microarray
Authors: Akkiprik Mustafa , Nicorici Daniel , Cogdell David , Jia Yu Jack , Hategan Andrea , Tabus Ioan , Yli-Harja Olli , Yu Dihua , Sahin Aysegul , Zhang Wei
Published: October 2014

Signal transduction pathways play a crucial role in breast cancer development, progression, and response to different therapies. A major problem in breast cancer therapy is the heterogeneity among different tumor types and cell lines commonly used in preclinical studies. To characterize the signaling pathways of some of the commonly used breast cancer cell lines and dissect the relationship among a number of pathways and some key genetic and molecular events in breast cancer development, such as p53 mutation, ErbB2 expression, and estrogen receptor (ER)/progesterone receptor (PR) status, we performed pathway profiling of 14 breast cancer cell lines by measuring the expression and phosphorylation status of 40 different cell signaling proteins with 53 specific antibodies using a protein lysate array. Cluster analysis of the expression data showed that there was close clustering of phosphatidylinositol 3-kinase, Akt, mammalian target of rapamycin (mTOR), Src, and platelet-derived growth factor receptor β (PDGFRβ) in all of the cell lines. The most differentially expressed proteins between ER- and PR-positive and ER- and PR-negative breast cells were mTOR, Akt (pThr308), PDGFRβ, PDGFRβ (pTyr751), panSrc, Akt (pSer473), insulin-like growth factor-binding protein 5 (IGFBP5), Src (pTyr418), mTOR (pSer2448), and IGFBP2. Many apoptotic proteins, such as apoptosis-inducing factor, IGFBP3, bad, bax, and cleaved caspase 9, were overexpressed in mutant p53-carrying breast cancer cells. Hexokinase isoenzyme 1, ND2, and c-kit were the most differentially expressed proteins in high and low ErbB2-expressing breast cancer cells. This study demonstrated that ER/PR status, ErbB2 expression, and p53 status are major molecules that impact downstream signaling pathways.
Clusterin Expression and Univariate Analysis of Overall Survival in Human Breast Cancer
Authors: Zhang Shiwu , Zhang Danfang , Zhu Yue , Guo Hua , Zhao Xiulan , Sun Baocun
Published: October 2014

The aim of this research is to investigate the significance of clusterin (CLU) expression as a risk factor for breast cancer through tissue microarray technology and univariate analysis of overall survival. Formalin-fixed, paraffin-embedded tissues from 158 cases of breast cancer and 31 cases of normal adjacent tissues assembled into a tissue microarray. Cytoplasmic CLU expression in tumor tissues was measured by immunochemistry. Survival analysis was used to investigate the relationship between CLU expression and prognosis, tumor volume, pathological classification, and recurrence. Survival time of patients with CLU expression, lymph node metastasis, and limited post-surgery chemotherapy (<6 cycles of treatment) was significantly shorter than that of patients with no detectable CLU expression ( P=0.000), without lymph node metastasis ( P=0.000) and more comprehensive post-surgery chemotherapy (≥6 cycles of treatment) ( P=0.035). CLU expression in tumor cells was higher than in normal adjacent breast epithelial cells ( P=0.03). The CLU expression staining coefficient of cancer tissues with lymph node metastasis was higher than those without lymph node metastasis ( P=0.000). Cytoplasmic CLU expression was found to be a prognostic factor for human breast cancer.
The Role for Intensity Modulated Radiation Therapy (IMRT) in Pediatric Population
Authors: Bhatnagar Ajay , Deutsch Melvin
Published: October 2014

The purpose of this study was to evaluate our initial experience on the use of IMRT in children with tumors in eloquent or critical locations. Twenty-two children with a median age of 12 years (range 1–17) were treated using IMRT for tumors which were within 2 cm of a critical structure. The treatment locations were spine [2], head and neck [5], abdominopelvic [8], and intracranial [7]. Eighty-two percent (82%) of patients were treated with curative intent despite most patients having advanced or metastatic disease and two patients having previously received standard external beam radiation. IMRT was delivered with a 6MV linear accelerator using dynamic multileaf collimators with a median of six fields. The median follow-up was five months [1–21]. The median administered dose was 45 Gy. The median planning treatment volume (PTV) was 105.4 cc. For the intracranial lesions, the mean doses to the pituitary, brainstem, cochlea, optic nerve, and lens were 31%, 42%, 17%, 27%, and 6% of the total dose, respectively. For the head and neck tumors, the mean doses to the spinal cord and parotid glands were 47% and 49%, respectively. For the pelvic tumors, the mean dose to the bladder, rectum, and small bowel were 51%, 63%, and 22%, respectively. Local failure occurred in one patient. IMRT resulted in substantial sparing of surrounding critical structures and acceptable local control rate for these tumors in children. Further follow-up is needed to assess long-term local control and late effects.
Development of a Tissue Engineered Human Prostate Tumor Equivalent for Use in the Evaluation of Cryoablative Techniques
Authors: Robilotto Anthony T. , Clarke Dominic , Baust John M. , Van Buskirk Robert G. , Gage Andrew A. , Baust John G.
Published: October 2014

The study of the effectiveness of cryotherapy as a curative treatment for prostate cancer has often relied on the use of either in vitro cell culture monolayers or animal models. While the data gleaned from these studies have been valuable, each model has inherent limitations. In order to bridge the gap between in vitro studies and clinical applications, we developed a 3-dimensional, tissue engineered human prostate cancer model to simulate and assess the effects of cryotherapy and adjunctive treatments on cell viability and activation of cell death pathways throughout the thermally variable freeze zone.

Human prostate cancer cells (PC3) were seeded into collagen based matrices and cryolesions were generated using an Oncura SeedNet® Gold cryosurgical device with 17-gauge cryoprobes. Analyses revealed widespread necrosis diminishing towards the edge of the freeze zone, and a time-dependent wave of apoptosis starting as early as 1 hr post-thaw at low temperatures (< −40°C) and moving toward the periphery (−20°C) as recovery times reached 12 and 24 hr. Distal to the −10°C isotherm, minimal cell death was apparent (< 20%) over controls. The adjunctive use of chemotherapeutic agents in conjunction with cryosurgery displayed a similar induction of cell death cascades, but with the zone of cryodestruction extending ~10 to 15°C further into the freeze zone periphery.

By providing an extracellular environment and a matrix to minimize innate variables, the tissue engineered model yielded a more in vivo-like, tumor-like environment supportive of a deeper understanding of the specific biological responses of cancer cells/tumors to cryotherapeutic intervention.
Technical and Clinical Experience with Spine Radiosurgery: A New Technology for Management of Localized Spine Metastases
Authors: Jin Jian-Yue , Chen Qing , Jin Ryan , Rock Jack , Anderson Joseph , Li Shidong , Movsas Benjamin , Ryu Samuel
Published: October 2014

This study is to demonstrate the technical and clinical experience of applying image guided spinal radiosurgery for treatment of localized spinal metastasis. A dedicated shaped beam radiosurgery unit with intensity modulated radiotherapy (IMRT) and x-ray based image-guided radiotherapy (IGRT) were used for the radiosurgery procedure. A total of 196 patients with 270 lesions of spinal metastases were treated with this procedure from May 2001 to October 2005. All patients received single dose radiosurgery to the involved spine only. The radiosurgery dose was escalated from 10 to 18 Gy in 2 Gy increments. The technical experience using IMRT planning and IGRT implementation has been summarized. Clinical results reporting pain relief responses have been analyzed for the first 49 patients treated with this procedure. For IMRT treatment planning, seven posterior/oblique fields were generally used for spinal radiosurgery as the optimal setup to balance conformality versus complexity. A criterion of 10 Gy to 10% of the adjacent spinal cord volume has been met with satisfactory target dose coverage for most of the cases. When the spinal cord dose exceeded this constraint, the tumor coverage was somewhat compromised. Accurate target localization has been achieved for all patients using the x-ray image-guided system. The preliminary clinical results have demonstrated that pain response was achieved in 85% of patients, with neurological improvement in patients with spinal cord compression. Patients tolerated the treatment well without major acute toxicities. Image guided spinal radiosurgery can be successfully applied to treat patients with focal spine metastases.
Comparison of Contralateral Breast Dose for Various Tangential Field Techniques in Clinical Radiotherapy
Authors: Prabhakar R. , Julka P. K. , Malik M. , Ganesh T. , Joshi R. C. , Sridhar P. S. , Rath G. K. , Pant G. S. , Thulkar S.
Published: October 2014

Contralateral breast (CLB) cancer is a rare but serious concern in radiotherapy. In this study, the CLB dose was measured using MOSFET dosimeter in 49 patients who underwent breast conservation surgery treated by different radiotherapy tangential field techniques, which included enhanced dynamic wedge (EDW), physical wedge, and intensity modulated radiation therapy (IMRT). The mean percent of the prescribed dose received by the contralateral areola in treatment technique using physical wedge (Cobalt), physical wedge (Linac), EDW, and IMRT were 4.27% (SD: 0.65), 3.61% (SD: 0.60), 3.38% (SD: 0.58), and 1.65% (SD: 0.24), respectively. There was a 29% CLB dose reduction at 3 cm from the medial tangential field border with IMRT compared to other wedged tangential field techniques. The study shows that the CLB dose could be reduced with IMRT or reducing or avoiding the medial wedge in conventional tangential field planning for breast cancer.
Recursive Partitioning Analysis of Prognostic Factors for Patients with Four or More Intracranial Metastases Treated with Radiosurgery
Authors: Bhatnagar A. K. , Kondziolka D. , Lunsford L. Dade , Flickinger John C.
Published: October 2014

The purpose of this study was to devise a new recursive partitioning analysis (RPA) of patients with four or more intracranial metastases treated with a single radiosurgery procedure to identify a class of patients with extended survival. 205 patients underwent Gamma Knife radiosurgery for four or more intracranial metastases (median = 5, range 4–18) during one session. The median total treatment volume was 6.8 cc (range 0.6–51.0 cc). Radiosurgery was used as sole management (17% of patients), or in combination with WB-RT (46%), or after failure of WB-RT (38%). The median marginal radiosurgery dose was 16 Gy (range 12–20 Gy). RPA assessed the effects of age, Karnofsky >70, extracranial disease, visceral metastases, number of metastases, total treatment volume, history of breast and melanoma primaries on survival. The median overall survival after radiosurgery for all patients was 8 months. RPA identified a favorable subgroup of 78 patients (43% of the series) with a total treatment volume <7 cc and < 7 brain metastases (Class 1), with a median survival of 13 months. This subgroup's survival was significantly better (p <0.00005) than the remaining patients (Class 2) (n=111) with a median survival of 6 months. In conclusion, RPA of multiple brain metastasis patients identified 2 distinct cohorts of patients. Class 1 patients have a total treatment volume <7 cc and < 7 metastases (4–6) with favorable survival after Radiosurgery and Class 2 patients have a total treatment volume ≥ 7 cc and/or ≥ 7 metastases and have a significantly poorer survival.
Fractionated Stereotactic Radiotherapy for Pituitary Adenomas following Microsurgical Resection: Safety and Efficacy
Authors: McClelland Shearwood , Higgins Patrick D , Gerbi Bruce J , Orner James B , Hall Walter A
Published: October 2014

The treatment of pituitary adenomas following medical management has historically involved surgical excision or stereotactic radiosurgery, with the two modalities often utilized collectively. However, there have been only a limited number of reports on the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of pituitary adenomas. To enhance the existing knowledge regarding the safety and efficacy of this treatment modality, we describe our initial experience with FSRT for residual pituitary adenomas following microsurgical resection. From 1999 to 2005, 14 patients (7F, 7M) with residual pituitary adenomas (7 nonsecretory, 2 growth hormone secreting, 2 prolactin secreting, 2 thyrotropin secreting, 1 adrenocorticotropic hormone secreting) underwent FSRT. All patients were planned using the Radionics X-Knife 3D planning system, and received a median dose of 50.4 Gy in daily 1.8 Gy fractions administered to the 90% prescription isodose line. Treatments were delivered stereotactically using a dedicated Varian 6/100 linear accelerator, with immobilization achieved with the Gill-Thomas-Cosman relocatable head frame. Mean tumor size was 3.6 cm (median, 3.2 cm), and mean patient age was 44.6 years (median, 47 years). The mean dosages to the optic chiasm and brainstem were 0.159 and 0.040 Gy (median, 0.163 and 0.031 Gy) per fraction. All patients were evaluated with visual field testing and pre- and postgadolinium-enhanced magnetic resonance imaging at a minimum of one year follow-up (median, 22.5 months; mean, 27.8 months). Following FSRT, local control (defined as absence of tumor progression) was achieved in all fourteen patients. Three patients developed hypopituitarism (average, 30 months after treatment), with no patient experiencing visual changes or acute complications following FSRT. These results demonstrate the efficacy and safety of FSRT for achieving long-term local tumor control for pituitary adenomas, further validating this technique as an appropriate treatment modality for residual adenomas following microsurgery.
Automatic Target Localization and Verification for On-Line Image-Guided Stereotactic Body Radiotherapy of the Spine
Authors: Wang Congjun , Shiu Almon , Lii MingFwu , Woo Shiao , Chang Eric L.
Published: October 2014

To facilitate image-guided stereotactic body radiotherapy (IG-SBRT) of spinal and paraspinal tumors, the authors have developed an on-line image registration system for automated target localization and patient position verification with high precision. When rotations are present in a patient's daily setup position, a setup error of a few millimeters can be introduced in localization of the isocenter by using surrounding bony structures. This setup error not only will deteriorate the dose coverage of the tumor, more importantly it will overdose the spinal cord. To resolve this issue, the image registration program developed by the authors detects translational shifts as well as rotational shifts using 3D CT image registration. Unacceptable rotations were corrected by either repositioning the patient or adjusting the treatment couch that was capable of rotational corrections when such a couch was available for clinical use. One pair of orthogonal digitally reconstructed radiographs (DRR) were generated from the daily pretreatment CT scan to compare with the corresponding DRRs generated from the planning CT scan to confirm the target shift correction. After the patient's position was corrected a pair of orthogonal portal images were taken for final verification. The accuracy of the image registration result was found to be within 0.1 mm on a head and neck phantom. Target shifts of a fraction of a millimeter were readily visible in our DRR comparison and portal image verification. The time needed to complete the image registration and DRR comparison was about 3 minutes. An integrated system that combines a high-speed CT scanner and a linear accelerator was used for imaging and treatment delivery. Application of the program in actual IG-SBRT cases demonstrated that it was accurate, fast, and reliable. It serves as a useful tool for image-guided radiotherapy where high precision of target localization is required.
Intensity-Modulated Radiosurgery: Improving Dose Gradients and Maximum Dose Using Post Inverse-Optimization Interactive Dose Shaping
Authors: Fuss Martin , Salter Bill J.
Published: October 2014

Intensity-modulated radiosurgery (IMRS) for brain metastases and arterio-venous malformations (AVM) using a serial tomotherapy system (Nomos Corp., Cranberry Township, PA) has been delivered in >150 cases over the last 5 years. A new software tool provided within the Corvus inverse planning software (ActiveRx) allows for post inverse planning re-optimization and individualization of the dose distribution. We analyzed this tool with respect to increasing the steepness of the dose gradient and in-target dose inhomogeneity while maintaining conformity. Fifteen clinically delivered IMRS plans for solitary brain metastases provided the basis for this analysis. The clinical IMRS plans were copied and the ActiveRx module was opened. The toolset in ActiveRx includes a hot spot eraser, a pencil tool to redefine isodose lines and a drag and drop tool, allowing reshaping of existing isodose lines. To assess changes in the steepness of the dose gradient and dose homogeneity, the 100%, 90%, 50% and 25% isodose volume, the volume of the target, maximum dose and mean dose to the target were recorded. We also recorded total monitor units and calculated treatment delivery times. Target volumes ranged from 0.6 to 14.1 cm3 (mean/median 3.9/1.8 cm3). Mean RTOG conformity index (CI) of plans clinically delivered was 1.23±0.31; mean homogeneity index (HI) was 115±5%. After using the ActiveRx tool-set, the mean CI was slightly improved to 1.14±0.1, with an associated increase in HI to 141±10%. The average, respective Ian Paddick CI for the 100%, 90% 50% and 25% isodose lines were 0.79 vs. 0.83, 0.44 vs. 0.59, 0.12 vs. 0.19, and 0.04 vs. 0.07, representing significant improvements after using ActiveRx post-optimization. Total MU were reduced by a mean of 12.3% using ActiveRx, shortening estimated treatment delivery times by 3.2 minutes on average. A post inverse planning optimization tool for IMRS plans allowed for statistically significant improvements in the steepness of the dose gradient, and increased maximum and mean target doses compared to clinically delivered plans that were already considered excellent. Gains were especially pronounced in the reduction of normal brain tissue included into the 90%, and 50% isodose lines. We have since made this process part of the clinical routine for all cranial IMRS procedures.
Towards Solid Tumor Treatment by Irreversible Electroporation: Intrinsic Redistribution of Fields and Currents in Tissue
Authors: Esser Axel T. , Smith Kyle C. , Gowrishankar Thiruvallur R. , Weaver James C.
Published: October 2014

Local and drug-free tissue treatment by irreversible electroporation (IRE) involves the creation of aqueous pores in a cell's plasma membrane (PM) and leads to non-thermal cell death by necrosis. To investigate explicit pore-based effects we use two-dimensional system models with different spatial scales. The first is a multicellular system model (spatial scale 100 μm) that has irregularly shaped cells, and quantitatively describes dynamic (creation and destruction, evolution in pore size) pore behavior at the PM. The second is a tissue model (spatial scale 200 mm) that is constructed from a unit cell and uses the asymptotic (fixed pore size) electroporation model. Both system models show that significant redistribution of fields and currents occurs through transient PM pores. Pore histograms for the multicellular model demonstrate the simultaneous presence of small and large pores during IRE pulses. The associated significant increase of PM permeability may prove to be essential to understanding how cell death by necrosis occurs. The averaged tissue conductivity in both models increases during IRE pulses because of electroporation. This leads to greater electrical dissipation (heating) and, thus, to larger temperature increases than suggested by tissue models with passive and static electrical properties.
Mathematical Modeling of Irreversible Electroporation for Treatment Planning
Authors: Edd Jon F. , Davalos Rafael V.
Published: October 2014

Irreversible Electroporation (IRE) is a new drug-free method to ablate undesirable tissue of particular use in cancer therapy. IRE achieves cell death within the targeted tissue through a series of electric pulses that elevate the transmembrane potentials to an extent that permanently damages the lipid bilayers throughout the treated region. Although the IRE procedure is easy to perform, treatment planning is complicated by the fact that the electric field distribution within the tissue, the greatest single factor controlling the extents of IRE, depends non-trivially on the electrode configuration, pulse parameters and any tissue heterogeneities. To address this difficulty, we instruct on how to properly model IRE and discuss the benefit of modeling in designing treatment protocols. The necessary theoretical basis is introduced and discussed through the detailed analysis of two classic dual-electrode configurations from electrochemotherapy: coaxial disk electrodes and parallel needle electrodes. Dimensionless figures for these cases are also provided that allow cell constants, treated areas, and the details of heating to be determined for a wide range of conditions, for uniform tissues, simply by plugging in the appropriate physical property values and pulse parameters such as electrode spacing, size, and pulse amplitude. Complexities, such as heterogeneous tissues and changes in conductivity due to electroporation, are also discussed. The synthesis of these details can be used directly by surgeons in treatment planning. Irreversible electroporation is a promising new technique to treat cancer in a targeted manner without the use of drugs; however, it does require a detailed understanding of how electric currents flow within biological tissues. By providing the understanding and tools necessary to design an IRE protocol, this study seeks to facilitate the translation of this new and exciting cancer therapy into clinical practice.
Confocal Microscopy and Molecular-Specific Optical Contrast Agents for the Detection of Oral Neoplasia
Authors: Carlson Alicia L. , Gillenwater Ann M. , Williams Michelle D. , El-Naggar Adel K. , Richards-Kortum R. R.
Published: October 2014

Using current clinical diagnostic techniques, it is difficult to visualize tumor morphology and architecture at the cellular level, which is necessary for diagnostic localization of pathologic lesions. Optical imaging techniques have the potential to address this clinical need by providing real-time, sub-cellular resolution images. This paper describes the use of dual mode confocal microscopy and optical molecular-specific contrast agents to image tissue architecture, cellular morphology, and sub-cellular molecular features of normal and neoplastic oral tissues.

Fresh tissue slices were prepared from 33 biopsies of clinically normal and abnormal oral mucosa obtained from 14 patients. Reflectance confocal images were acquired after the application of 6% acetic acid, and fluorescence confocal images were acquired after the application of a fluorescence contrast agent targeting the epidermal growth factor receptor (EGFR). The dual imaging modes provided images similar to light microscopy of hematoxylin and eosin and immunohistochemistry staining, but from thick fresh tissue slices. Reflectance images provided information on the architecture of the tissue and the cellular morphology. The nuclear-to-cytoplasmic (N/C) ratio from the reflectance images was at least 7.5 times greater for the carcinoma than the corresponding normal samples, except for one case of highly keratinized carcinoma. Separation of carcinoma from normal and mild dysplasia was achieved using this ratio (p<0.01). Fluorescence images of EGFR expression yielded a mean fluorescence labeling intensity (FLI) that was at least 2.7 times higher for severe dysplasia and carcinoma samples than for the corresponding normal sample, and could be used to distinguish carcinoma from normal and mild dysplasia (p<0.01). Analyzed together, the N/C ratio and the mean FLI may improve the ability to distinguish carcinoma from normal squamous epithelium.
Quantitative Measurement of CyberKnife Robotic Arm Steering
Authors: Wong Kenneth H. , Dieterich Sonja , Tang Jonathan , Cleary Kevin
Published: October 2014

Respiratory motion is a significant and challenging problem for radiation medicine. Without adequate compensation for respiratory motion, it is impossible to deliver highly conformal doses to tumors in the thorax and abdomen. The CyberKnife frameless stereotactic radiosurgery system with Synchrony provides respiratory motion adaptation by monitoring skin motion and dynamically steering the beam to follow the moving tumor. This study quantitatively evaluated this beam steering technology using optical tracking of both the linear accelerator and a ball-cube target. Respiratory motion of the target was simulated using a robotic motion platform and movement patterns recorded from previous CyberKnife patients. Our results show that Synchrony respiratory tracking can achieve sub-millimeter precision when following a moving object.
Image-Guided Robotic Stereotactic Body Radiotherapy for Benign Spinal Tumors: The University of California San Francisco Preliminary Experience
Authors: Sahgal Arjun , Chou Dean , Ames Christopher , Ma Lijun , Lamborn Kathleen , Huang Kim , Chuang Cynthia , Aiken Ashley , Petti Paula , Weinstein Phil , Larson David
Published: October 2014

We evaluate our preliminary experience using the Cyberknife® Radiosurgery System in treating benign spinal tumors. A retrospective review of 16 consecutively treated patients, comprising 19 benign spinal tumors, was performed. Histologic types included neurofibroma [11], chordoma [4], hemangioma [2], and meningioma [2]. Three patients had Neurofibromatosis Type 1 (NF1). Only one tumor, recurrent chordoma, had been previously irradiated, and as such not considered in the local failure analysis. Local failure, for the remaining 18 tumors, was based clinically on symptom progression and/or tumor enlargement based on imaging. Indications for spine stereotactic body radiotherapy (SBRT) consisted of either adjuvant to subtotal resection (5/19), primary treatment alone (12/19), boost following external beam radiotherapy (1/19), and salvage following previous radiation (1/19). Median tumor follow-up is 25 months (2–37), and one patient (with NF1) died at 12 months from a stroke. The median total dose, number of fractions, and prescription isodose was 21 Gy (10–30 Gy), 3 fx (1–5 fx), 80% (42–87%). The median tumor volume was 7.6 cc (0.2–274.1 cc). The median V100 (volume V receiving 100% of the prescribed dose) and maximum tumor dose was 95% (77–100%) and 26.7 Gy (15.4–59.7 Gy), respectively. Three tumors progressed at 2, 4, and 36 months post-SR (n=18). Two tumors were neurofibromas (both in NF1 patients), and the third was an intramedullary hemangioblastoma. Based on imaging, two tumors had MRI documented progression, three had regressed, and 13 were unchanged (n=18). With short follow-up, local control following Cyberknife spine SBRT for benign spinal tumors appear acceptable.
Robotic Radiosurgery vs. Brachytherapy as a Boost to Intensity Modulated Radiotherapy for Tonsillar Fossa and Soft Palate Tumors: The Clinical and Economic Impact of an Emerging Technology
Authors: Nijdam Wideke , Levendag Peter , Fuller Donald , Schulz Raymond , Prévost Jean-Briac , Noever Inge , Uyl-de Groot Carin
Published: October 2014

As a basis for making decisions regarding optimal treatment for patients with tonsillar fossa and soft palate tumors, we conducted a preliminary investigation of costs and quality of life (QoL) for two modalities [brachytherapy (BT) and robotic radiosurgery] used to boost radiation to the primary tumors following external beam radiotherapy. BT was well established in our center; a boost by robotic radiosurgery was begun more recently in patients for whom BT was not technically feasible. Robotic radiosurgery boost treatment has the advantage of being non-invasive and is able to reach tumors in cases where there is deep parapharyngeal tumor extension. A neck dissection was performed for patients with nodal-positive disease. Quality of life (pain and difficulty swallowing) was established in long-term follow-up for patients undergoing BT and over a one-year follow-up in robotic radiosurgery patients. Total hospital costs for both groups were computed. Our results show that efficacy and quality of life at one year are comparable for BT and robotic radiosurgery. Total cost for robotic radiosurgery was found to be less than BT primarily due to the elimination of hospital admission and operating room expenses. Confirmation of robotic radiosurgery treatment efficacy and reduced morbidity in the long term requires further study. Quality of life and cost analyses are critical to Health Technology Assessments (HTA). The present study shows how a preliminary HTA of a new medical technology such as robotic radiosurgery with its typical hypofractionation characteristics might be based on short-term clinical outcomes and assumptions of equivalence.
Cryoinjury of MCF-7 Human Breast Cancer Cells and Inhibition of Post-Thaw Recovery Using TNF-α
Authors: Han Bumsoo , Swanlund David J. , Bischof John C.
Published: October 2014

Cryoinjury of MCF-7 human breast cancer cells and its enhancement using tumor necrosis factor-alpha (TNF-α) as an adjuvant, were investigated. Through a series of experiments in a two level factorial design critical parameters affecting cryotherapy responses were identified. The cryoinjury was investigated by quantifying the effects of four freeze/thaw (F/T) parameters, selected to be within the expected range for a cryosurgical iceball. Thermal parameters considered were cooling rate (5 and 50 °C/min), end temperature (−20 and −80 °C), hold time (0 and 10 min), and thawing rate (20 and 100 °C/min). After exposing the cells to the selected F/T conditions, survival was assessed and statistically analyzed to determine the effect of each parameter and their interactions. A statistical analysis shows that the end temperature and hold time were the two most significant parameters in the range studied. This suggests that proper control of these two parameters is important to achieve desired cryodestruction of MCF-7 cells. Enhancement of cryoinjury by TNF-α was also investigated in a tissue equivalent cryoinjury model in which a cryosurgical iceball is formed. MCF-7 cells cultured in a collagen matrix underwent a controlled F/T with or without TNF-α pre-treatment at 100 ng/ml for 24 hours. Post-thaw viability of MCF-7 cells was assessed at three hours, and at one and three days after freezing. Although the TNF-α treatment alone induced neither apoptotic nor necrotic cell death, the combination of TNF-α pre-treatment and freezing enhanced the immediate cryoinjury of MCF-7 cells, and significantly impaired the post-thaw recovery. Without TNF-α treatment, MCF-7 cell cultures were repopulated, reaching approximately 80% survival at day 3 even after severe cryoinjury (≤ 20% survival) at three hours. In contrast, this repopulation was significantly inhibited by TNF-α pre-treatment, in which case the viability of the frozen region remained below 40% at day 3. The effects of TNF-α on the cryoinjury of MCF-7 cells suggest that TNF-α may serve as a potent adjuvant to cryosurgery of breast cancer.
A Non-invasive, in Vivo Technique for Monitoring Vascular Status of Glioblastoma during Angiogenesis
Authors: Saxena Vishal , Gonzalez-Gomez Ignacio , Laug Walter E
Published: October 2014

The growth of solid tumors dependent on the process of angiogenesis in which growth factors secreted by tumor and stromal cells promote endothelial cell proliferation, migration, and maturation. This process generates a tumor-specific vascular supply and enables small or dormant tumors to grow rapidly with exponential increases in tumor volume. Determination of tumor oxygenation at the microvascular level will provide important insight into tumor growth, angiogenesis, necrosis, and therapeutic response, and will facilitate to develop protocols for studying tumor behavior.

A non-invasive multi-modality approach based on near infrared spectroscopy (NIRS) technique, namely: Steady State Diffuse Optical Spectroscopy (SSDOS) along with Magnetic Resonance Imaging (MRI) is applied for monitoring the concentration of oxyhemoglobin, deoxyhemoglobin and water within tumor region and for studying the vascular status of tumor and the patho-physiological changes that occur during angiogenesis. Since, the growth of solid tumors depends on the formation of new blood vessels, an association between intramural microvessel density (MVD) and tumor oxygenation is also investigated. The relative decrease in oxygenation value with tumor growth indicates that though blood vessels infiltrate and proliferate the tumor region, a hypoxic trend is clearly present.
Use of a Fluorescently Labeled Poly-Caspase Inhibitor for in Vivo Detection of Apoptosis Related to Vascular-Targeting Agent Arsenic Trioxide for Cancer Therapy
Authors: Griffin Robert J. , Williams Brent W. , Bischof John C. , Olin Michael , Johnson Gary L. , Lee Brian W.
Published: October 2014

Arsenic trioxide (ATO, Trisenox) is a potent anti-vascular agent and significantly enhances hyperthermia and radiation response. To understand the mechanism of the anti-tumor effect in vivo we imaged the binding of a fluorescently-labeled poly-caspase inhibitor (FLIVO) in real time before and 3 h or 24 h after injection of 8 mg/kg ATO. FSaII tumors were grown in dorsal skin-fold window chambers or on the rear limb and we observed substantial polycaspase binding associated with vascular damage induced by ATO treatment at 3 and 24 h after ATO injection. Flow cytometric analysis of cells dissociated from the imaged tumor confirmed cellular uptake and binding of the FLIVO probe. Apoptosis appears to be a major mode of cell death induced by ATO in the tumor and the use of fluorescently tagged caspase inhibitors to assess cell death in live animals appears feasible to monitor and/or confirm anti-tumor effects of therapy.
Four-dimensional Stereotactic Radiotherapy for Early Stage Non-Small Cell Lung Cancer: A Comparative Planning Study
Authors: Prévost Jean-Briac , Voet Peter , Hoogeman Mischa , Praag John , Levendag Peter , Nuyttens Joost Jan
Published: October 2014

In this study we sought to assess the potential of the respiratory tumor tracking system of the CyberKnife to administer 3 fractions of 15 Gy in the treatment of early stage non-small cell lung cancer (NSCLC). The CyberKnife plans were compared to those developed for 3-D conformal radiotherapy (3-D CRT) administering 20 fractions of 3 Gy based on a slow CT. Ten patients with stage I NSCLC, who were previously treated with 3-D CRT, were re-planned with the CyberKnife treatment planning system. In the 3-D CRT plan, the planning target volume (PTV) included the gross tumor volume (GTV)slow and a 15-mm margin, whereas in the CyberKnife plan the margin was 8 mm. The physical doses from both treatment plans were converted to normalized total doses (NTD) using the linear quadratic model with an α/βtumor of 10 Gy and α/βorgansatrisk(OAR) of 3 Gy. The average minimal and mean doses administered to the PTV with the CyberKnife and 3-D CRT were 93 and 115.8 Gy and 61 and 66 Gy, respectively (p<0.0001). The mean V20 of the CyberKnife and 3-D CRT plans were 8.2% and 6.8%, respectively (p=0.124). Both plans complied with the OAR constraints. In conclusion, 4-dimensional stereotactic radiotherapy can increase the minimal and mean biological dose with 51% and 75%, in comparison with 3-D CRT without significantly increasing the V20, respectively.
Efficient Electrotransfection into Canine Muscle
Authors: Pavlin Darja , Tozon Natasa , Sersa Gregor , Pogacnik Azra , Cemazar Maja
Published: October 2014

Two different types of electroporation protocols have been developed for efficient electro-transfer of plasmid DNA into skeletal muscle of experimental animals. At first, only low voltage electric pulses have been used, but lately, a combination of high and low voltage pulses has been suggested as more efficient. Up to date, in dogs, this type of electroporation protocol has never been used for muscle targeted plasmid DNA electrotransfection. In this study, we used two different DNA plasmids, one encoding green fluorescent protein and one encoding human interleukin-12. Five different electroporation protocols were evaluated. Three of them featured different combinations of high and low voltage pulses, and two were performed with delivery of low voltage pulses only. Our study shows that combination of 1 high voltage pulse (600 V/cm, 100 μs), followed by 4 low voltage pulses (80 V/cm, 100 ms, 1 Hz) yielded in the same transfection efficiency as the standard trains of low voltage pulses. However, this protocol is performed quicker and, thus, more suitable for potential use in clinical practice. In addition, it yielded in detectable systemic expression of human interleukin-12. Electrotransfer of either of the plasmids was associated with only mild and transitory local side effects, without clinically detectable systemic side effects. The results indicate that electrotransfection is a feasible, effective, and safe method for muscle targeted gene therapy in dogs, which could have potential for clinical applications in veterinary medicine of small animals.
Microarray Technologies for Gene Transcript Analysis in Pancreatic Cancer
Authors: Kolbert C. P. , Chari S. , Sreekumar R.
Published: October 2014

Pancreatic cancer is a devastating condition that is most often characterized by a poor prognosis. Microarray technologies are promising screening methods for the identification of potential markers for early diagnosis and chemotherapeutic intervention. In this article, we review the current state of pancreatic cancer research as it relates to the measurement of gene transcript levels by DNA microarray analysis.
Boron Neutron Capture Therapy for Glioblastoma: Is it Worth Pursuing?
Authors: Linz Ute
Published: October 2014

Presently glioblastomas are incurable brain tumors. The prospect of treating this deadly disease has been the major justification for the current programs of boron neutron capture therapy (BNCT) throughout the world. However, based on pharmacological and cell biological considerations, it is improbable that BNCT will ever be an effective therapy for this tumor. Indeed, a review of the published literature over the last 50 years fails to provide justification for developing BNCT past its present experimental stage.
Low Generation Polypropylenimine Dendrimer Graft β-cyclodextrin: An Efficient Vector for Gene Delivery System
Authors: Zhang Wei , Chen Zhe , Song Xiaoxiao , Si Jianmin , Tang Guping
Published: October 2014

The purpose of this study was to evaluate the characterization of a new cationic vector. Low generation polypropylenimine (DAB-8) was conjugated to β-cyclodextrin (β-CyD), and the chemical characters of the vector were investigated and confirmed by 1 H NMR, FT-IR, TGA, TEM, particle size, and zeta potential assay. The biological property was identified by MTT assay and gene transfer efficiency was performed in cell lines. The results showed that the new vector had low cytotoxicity and high transfection efficiency in vitro. This suggested that β-CyD-DAB-8 has a potential ability to act as a non-viral vector in gene delivery.