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1.  Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image-Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts1 
Translational Oncology  2012;5(2):77-84.
PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. RESULTS: Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. CONCLUSIONS: We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.
PMCID: PMC3323928  PMID: 22496923
2.  CT Guidance is Needed to Achieve Reproducible Positioning of the Mouse Head for Repeat Precision Cranial Irradiation 
Radiation Research  2010;173(1):119-123.
To study the effects of cranial irradiation, we have constructed an all-plastic mouse bed equipped with an immobilizing head holder. The bed integrates with our in-house Small Animal Radiation Research Platform (SARRP) for precision focal irradiation experiments and cone-beam CT. We assessed the reproducibility of our head holder to determine the need for CT based targeting in cranial irradiation studies. To measure the holder’s reproducibility, a C57BL/6 mouse was positioned and CT scanned nine times. Image sets were loaded into the Pinnacle3 radiation treatment planning system and were registered to one another by one investigator using rigid body alignment of the cranial regions. Rotational and translational offsets were measured. The average vector shift between scans was 0.80 ± 0.49 mm. Such a shift is too large to selectively treat subregions of the mouse brain. In response, we use onboard imaging to guide cranial irradiation applications that require sub-millimeter precision.
doi:10.1667/RR1845.1
PMCID: PMC3365529  PMID: 20041766
3.  Firefly Luciferase–Based Dynamic Bioluminescence Imaging: A Noninvasive Technique to Assess Tumor Angiogenesis 
Neurosurgery  2010;66(4):751-757.
OBJECTIVE
Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth.
METHODS
With the use of stereotactic technique, 105 firefly luciferase–transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80). After intraperitoneal injection of d-luciferin (150 mg/kg), serial dynamic BLI was performed at 1-minute intervals (30 seconds exposure) every 2 to 3 days until death of the animals. The maximum intensity was used as an indirect measurement of tumor growth. The adjusted slope of initial intensity (I90/Im) was used as a proxy to monitor the flow rate of blood into the vascular tree. Using a modified Evans blue perfusion protocol, we calculated the relative permeability of the vascular tree at various time points.
RESULTS
Daily maximum intensity correlated strongly with tumor volume. At postinjection day 23, histology and BLI demonstrated an exponential growth of the tumor mass. Slopes were calculated to reflect the flow in the vessels feeding the tumor (adjusted slope = I90/Im). The increase in BLI intensity was correlated with a decrease in adjusted slope, reflecting a decrease in the rate of blood flow as tumor volume increased (y = 93.8e−0.49, R2 = 0.63). Examination of calculated slopes revealed a peak in permeability around postinjection day 20 (n = 42, P < .02 by 1-way analysis of variance) and showed a downward trend in relation to both postinjection day and maximum intensity observed; as angiogenesis progressed, tumor vessel caliber increased dramatically, resulting in sluggish but increased flow. This trend was correlated with Evans blue histology, revealing an increase in Evans blue dye uptake into the tumor, as slope calculated by BLI increases.
CONCLUSION
Dynamic BLI is a practical, noninvasive technique that can semiquantitatively monitor changes in vascular permeability and therefore facilitate the study of tumor angiogenesis in animal models of disease.
doi:10.1227/01.NEU.0000367452.37534.B1
PMCID: PMC3632432  PMID: 20305496
Angiogenesis; Dynamic bioluminescence imaging; Luciferase; Tumor
4.  Development of a novel animal model to differentiate radiation necrosis from tumor recurrence 
Journal of Neuro-Oncology  2012;108(3):411-420.
Distinguishing tumor progression from radiation necrosis after treatment in patients with brain tumors presents a clinical dilemma. A well-characterized, orthotopic rodent model of radiation-induced brain necrosis including a tumor is not currently available The objective of the study was to create focal radiation necrosis in rat brain bearing human glioblastoma (GBM) using stereotactic radiosurgery and confirm it by immuno-histological analysis. Nude rats implanted with primary GBM cells were irradiated using a stereotactic setup (n = 3) or received no radiation (n = 3). Ten weeks after the implantation, growth of the tumor was confirmed by magnetic resonance imaging (MRI). For each animal, MRI and contrast-enhanced CT images were obtained and fused using registration software. The tumor was identified and delineated using the fused CT/MR images. A treatment plan was generated using a 4 mm radiosurgery cone such that one portion of the tumor receives 100% dose of 60 Gy sufficient to cause necrosis, whereas the tumor edge at depth receives only 50% or less dose, allowing for regrowth of the tumor. The brains were collected 10 weeks after irradiation and immuno-histological analysis was performed. Hematoxylin and eosin staining showed central liquefaction necrosis in the high dose region consistent with necrosis and viable tumor in the peripheral low dose region. Ki-67 staining showed highly proliferative tumor cells surrounding the necrotic parts of the tumor. Luxol fast blue and lectin staining showed demyelination and vascular injury in brain tissue consistent with radiation necrosis. We have developed a novel model of radiation necrosis in rats bearing glioma.
doi:10.1007/s11060-012-0846-z
PMCID: PMC3369018  PMID: 22407176
Glioma; Radiation necrosis; Recurrence; Radiosurgery
5.  A human brainstem glioma xenograft model enabled for bioluminescence imaging 
Journal of Neuro-Oncology  2009;96(2):151-159.
Despite the use of radiation and chemotherapy, the prognosis for children with diffuse brainstem gliomas is extremely poor. There is a need for relevant brainstem tumor models that can be used to test new therapeutic agents and delivery systems in pre-clinical studies. We report the development of a brainstem-tumor model in rats and the application of bioluminescence imaging (BLI) for monitoring tumor growth and response to therapy as part of this model. Luciferase-modified human glioblastoma cells from five different tumor cell sources (either cell lines or serially-passaged xenografts) were implanted into the pontine tegmentum of athymic rats using an implantable guide-screw system. Tumor growth was monitored by BLI and tumor volume was calculated by three-dimensional measurements from serial histopathologic sections. To evaluate if this model would allow detection of therapeutic response, rats bearing brainstem U-87 MG or GS2 glioblastoma xenografts were treated with the DNA methylating agent temozolomide (TMZ). For each of the tumor cell sources tested, BLI monitoring revealed progressive tumor growth in all animals, and symptoms caused by tumor burden were evident 26–29 days after implantation of U-87 MG, U-251 MG, GBM6, and GBM14 cells, and 37–47 days after implantation of GS2 cells. Histopathologic analysis revealed tumor growth within the pons in all rats and BLI correlated quantitatively with tumor volume. Variable infiltration was evident among the different tumors, with GS2 tumor cells exhibiting the greatest degree of infiltration. TMZ treatment groups were included for experiments involving U-87 MG and GS2 cells, and in each case TMZ delayed tumor growth, as indicated by BLI monitoring, and significantly extended survival of animal subjects. Our results demonstrate the development of a brainstem tumor model in athymic rats, in which tumor growth and response to therapy can be accurately monitored by BLI. This model is well suited for pre-clinical testing of therapeutics that are being considered for treatment of patients with brainstem tumors.
doi:10.1007/s11060-009-9954-9
PMCID: PMC2808534  PMID: 19585223
Brainstem tumor; Animal model; Bioluminescence; Temozolomide
6.  The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT) 
Purpose:
Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors’ initial experience with image-guided SBRT in treating primary and metastatic RCC.
Materials and methods:
The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins.
Results:
Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects.
Conclusion:
Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC.
doi:10.2349/biij.3.1.e6
PMCID: PMC3097653  PMID: 21614267
Renal cell carcinoma (RCC); primary and metastatic RCC; Image Guided Radiation Therapy (IGRT); Stereotactic Body Radiation Therapy (SBRT)
7.  Molecular bioluminescence imaging as a non-invasive tool for monitoring tumor growth and therapeutic response to MRI-guided laser ablation in a rat model of hepatocellular carcinoma 
Investigative radiology  2013;48(6):413-421.
Objectives
To quantitatively compare tumor imaging by MRI and molecular bioluminescence imaging (BLI) and test the feasibility of monitoring the effect of MRI-guided laser ablation on tumor viability by 2D BLI and 3D DLIT in an orthotopic rat model of hepatocellular carcinoma (HCC).
Materials and Methods
This study was approved by the animal care committee. Rats underwent injection of N1S1 cells stably transfected with an empty vector (N=3) or a luciferase reporter (HSE-luc; N=4) into the liver. All rats underwent MR imaging to assess tumor establishment and volume and 2D BLI to assess tumor luminescence at day 7 with repeat MR imaging and 2D BLI and 3D diffuse luminescence tomography (3D DLIT) in select animals at day 14 and 21. MRI-guided laser ablation of the tumor was performed with pre and post-ablation 2D BLI and/or 3D DLIT (N=2). Tumors underwent histopathologic analysis to assess tumor viability.
Results
MR imaging demonstrated hyperintense T2-weighted lesions at 3/3 and 4/4 sites in empty vector and HSE-luc rats, respectively. 2D BLI quantitation demonstrated 23.0 fold higher radiance in the HSE-luc group compared to the empty vector group at day 7 (p<0.01) and a significant correlation with tumor volume by MRI (r=0.86; p<0.03). Tumor dimensions by 3D DLIT and MRI demonstrated good agreement. 3D DLIT quantitation better agreed with the % of non-viable tumor by histopathology than 2D BLI quantitation following MRI-guided laser ablation.
Conclusion
Bioluminescence imaging is a feasible as non-invasive, quantitative tool for monitoring tumor growth and therapeutic response to thermal ablation in a rat model of HCC.
doi:10.1097/RLI.0b013e31827a4a3f
PMCID: PMC3904185  PMID: 23262791
Magnetic Resonance Imaging; Laser Ablation; Bioluminescence Imaging; Hepatocellular Carcinoma; Animal Model
8.  Measuring Brain Tumor Growth: A Combined BLI / MRI Strategy 
Molecular imaging  2009;8(5):245-253.
Small-animal tumor models are essential for developing translational therapeutic strategies in oncology research, with imaging having an increasingly important role. Magnetic Resonance Imaging (MRI) offers tumor localization, volumetric measurement, and the potential for advanced physiologic imaging, but is less well suited to high throughput studies and has limited capacity to assess early tumor growth. Bioluminescence imaging (BLI) identifies tumors early, monitors tumor growth, and efficiently measures response to therapeutic intervention. Generally, BLI signals have been found to correlate well with MR measurements of tumor volume. However, in our studies of small-animal models of malignant brain tumors, we have observed specific instances in which BLI data do not correlate with corresponding MR images. These observations led us to hypothesize that use of BLI and MR imaging together, rather than in isolation, would allow more effective and efficient measures of tumor growth in preclinical studies. Herein, we describe combining BLI and MRI studies to characterize tumor growth in a mouse model of glioblastoma. Results lead us to suggest a cost-effective, multi-modality strategy for selecting cohorts of animals with similar tumor growth patterns that improves the accuracy of longitudinal in vivo measurements of tumor growth and treatment response in pre-clinical therapeutic studies.
PMCID: PMC3831362  PMID: 19796602
Bioluminescence Imaging (BLI); Magnetic Resonance Imaging (MRI); Small-animal imaging; Brain tumor; Tumor growth
9.  Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy 
Oncotarget  2013;4(1):64-79.
Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p<0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM.
PMCID: PMC3702208  PMID: 23296073
glioblastoma multiforme; nanocarrier; radiation therapy; brain tumors; chemotherapy
10.  Potential Applications of Imaging and Image-Guided Radiotherapy for Brain Metastases and Glioblastoma to Improve Patient Quality of Life 
Frontiers in Oncology  2013;3:284.
Treatment of glioblastoma multiforme (GBM) and brain metastasis remains a challenge because of the poor survival and the potential for brain damage following radiation. Despite concurrent chemotherapy and radiation dose escalation, local recurrence remains the predominant pattern of failure in GBM most likely secondary to repopulation of cancer stem cells. Even though radiotherapy is highly effective for local control of radio-resistant tumors such as melanoma and renal cell cancer, systemic disease progression is the cause of death in most patients with brain metastasis. Preservation of quality of life (QOL) of cancer survivors is the main issue for patients with brain metastasis. Image-guided radiotherapy (IGRT) by virtue of precise radiation dose delivery may reduce treatment time of patients with GBM without excessive toxicity and potentially improve neurocognitive function with preservation of local control in patients with brain metastasis. Future prospective trials for primary brain tumors or brain metastasis should include IGRT to assess its efficacy to improve patient QOL.
doi:10.3389/fonc.2013.00284
PMCID: PMC3832799  PMID: 24312897
glioblastoma; brain metastases; image-guided radiotherapy; neurotoxicity
11.  Radiation techniques for acromegaly 
Radiotherapy (RT) remains an effective treatment in patients with acromegaly refractory to medical and/or surgical interventions, with durable tumor control and biochemical remission; however, there are still concerns about delayed biochemical effect and potential late toxicity of radiation treatment, especially high rates of hypopituitarism. Stereotactic radiotherapy has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. Radiation can be delivered in a single fraction by stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT) in which smaller doses are delivered over 5-6 weeks in 25-30 treatments. A review of the recent literature suggests that pituitary irradiation is an effective treatment for acromegaly. Stereotactic techniques for GH-secreting pituitary tumors are discussed with the aim to define the efficacy and potential adverse effects of each of these techniques.
doi:10.1186/1748-717X-6-167
PMCID: PMC3275813  PMID: 22136376
acromegaly; fractionated stereotactic radiotherapy; radiosurgery; toxicity; GH-secreting pituitary tumors
12.  Robotic Delivery of Complex Radiation Volumes for Small Animal Research 
The Small Animal Radiation Research Platform (SARRP) is a novel and complete system capable of delivering multidirectional (focal), kilo-voltage radiation fields to targets in small animals under robotic control using cone-beam CT (CBCT) image guidance. The capability of the SARRP to deliver highly focused beams to multiple animal models provides new research opportunities that more realistically bridge laboratory research and clinical translation. This paper describes the design and operation of the SARRP for precise radiation delivery. Different delivery procedures are presented which enable the system to radiate through a series of points, representative of a complex shape. A particularly interesting case is shell dose irradiation, where the goal is to deliver a high dose of radiation to the shape surface, with minimal dose to the shape interior. The ability to deliver a dose shell allows mechanistic research of how a tumor interacts with its microenvironment to sustain its growth and lead to its resistance or recurrence.
doi:10.1109/ROBOT.2010.5509898
PMCID: PMC3106280  PMID: 21643448
13.  Imaging and IGRT in Liver Cancer 
Seminars in radiation oncology  2011;21(4):247-255.
Imaging for radiation therapy treatment planning and delivery is a critical component of the radiation planning process for liver cancer. Due to the lack of inherent contrast between liver tumors and the surrounding liver, intravenous contrast is required for accurate target delineation on the planning CT. The appropriate phase of contrast is tumor specific, with arterial phase imaging usually used to define hepatocellular carcinoma, and venous phase imaging for vascular thrombosis related to hepatocellular carcinoma and most types of liver metastases. Breathing motion and changes in the liver position day-to-day may be substantial and need to be considered at the time of radiation planning and treatment. Many types of integrated imaging-radiation treatment systems and image guidance strategies are available to produce volumetric and/or planar imaging at the time of treatment delivery to reduce the negative impact of geometric changes that may occur. Image guided radiation therapy (IGRT) can improve the precision of radiation therapy, so that the prescribed doses are more likely to represent those actually delivered.
doi:10.1016/j.semradonc.2011.05.001
PMCID: PMC3428059  PMID: 21939853
14.  A robust MRI-compatible system to facilitate highly accurate stereotactic administration of therapeutic agents to targets within the brain of a large animal model 
Journal of Neuroscience Methods  2011;195(1):78-87.
Research highlights
▶ Development of a highly accurate and robust method for MRI-guided, stereotactic delivery of catheters into the brain of pigs. ▶ Reliable head immobilisation, acquisition of high-resolution MR images, precise co-registration of MRI and stereotactic spaces to facilitate accurate burr hole-generation and catheter implantation. ▶ Implants were accurately placed into the putamen with a mean Euclidean distance of 0.623 mm (standard deviation of 0.33 mm).
Achieving accurate intracranial electrode or catheter placement is critical in clinical practice in order to maximise the efficacy of deep brain stimulation and drug delivery respectively as well as to minimise side-effects. We have developed a highly accurate and robust method for MRI-guided, stereotactic delivery of catheters and electrodes to deep target structures in the brain of pigs. This study outlines the development of this equipment and animal model. Specifically this system enables reliable head immobilisation, acquisition of high-resolution MR images, precise co-registration of MRI and stereotactic spaces and overall rigidity to facilitate accurate burr hole-generation and catheter implantation.
To demonstrate the utility of this system, in this study a total of twelve catheters were implanted into the putamen of six Large White Landrace pigs. All implants were accurately placed into the putamen. Target accuracy had a mean Euclidean distance of 0.623 mm (standard deviation of 0.33 mm). This method has allowed us to accurately insert fine cannulae, suitable for the administration of therapeutic agents by convection-enhanced delivery (CED), into the brain of pigs. This study provides summary evidence of a robust system for catheter implantation into the brain of a large animal model. We are currently using this stereotactic system, implantation procedure and animal model to develop catheter-based drug delivery systems that will be translated into human clinical trials, as well as to model the distribution of therapeutic agents administered by CED over large volumes of brain.
doi:10.1016/j.jneumeth.2010.10.023
PMCID: PMC3396852  PMID: 21074564
Convection-enhanced delivery; Pig model; Stereotactic delivery; Viral vector
15.  Precision Radiotherapy for Small Animal Research 
Preclinical research using well characterized small animal models has provided tremendous benefits to medical research, enabling low cost, large scale trials with high statistical significance of observed effects. The goal of the Small Animal Radiation Research Platform (SARRP) is to make those models available for the development and evaluation of novel radiation therapies. SARRP demonstrates the capabilities of delivering high resolution, sub-millimeter, optimally planned conformal radiation with on-board cone-beam CT (CBCT) guidance. The system requires accurate calibration of the x-ray beam for both imaging and radiation treatment. In this paper, we present a novel technique using an x-ray camera for calibration of the treatment beam. This technique does not require precise positioning or calibration of the x-ray camera.
PMCID: PMC2958212  PMID: 18982656
16.  The Use of Medical Images in Planning and Delivery of Radiation Therapy 
Abstract
The authors provide a survey of how images are used in radiation therapy to improve the precision of radiation therapy plans, and delivery of radiation treatment. In contrast to diagnostic radiology, where the focus is on interpretation of the images to decide if disease is present, radiation therapy quantifies the extent of the region to be treated, and relates it to the proposed treatment using a quantitative modeling system called a radiation treatment planning (RTP) system. This necessitates several requirements of image display and manipulation in radiation therapy that are not usually important in diagnosis. The images must have uniform spatial fidelity: i.e., the pixel size must be known and consistent throughout individual images, and between spatially related sets. The exact spatial relation of images in a set must be known. Radiation oncologists draw on images to define target volumes; dosimetrists use RTP systems to superimpose quantitative models of radiation beams and radiation dose distributions on the images and on the sets of organ and target contours derived from them. While this mainly uses transverse cross-sectional images, projected images are also important, both those produced by the radiation treatment simulator and the treatment machines, and so-called “digital reconstructed radiographs,” computed from spatially related sets of cross-sectional images. These requirements are not typically met by software produced for radiologists but are addressed by RTP systems. This review briefly summarizes ongoing work on software development in this area at the University of Washington Department of Radiation Oncology.
PMCID: PMC61250  PMID: 9292839
17.  MRI-Guided Focused Ultrasound Surgery 
Annual review of medicine  2009;60:417-430.
MRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines.
doi:10.1146/annurev.med.60.041707.170303
PMCID: PMC4005559  PMID: 19630579
focused ultrasound surgery; MRI-guided therapy; thermal ablation; targeted drug delivery
18.  Bioluminescent Imaging of Intracranial Vestibular Schwannoma Xenografts in NOD/SCID Mice 
Hypothesis
Intracranial vestibular schwannoma xenografts can be successfully established and followed with bioluminescent imaging (BLI).
Background
Transgenic and xenograft mouse models of vestibular schwannomas have been previously reported in the literature. However, none of these models replicate the intracranial location of these tumors to reflect the human disease. Additionally, traditional imaging methods (magnetic resonance imaging, computed tomography) for following tumor engraftment and growth are expensive and time consuming. BLI has been successfully used to longitudinally follow tumor treatment responses in a noninvasive manner. BLI’s lower cost and labor demands make this a more feasible approach for tumor monitoring in studies involving large numbers of mice.
Methods
Patient excised vestibular schwannomas were cultured and transduced with firefly luciferase expressing lentivirus. One million cells were stereotactically injected into the right caudate nucleus of 21 nonobese diabetic/severe combined immunodeficient mice. Schwannoma engraftment and growth was prospectively followed for 30 weeks after injection with BLI. After animal sacrifice, the presence of human tumor cells was confirmed with fluorescent in situ hybridization.
Results
Eight (38%) of 21 mice successfully engrafted the schwannoma cells. All of these mice were generated from 4 (67%) of the 6 patient excised tumors. These 8 mice could be differentiated from the nonengrafted mice at 21 weeks. The engrafted group emitted BLI of greater than 100,000 photons/s (range, 142,478–3,106,300 photons/s; average, 618,740 photons/s), whereas the nonengrafted group were all under 100,000 photons/s (range, 0–76,010 photons/s; average, 10,737 photons/s) (p < 0.001). Fluorescent in situ hybridization analysis confirmed the presence of viable human schwannoma cells in much greater numbers in those mice with stable or growing tumors compared with those whose tumors regressed.
Conclusion
We have successfully established an intracranial schwannoma xenograft model that can be followed with noninvasive BLI. We hope to use this model for in vivo testing of schwannoma tumor therapies.
doi:10.1097/MAO.0b013e31818b6cea
PMCID: PMC3918230  PMID: 18931645
Acoustic neuroma; Bioluminescence; NOD/SCID mice; Vestibular schwannoma; Xenograft
19.  Radiotherapy and radiosurgery for benign skull base meningiomas 
Meningiomas located in the region of the base of skull are difficult to access. Complex combined surgical approaches are more likely to achieve complete tumor removal, but frequently at a cost of treatment related high morbidity. Local control following subtotal excision of benign meningiomas can be improved with conventional fractionated external beam radiation therapy with a reported 5-year progression-free survival up to 95%. New radiation techniques, including stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), and intensity-modulated radiotherapy (IMRT) have been developed as a more accurate technique of irradiation with more precise tumor localization, and consequently a reduction in the volume of normal brain irradiated to high radiation doses. SRS achieves a high tumour control rate in the range of 85-97% at 5 years, although it should be recommended only for tumors less than 3 cm away more than 3 mm from the optic pathway because of high risk of long-term neurological deficits. Fractionated RT delivered as FSRT, IMRT and protons is useful for larger and irregularly or complex-shaped skull base meningiomas close to critical structures not suitable for single-fraction SRS. The reported results indicate a high tumour control rate in the range of 85-100% at 5 years with a low risk of significant incidence of long-term toxicity. Because of the long natural history of benign meningiomas, larger series and longer follow-up are necessary to compare results and toxicity of different techniques.
doi:10.1186/1748-717X-4-42
PMCID: PMC2768735  PMID: 19828022
20.  Bioluminescence imaging of therapy response does not correlate with FDG-PET response in a mouse model of Burkitt lymphoma 
Since the development and evaluation of novel anti-cancer therapies require molecular insight in the disease state, both FDG-PET and BLI imaging were evaluated in a Burkitt B-cell lymphoma xenograft model treated with cyclophosphamide or temsirolimus. Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with BLI and FDG-PET on d0 (before treatment), d2, d4, d7, d9 and d14 following the start of therapy. Besides tumor volume changes, therapy response was assessed with immunohistochemical analysis (apoptosis). BLI revealed a flare following both therapeutics that was significantly higher when compared to control tumors. FDG-PET decreased immediatelly, long before the tumor reduced in size. Late after therapy, BLI signal intensities decreased significantly compared to baseline subsequent to tumor size reduction while apoptosis was immediately induced following both treatment regimen. Unlike FDG, BLI was not able to reflect reduced levels of viable cells and was not able to predict tumor size response and apoptosis response.
PMCID: PMC3477743  PMID: 23133822
Bioluminescence imaging; therapy response; FDG-PET
21.  The Role of a Prone Setup in Breast Radiation Therapy 
Most patients undergoing breast conservation therapy receive radiotherapy in the supine position. Historically, prone breast irradiation has been advocated for women with large pendulous breasts in order to decrease acute and late toxicities. With the advent of CT planning, the prone technique has become both feasible and reproducible. It was shown to be advantageous not only for women with larger breasts but in most patients since it consistently reduces, if not eliminates, the inclusion of heart and lung within the field. The prone setup has been accepted as the best localizing position for both MRI and stereotactic biopsy, but its adoption has been delayed in radiotherapy. New technological advances including image-modulated radiation therapy and image-guided radiation therapy have made possible the exploration of accelerated fractionation schemes with a concomitant boost to the tumor bed in the prone position, along with better imaging and verification of reproducibility of patient setup. This review describes some of the available techniques for prone breast radiotherapy and the available experience in their application. The NYU prone breast radiotherapy approach is discussed, including a summary of the results from several prospective trials.
doi:10.3389/fonc.2011.00031
PMCID: PMC3356107  PMID: 22655240
breast cancer; prone setup
22.  Treating Adrenal Tumors in 26 Patients with CyberKnife: A Mono-Institutional Experience 
PLoS ONE  2013;8(11):e80654.
Background
CyberKnife (CK) is a novel stereotactic radiosurgery system for treating tumors in any part of the body. It is a non-invasive or minimally invasive tumor treatment modality that can deliver high doses of spatially precise radiation and minimize exposure to neighboring healthy tissues or vital organs. The purpose of this study was to investigate the safety and efficacy of CK in the treatment of adrenal tumors.
Methods and Results
We performed a retrospective analysis of 26 patients with adrenal tumors who had been treated with CK in the radiotherapy center of our hospital between March 2009 and March 2012. Eight patients had primary adrenal tumors and 18 patients had metastatic adrenal tumors. In addition to CK, 4 patients received chemotherapy and 2 patients received immunotherapy. The average tumor volume was 72.1 cm3 and the prescribed radiation dosage ranged from 30 to 50 Gy and was fractionated 3 to 5 times with a 58% to 80% isodose line. Abdominal CT was performed between 1 to 3 months after the CK treatment to evaluate the short-term efficacy with follow-up examinations once every 3 months. Three patients had complete remission, 12 patients had partial remission, 5 patients had stable disease, and 6 patients had progressive illness. The effective rate of pain relief was 93.8% and the disease control rate was 77% with a median overall survival of 17 months and a median progression-free survival of 14 months. Treatment Related toxicity was well-tolerated, but preventative measure need to be taken for radiation enteritis.
Conclusions
CK is safe and effective for treating adrenal tumors with few adverse reactions. Nonetheless, its long-term effects requires further follow-up.
doi:10.1371/journal.pone.0080654
PMCID: PMC3835566  PMID: 24278303
23.  Canine spontaneous glioma: A translational model system for convection-enhanced delivery 
Neuro-Oncology  2010;12(9):928-940.
Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.
doi:10.1093/neuonc/noq046
PMCID: PMC2940703  PMID: 20488958
brain tumors; canine; CPT-11; convection-enhanced delivery; magnetic resonance imaging
24.  Image-guided radiation therapy: Physician's perspectives 
The evolution of radiotherapy has been ontogenetically linked to medical imaging. Over the years, major technological innovations have resulted in substantial improvements in radiotherapy planning, delivery, and verification. The increasing use of computed tomography imaging for target volume delineation coupled with availability of computer-controlled treatment planning and delivery systems have progressively led to conformation of radiation dose to the target tissues while sparing surrounding normal tissues. Recent advances in imaging technology coupled with improved treatment delivery allow near-simultaneous soft-tissue localization of tumor and repositioning of patient. The integration of various imaging modalities within the treatment room for guiding radiation delivery has vastly improved the management of geometric uncertainties in contemporary radiotherapy practice ushering in the paradigm of image-guided radiation therapy (IGRT). Image-guidance should be considered a necessary and natural corollary to high-precision radiotherapy that was long overdue. Image-guided radiation therapy not only provides accurate information on patient and tumor position on a quantitative scale, it also gives an opportunity to verify consistency of planned and actual treatment geometry including adaptation to daily variations resulting in improved dose delivery. The two main concerns with IGRT are resource-intensive nature of delivery and increasing dose from additional imaging. However, increasing the precision and accuracy of radiation delivery through IGRT is likely to reduce toxicity with potential for dose escalation and improved tumor control resulting in favourable therapeutic index. The radiation oncology community needs to leverage this technology to generate high-quality evidence to support widespread adoption of IGRT in contemporary radiotherapy practice.
doi:10.4103/0971-6203.103602
PMCID: PMC3532745  PMID: 23293448
Conformal radiotherapy; high-precision; image-guidance; verification
25.  Radiation induced currents in MRI RF coils: application to linac/MRI integration 
Physics in medicine and biology  2010;55(3):735-746.
The integration of medical linear accelerators (linac) with magnetic resonance imaging (MRI) systems is advancing the current state of image-guided radiotherapy. The MRI in these integrated units will provide real-time, accurate tumor locations for radiotherapy treatment, thus decreasing geometric margins around tumors and reducing normal tissue damage. In the real-time operation of these integrated systems, the radiofrequency (RF) coils of MRI will be irradiated with radiation pulses from the linac. The effect of pulsed radiation on MRI radio frequency (RF) coils is not known and must be studied. The instantaneous radiation induced current (RIC) in two different MRI RF coils were measured and presented. The frequency spectra of the induced currents were calculated. Some basic characterization of the RIC was also done: isolation of the RF coil component responsible for RIC, dependence of RIC on dose rate, and effect of wax buildup placed on coil on RIC. Both the time and frequency characteristics of the RIC were seen to vary with the MRI RF coil used. The copper windings of the RF coils were isolated as the main source of RIC. A linear dependence on dose rate was seen. The RIC was decreased with wax buildup, suggesting an electronic disequilibrium as the cause of RIC. This study shows a measurable RIC present in MRI RF coils. This unwanted current could be possibly detrimental to the signal to noise ratio in MRI and produce image artifacts.
doi:10.1088/0031-9155/55/3/013
PMCID: PMC2910755  PMID: 20071754 CAMSID: cams1344

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