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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.  Trans-cranial opening of the blood-brain barrier in targeted regions using a stereotaxic brain atlas and focused ultrasound energy 
The blood-brain barrier (BBB) protects the brain by preventing the entry of large molecules; this poses a major obstacle for the delivery of drugs to the brain. A novel technique using focused ultrasound (FUS) energy combined with microbubble contrast agents has been widely used for non-invasive trans-cranial BBB opening. Traditionally, FUS research is conducted with magnetic resonance imaging (MRI) guidance, which is expensive and poses physical limitations due to the magnetic field. A system that could allow researchers to test brain therapies without MR intervention could facilitate and accelerate translational research.
In this study, we present a novel FUS system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the BBB in rodents. The system was initially characterized using a tissue-mimicking phantom. Rodent studies were also performed to evaluate whether non-invasive, localized BBB opening could be achieved using brain atlas-based targeting. Brains were exposed to pulsed focused ultrasound energy at 1.06 MHz in rats and 3.23 MHz in mice, with the focal pressure estimated to be 0.5–0.6 MPa through the skull. BBB opening was confirmed in gross tissue sections by the presence of Evans blue leakage in the exposed region of the brain and by histological assessment.
The targeting accuracy of the stereotaxic system was better than 0.5 mm in the tissue-mimicking phantom. Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm. The use of higher frequency exposures in mice enabled a similar precision of localized BBB opening as was observed with the low frequency in the rat model.
With this dedicated small-animal motorized stereotaxic-FUS system, we achieved accurate targeting of focused ultrasound exposures in the brain for non-invasive opening of the BBB. This system can be used as an alternative to MR-guided FUS and offers researchers the ability to perform efficient studies (30 min per experiment including preparation) at a reduced cost in a conventional laboratory environment.
PMCID: PMC4160001  PMID: 25232482
BBB opening; Focused ultrasound; Stereotaxic system; Drug delivery
3.  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.
PMCID: PMC3365529  PMID: 20041766
4.  The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT) 
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.
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.
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.
PMCID: PMC3097653  PMID: 21614267
Renal cell carcinoma (RCC); primary and metastatic RCC; Image Guided Radiation Therapy (IGRT); Stereotactic Body Radiation Therapy (SBRT)
5.  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.
PMCID: PMC3369018  PMID: 22407176
Glioma; Radiation necrosis; Recurrence; Radiosurgery
6.  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
7.  Stereotactic Radiosurgery for Gynecologic Cancer 
Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow 'pencil beam' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments.
Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient-independent abdominal compression.1-3 Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,4 patient mouthpiece active breathing coordination,5 respiration-correlated computed tomography,6 or image-guided tracking of fiducials implanted within and around a moving tumor.7-9 The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera-tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.10 Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.11-13
Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.7,8 Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET).8 Use of 18F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers.
PMCID: PMC3466654  PMID: 22546879
Medicine;  Issue 62;  radiosurgery;  Cyberknife stereotactic radiosurgery;  radiation;  ovarian cancer;  cervix cancer
8.  Precision radiotherapy for brain tumors 
Neural Regeneration Research  2012;7(22):1752-1759.
Precision radiotherapy plays an important role in the management of brain tumors. This study aimed to identify global research trends in precision radiotherapy for brain tumors using a bibliometric analysis of the Web of Science.
We performed a bibliometric analysis of data retrievals for precision radiotherapy for brain tumors containing the key words cerebral tumor, brain tumor, intensity-modulated radiotherapy, stereotactic body radiation therapy, stereotactic ablative radiotherapy, imaging-guided radiotherapy, dose-guided radiotherapy, stereotactic brachytherapy, and stereotactic radiotherapy using the Web of Science.
Inclusion criteria: (a) peer-reviewed articles on precision radiotherapy for brain tumors which were published and indexed in the Web of Science; (b) type of articles: original research articles and reviews; (c) year of publication: 2002-2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) Corrected papers or book chapters.
(1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on precision radiotherapy for brain tumors.
The stereotactic radiotherapy, intensity-modulated radiotherapy, and imaging-guided radiotherapy are three major methods of precision radiotherapy for brain tumors. There were 260 research articles addressing precision radiotherapy for brain tumors found within the Web of Science. The USA published the most papers on precision radiotherapy for brain tumors, followed by Germany and France. European Synchrotron Radiation Facility, German Cancer Research Center and Heidelberg University were the most prolific research institutes for publications on precision radiotherapy for brain tumors. Among the top 13 research institutes publishing in this field, seven are in the USA, three are in Germany, two are in France, and there is one institute in India. Research interests including urology and nephrology, clinical neurology, as well as rehabilitation are involved in precision radiotherapy for brain tumors studies.
Precision radiotherapy for brain tumors remains a highly active area of research and development.
PMCID: PMC4302458  PMID: 25624798
Cerebral tumor; brain tumor; intensity-modulated radiotherapy; stereotactic body radiation therapy; stereotactic ablative radiotherapy; imaging-guided radiotherapy; dose-guided radiotherapy; stereotactic brachytherapy; stereotactic radiotherapy
9.  Murine Cell Line Model of Proneural Glioma for Evaluation of Anti-Tumor Therapies 
Journal of neuro-oncology  2013;112(3):375-382.
Molecular subtypes of glioblastoma (GBM) with distinct alterations have been identified. There is need for reproducible, versatile preclinical models that resemble specific GBM phenotypes to facilitate preclinical testing of novel therapies. We present a cell line-based murine Proneural GBM model and characterize its response to radiation therapy.
Proneural gliomas were generated by injecting PDGF-IRES-Cre retrovirus into the subcortical white matter of adult mice that harbor floxed tumor suppressors (Pten and p53) and stop-floxed reporters. Primary cell cultures were generated from the retrovirus induced tumors and maintained in vitro for multiple passages. RNA sequencing-based expression profiling of the resulting cell lines was performed. The tumorigenic potential of the cells was assessed by intracranial injection into adult naïve mice from different strains. Tumor growth was assessed by bioluminescence imaging (BLI). BLI for tumor cells and brain slices were obtained and compared to in vivo BLI. Response to whole-brain radiation was assessed in glioma-bearing animals.
Intracranial injection of Pdgf+Pten−/−p53−/−luciferase+ glioma cells led to formation of GBM-like tumors with 100% efficiency (n=48) and tumorigenesis was retained for more than 3 generations. The cell lines specifically resembled Proneural GBM based on expression profiling by RNA-Seq. Pdgf+Pten−/−p53−/−luciferase+ cell number correlated with BLI signal. Serial BLI measured tumor growth and correlated with size and location by ex-vivo imaging. Moreover, BLI predicted tumor-related mortality with a 93% risk of death within 5 days following a BLI signal between 1×108−5×108 photons/sec/cm2. BLI signal had transient but significant response following radiotherapy, which corresponded to a modest survival benefit for radiated mice (p<0.05).
Intracranial injection of Pdgf+Pten−/−p53−/−luciferase+ cells constitutes a novel and highly reproducible model, recapitulating key features of human Proneural GBM, and can be used to evaluate tumor-growth and response to therapy.
PMCID: PMC3694577  PMID: 23504257
glioma; proneural; murine; radiotherapy; cell line
10.  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.
PMCID: PMC2808534  PMID: 19585223
Brainstem tumor; Animal model; Bioluminescence; Temozolomide
11.  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.
PMCID: PMC3396852  PMID: 21074564
Convection-enhanced delivery; Pig model; Stereotactic delivery; Viral vector
12.  Juvenile nasopharyngeal angiofibroma: current treatment modalities and future considerations 
Juvenile angiofibroma (JNA) is a relatively uncommon, highly vascular and benign tumor that presents most commonly in adolescent males. Symptoms may persist from months to years and often times, these tumors are asymptomatic until they increase and encroach on critical structures. Because of technological advances both in surgery and radiology, management of JNA patients has been refined. With the advent of more sophisticated capabilities such as CT, MRI, intensity-modulated radiation therapy (IMRT), stereotactic guidance systems as well as advanced embolization techniques, these tumors can be diagnosed and managed more effectively.
Patients with juvenile angiofibroma (JNA) are typically silent for years and often present with epistaxis, nasal obstruction, facial numbness, rhinorrhea, ear popping, sinusitis, cheek swelling, visual changes and headaches. In addition to these symptoms, up to one-third of patients with this condition may present with proptosis or other orbital involvement, which are late symptoms and findings.
Most physicians agree that surgery is the primary treatment modality for the early-stage disease process. However, controversy arises regarding the best treatment when a patient presents with more locally advanced disease involving widespread cranial-based extension or intracranial involvement which may necessitate a combination of treatment modalities including surgery and postoperative radiation.
With the advancement of endoscopic surgery, there have been a number of cases reporting the value of its use. The purpose of this review, however, will address not only endoscopic alternatives, but will discuss other treatment options as reported in the literature. Robotic surgery of the skull base for JNA is something to expect for the future.
Finally, with the advent of IMRT and an image-guided robotic radiotherapy delivery system, some researchers speculate that this will result in less objections for radiation in general and certainly less reservations for the use radiotherapy in certain circumstances, i.e. patient refusal of surgery or extensive non-resectable or recurrent JNA tumors.
PMCID: PMC3450247  PMID: 23120720
Angiofibroma; Vascular tumor; Skull base; Endoscopic surgery; Image guided robotic radiotherapy; IMRT; Cyberknife; Embolization
13.  Defining functional changes in the brain caused by targeted stereotaxic radiosurgery 
Translational cancer research  2014;3(2):124-137.
Brain tumor patients routinely undergo cranial radiotherapy, and while beneficial, this treatment often results in debilitating cognitive dysfunction. This serious and unresolved problem has at present, no clinical recourse, and has driven our efforts to more clearly define the consequences of different brain irradiation paradigms on specific indices of cognitive performance and on the underlying cellular mechanisms believed to affect these processes. To accomplish this we have developed the capability to deliver highly focused X-ray beams to small and precisely defined volumes of the athymic rat brain, thereby providing more realistic simulations of clinical irradiation scenarios. Using this technique, termed stereotaxic radiosurgery, we evaluated the cognitive consequences of irradiation targeted to the hippocampus in one or both hemispheres of the brain, and compared that to whole brain irradiation. While whole brain irradiation was found to elicit significant deficits in novel place recognition and fear conditioning, standard platforms for quantifying hippocampal and non-hippocampal decrements, irradiation targeted to both hippocampi was only found to elicit deficits in fear conditioning. Cognitive decrements were more difficult to demonstrate in animals subjected to unilateral hippocampal ablation. Immunohistochemical staining for newly born immature (doublecortin positive) and mature (NeuN positive) neurons confirmed our capability to target irradiation to the neurogenic regions of the hippocampus. Stereotaxic radiosurgery (SRS) of the ipsilateral hemisphere reduced significantly the number of doublecortin and NeuN positive neurons by 80% and 27% respectively. Interestingly, neurogenesis on the contralateral side was upregulated in response to stereotaxic radiosurgery, where the number of doublecortin and NeuN positive neurons increased by 22% and 36% respectively. Neuroinflammation measured by immunostaining for activated microglia (ED1 positive cells) was significantly higher on the ipsilateral versus contralateral sides, as assessed throughout the various subfields of the hippocampus. These data suggest that certain cognitive decrements are linked to changes in neurogenesis, and that the unilaterally irradiated brain exhibits distinct neurogenic responses that may be regulated by regional differences in neuroinflammation. Compensatory upregulation of neurogenesis on the contralateral hemisphere may suffice to maintain cognition under certain dose limits. Our results demonstrate unique cognitive and neurogenic consequences as a result of targeted stereotaxic radiosurgery, and suggest that these irradiation paradigms elicit responses distinct from those found after exposing the whole brain to more uniform radiation fields.
PMCID: PMC4043313  PMID: 24904783
Stereotaxic radiosurgery (SRS); radiation-induced cognitive dysfunction; neurogenesis; neuroinflammation
14.  Image Guided Small Animal Radiation Research Platform: Calibration of Treatment Beam Alignment 
Physics in medicine and biology  2009;54(4):891-905.
Small animal research allows detailed study of biological processes, disease progression, and response to therapy, with the potential to provide a natural bridge to the clinical environment. The Small Animal Radiation Research Platform (SARRP) is a portable system for precision irradiation with beam sizes down to approximately 0.5 mm and optimally planned radiation with on-board cone-beam CT (CBCT) guidance. This paper focuses on the geometric calibration of the system for high-precision irradiation. A novel technique for calibration of the treatment beam is presented, which employs an x-ray camera whose precise positioning need not be known. Using the camera system we acquired a digitally reconstructed 3D “star shot” for gantry calibration, and then developed a technique to align each beam to a common isocenter with the robotic animal positioning stages. The calibration incorporates localization by cone-beam CT guidance. Uncorrected offsets of the beams with respect to the calibration origin ranged from 0.4 mm to 5.2 mm. With corrections, these alignments can be brought to within < 1 mm. The calibration technique was used to deliver a stereotactic-like arc treatment to a phantom constructed with EBT Gafchromic films. All beams were shown to intersect at a common isocenter with a measured beam (FWHM) of approximately 1.07 mm using the 0.5 mm collimated beam. The desired positioning accuracy of the SARRP is 0.25 mm and the results indicate an accuracy of 0.2 mm. To fully realize the radiation localization capabilities of the SARRP, precise geometric calibration is required, as with any such system. The x-ray camera-based technique presented here provides a straightforward and semi-automatic method for system calibration.
PMCID: PMC2964666  PMID: 19141881
15.  Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part II: combination with external radiation improves survival 
A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR) exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated.
C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine) only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven). Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay.
GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001) and tumor size was smaller (P < 0.02) in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005) and contralateral tumor-free hemisphere (P < 0.01) was associated with treatment.
Specific populations of monocyte-derived brain cells develop critical relationships with malignant gliomas. The biological effect of GCLRP in combination with radiation may be more successful because of the damage incurred by tumor cells by radiation and the enhanced or preserved presentation of tumor cell antigens by GCLRP-activated immune cells. Monocyte-derived brain cells may be important targets for creating effective immunological modalities such as employing the receptor system described in this study.
PMCID: PMC3459592  PMID: 23049281
microglia; macrophages; peptide; brain tumor; glioblastoma; mouse; C-type lectin receptors
16.  MR-guidance – a clinical study to evaluate a shuttle- based MR-linac connection to provide MR-guided radiotherapy 
The purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR-guided radiotherapy.
A total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR-guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropiate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy.
Compared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response.
PMCID: PMC3904210  PMID: 24401489
IGRT; MR-guided radiotherapy; Dose reduction; Shuttle
17.  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.
PMCID: PMC3106280  PMID: 21643448
18.  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.
PMCID: PMC3532745  PMID: 23293448
Conformal radiotherapy; high-precision; image-guidance; verification
19.  Quantitative Sodium MR Imaging and Sodium Bioscales for the Management of Brain Tumors 
The standard of care for the comprehensive treatment of high-grade primary brain tumors includes surgery, radiation treatment and chemotherapy. Magnetic resonance (MR) imaging is involved in the initial diagnosis for detection and characterization of the lesion, focusing on size, location and its effect on surrounding brain and then on the heterogeneity of the signal characteristics, the presence of hemorrhage, MR perfusion characteristics and integrity of the blood-brain-barrier. These imaging properties have been correlated with tumor grade that has prognostic significance. Functional MRI can be used for presurgical planning and for image guidance of the surgical procedures (biopsy, resection) to minimize disruption of eloquent cortex. The surgical debulking is not considered curative for high-grade tumors but a preliminary step towards improving response to the subsequent treatments. After a short recovery period to allow some degree of healing of the surgical site, radiation planning and treatment begins. The radiation planning uses the X-ray attenuation coefficients from computed tomography (CT) to design the distribution of the radiation used in the treatment plan. Advantage is taken of the better display of tumors on MRI by fusing the MR and CT images. The course of radiation involves fractionated targeted radiation projected along multiple beams at many angles to achieve high dose over the tumor volume and margins while minimizing the dose to surrounding normal brain. The radiation is fractionated, usually administered for 5 days per week over about 6 weeks to a total dose of about 55 Gy. Imaging is not routinely performed during radiation treatment. Symptoms of brain swelling are controlled by use of oral steroids. Chemotherapy at low dose may be delivered during radiation treatment. Full dose, single agent chemotherapy then follows after the completion of radiation and is administered over multiple cycles to maintain tumor control. Follow-up MR imaging studies begin after radiation treatment is completed and are then performed every few months or more frequently depending on the clinical status of the patient. Although this protocol has been developed based on experience from large numbers of patients in multi-center trials, the prognosis has not changed in three decades (20% survival at 2 yrs, [1]). This extremely poor success rate for a not insignificant neoplasm, despite such this comprehensive protocol after decades of experience, suggests that there is a fundamental oversight in the current treatment of this disease. This material provides an imaging perspective of how regional responses of primary brain tumors may be examined during treatment to guide a flexible treatment plan to the response of each patient’s tumor, rather than using a fixed rigid protocol based on population studies. Sodium imaging provides a direct measurement of cell density that can be used to measure regional cell kill during treatment. These bioscales of regionally and temporally sensitive biological-based parameters may be helpful to measure tumor responsiveness that the oncologists can use to guide treatment for each patient. The suggestions are speculative and still being examined experimentally but are presented to challenge the medical community to be receptive to changes in the standard of care when that standard continues to fail.
PMCID: PMC3718497  PMID: 19959008
Brain tumor; Sodium MR imaging; Tissue viability; Bioscales; Treatment protocols; Imaging treatment response
20.  Improving radiotherapy planning, delivery accuracy, and normal tissue sparing using cutting edge technologies 
Journal of Thoracic Disease  2014;6(4):303-318.
In the United States, more than half of all new invasive cancers diagnosed are non-small cell lung cancer, with a significant number of these cases presenting at locally advanced stages, resulting in about one-third of all cancer deaths. While the advent of stereotactic ablative radiation therapy (SABR, also known as stereotactic body radiotherapy, or SBRT) for early-staged patients has improved local tumor control to >90%, survival results for locally advanced stage lung cancer remain grim. Significant challenges exist in lung cancer radiation therapy including tumor motion, accurate dose calculation in low density media, limiting dose to nearby organs at risk, and changing anatomy over the treatment course. However, many recent technological advancements have been introduced that can meet these challenges, including four-dimensional computed tomography (4DCT) and volumetric cone-beam computed tomography (CBCT) to enable more accurate target definition and precise tumor localization during radiation, respectively. In addition, advances in dose calculation algorithms have allowed for more accurate dosimetry in heterogeneous media, and intensity modulated and arc delivery techniques can help spare organs at risk. New delivery approaches, such as tumor tracking and gating, offer additional potential for further reducing target margins. Image-guided adaptive radiation therapy (IGART) introduces the potential for individualized plan adaptation based on imaging feedback, including bulky residual disease, tumor progression, and physiological changes that occur during the treatment course. This review provides an overview of the current state of the art technology for lung cancer volume definition, treatment planning, localization, and treatment plan adaptation.
PMCID: PMC3968554  PMID: 24688775
Lung cancer; motion management; dose calculation; treatment planning
21.  Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008 
Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational endpoints that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans.
PMCID: PMC2978526  PMID: 19723641
translational clinical studies; image-guided radiation therapy; radiosurgery; metastasis; tumor markers
22.  Review and Uses of Stereotactic Body Radiation Therapy for Oligometastases 
The Oncologist  2012;17(8):1100-1107.
The radiobiologic, technical, and clinical aspects of stereotactic body radiation therapy are reviewed for various anatomical sites of oligometastases.
Learning Objectives
After completing this course, the reader will be able to: Assess stereotactic body radiation therapy (SBRT) as an emerging modality in the treatment of oligometastatic patients.Discuss data on safety and efficacy of SBRT in the oligometastatic setting.Evaluate SBRT as a competitive option in patients with a low burden of disease in the metastatic setting.
This article is available for continuing medical education credit at
In patients with proven distant metastases from solid tumors, it has been a notion that the condition is incurable, warranting palliative care only. The term “oligometastases” was coined to refer to isolated sites of metastasis, whereby the entire burden of disease can be recognized as a finite number of discrete lesions that can be potentially cured with local therapies. Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient and tumor immobilization, image guidance, and treatment planning and delivery. A number of studies, both retrospective and prospective, showed promising results in terms of local tumor control and, in a limited subset of patients, of survival. This article reviews the radiobiologic, technical, and clinical aspects of SBRT for various anatomical sites.
PMCID: PMC3425528  PMID: 22723509
Radiotherapy; Image-guided; Metastases; Neoplasm; Health care economics
23.  Experimental iodine-125 seed irradiation of intracerebral brain tumors in nude mice 
High-dose radiotherapy is standard treatment for patients with brain cancer. However, in preclinical research external beam radiotherapy is limited to heterotopic murine models– high-dose radiotherapy to the murine head is fatal due to radiation toxicity. Therefore, we developed a stereotactic brachytherapy mouse model for high-dose focal irradiation of experimental intracerebral (orthotopic) brain tumors.
Twenty-one nude mice received a hollow guide-screw implanted in the skull. After three weeks, 5 × 105 U251-NG2 human glioblastoma cells were injected. Five days later, a 2 mCi iodine-125 brachytherapy seed was inserted through the guide-screw in 11 randomly selected mice; 10 mice received a sham seed. Mice were euthanized when severe neurological or physical symptoms occurred. The cumulative irradiation dose 5 mm below the active iodine-125 seeds was 23.0 Gy after 13 weeks (BEDtumor = 30.6 Gy).
In the sham group, 9/10 animals (90%) showed signs of lethal tumor progression within 6 weeks. In the experimental group, 2/11 mice (18%) died of tumor progression within 13 weeks. Acute side effects in terms of weight loss or neurological symptoms were not observed in the irradiated animals.
The intracerebral implantation of an iodine-125 brachytherapy seed through a stereotactic guide-screw in the skull of mice with implanted brain tumors resulted in a significantly prolonged survival, caused by high-dose irradiation of the brain tumor that is biologically comparable to high-dose fractionated radiotherapy– without fatal irradiation toxicity. This is an excellent mouse model for testing orthotopic brain tumor therapies in combination with radiation therapy.
PMCID: PMC2174502  PMID: 17897452
24.  Analysis of Gene Expression Using Gene Sets Discriminates Cancer Patients with and without Late Radiation Toxicity 
PLoS Medicine  2006;3(10):e422.
Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%–10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity.
Methods and Findings
Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization.
X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier.
Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.
Expression profiling can discriminate between groups of patients with and without severe late radiotherapy toxicity but not (yet) predict individual responses.
Editors' Summary
More than half the people who develop cancer receive radiotherapy as part of their treatment. That is, tumor cells are destroyed by exposing them to a source of ionizing radiation such as X-rays. Ionizing radiation damages the genetic material of cancer cells so that they can no longer divide. Unfortunately, it also damages nearby normal cells, although they are less sensitive to radiation than the cancer cells. Radiotherapists minimize how much radiation hits normal tissues by carefully aiming the X-rays at the tumor. Even so, patients often develop side effects such as sore skin or digestive problems during or soon after radiotherapy; the exact nature of the side effects depends on the part of the body exposed to the X-rays. In addition, a few patients develop severe late radiation toxicity, months or years after their treatment. Like early toxicity, late toxicity occurs in the normal tissues near the tumor site. For example, in prostate cancer—a tumor that forms in a gland in the male reproductive system that lies between the bladder and the end of the gut (the rectum)—late radiation toxicity affects rectal, bladder, and sexual function in 5%–10% of patients.
Why Was This Study Done?
It is not known why some patients develop late radiation toxicity, and it is impossible to predict before treatment which patients will have long-term health problems after radiotherapy. It would be useful to know this, because radiation levels might be reduced in those patients, while larger doses of radiation could be given to patients at low risk of late complications to ensure a complete eradication of their cancer. One theory is that some patients are genetically predisposed to develop severe late radiation toxicity. In other words, their genetic make-up makes it more likely that their tissues develop long-term complications after radiation damage. In this study, the researchers looked for markers of a genetic predisposition for late radiation toxicity by comparing radiation-induced changes in the pattern of cellular proteins in patients who had late radiation toxicity after radiotherapy with the changes seen in patients who did not develop such complications.
What Did the Researchers Do and Find?
The researchers recruited 38 patients who had been treated successfully with radiotherapy for prostate cancer two years previously. Of these, 21 had developed severe late radiation toxicity. They isolated lymphocytes (a type of immune system cell) from the patients' blood, stimulated the lymphocytes to divide, exposed them to X-rays, and analyzed the pattern of genes active in these cells—their gene expression profile—before and after irradiation. The researchers found that irradiation induced the expression of numerous genes in the lymphocytes, including many well-known radiation-responsive genes. They then used an analytical process called “random cross-validation” to look for a gene expression profile (or molecular signature) that was associated with late radiation toxicity. They report that a signature based on the radiation response of 50 individual genes correctly classified 63% of the patient population in terms of whether the patient had developed late radiation toxicity. A signature based on the radiation response of gene sets containing genes linked by function or cellular localization correctly classified 86% of the patient population.
What Do These Findings Mean?
Gene expression profiling identified groups of patients who had had severe late radiation toxicity pretty well, particularly when sets of related genes were used to classify the patients. The approach was not so good, however, at identifying individual patients who had had problems, being correct and certain only half the time. Additional studies are needed, therefore, before this promising approach can be used clinically to predict patient responses to radiotherapy. Overall, the study supports the idea that some patients are genetically predisposed to develop late radiation toxicity, and it also provides clues about which cellular pathways help to determine late radiation toxicity. Most of the genes and gene sets that discriminated between the patients with and without late radiation toxicity are involved in protein metabolism, apoptosis (a special sort of cell death), and stress signaling networks (pathways that protect cells from damage). This information, if confirmed, might help researchers to develop therapeutic interventions to minimize late radiation toxicity in vulnerable individuals.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Cancer Institute patient information on radiotherapy and on prostate cancer
American Cancer Society information on radiation therapy
Cancer Research UK patient information on radiotherapy
Wikipedia pages on radiotherapy (note that Wikipedia is a free online encyclopedia that anyone can edit)
PMCID: PMC1626552  PMID: 17076557
25.  Role of Radiation Therapy in the Management of Renal Cell Cancer 
Cancers  2011;3(4):4010-4023.
Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control.
PMCID: PMC3763407  PMID: 24213122
radiation therapy; stereotactic radiosurgery; renal cell carcinoma

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