An efficient and robust MRI-guided radiotherapy planning approach for targeting abdominal organs and tumours in the mouse
Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. A multimodality crad...
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| Published in: | PloS one Vol. 12; no. 4; p. e0176693 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
Public Library of Science
28.04.2017
Public Library of Science (PLoS) |
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| ISSN: | 1932-6203, 1932-6203 |
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| Abstract | Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.
A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.
The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.
This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. |
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| AbstractList | IntroductionPreclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.MethodsA multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.ResultsThe BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.ConclusionThis is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by [gamma]H2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. Methods A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. Results The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by [gamma]H2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. Conclusion This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.INTRODUCTIONPreclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.METHODSA multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.RESULTSThe BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given.CONCLUSIONThis is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. Methods A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. Results The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. Conclusion This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. Methods A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. Results The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. Conclusion This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given. |
| Audience | Academic |
| Author | Gomes, Ana L. Kinchesh, Paul Bird, Luke Kersemans, Veerle Gilchrist, Stuart Allen, Philip D. Falzone, Nadia Thompson, James Newman, Robert G. Corroyer-Dulmont, Aurelien Azad, Abul Sansom, Owen J. Muschel, Ruth J. Hill, Mark A. Tullis, Iain D. C. Vallis, Katherine A. Vojnovic, Borivoj Fokas, Emmanouil D’Costa, Zenobia Beech, John S. Smart, Sean C. |
| AuthorAffiliation | 1 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom North Shore Long Island Jewish Health System, UNITED STATES 3 Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, German 2 Cancer Research UK Beatson Institute, Glasgow, United Kingdom 4 German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK) (Partner Site), Frankfurt, Germany |
| AuthorAffiliation_xml | – name: North Shore Long Island Jewish Health System, UNITED STATES – name: 3 Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, German – name: 1 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom – name: 2 Cancer Research UK Beatson Institute, Glasgow, United Kingdom – name: 4 German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK) (Partner Site), Frankfurt, Germany |
| Author_xml | – sequence: 1 givenname: Veerle orcidid: 0000-0002-4669-236X surname: Kersemans fullname: Kersemans, Veerle – sequence: 2 givenname: John S. surname: Beech fullname: Beech, John S. – sequence: 3 givenname: Stuart surname: Gilchrist fullname: Gilchrist, Stuart – sequence: 4 givenname: Paul surname: Kinchesh fullname: Kinchesh, Paul – sequence: 5 givenname: Philip D. surname: Allen fullname: Allen, Philip D. – sequence: 6 givenname: James surname: Thompson fullname: Thompson, James – sequence: 7 givenname: Ana L. surname: Gomes fullname: Gomes, Ana L. – sequence: 8 givenname: Zenobia surname: D’Costa fullname: D’Costa, Zenobia – sequence: 9 givenname: Luke surname: Bird fullname: Bird, Luke – sequence: 10 givenname: Iain D. C. surname: Tullis fullname: Tullis, Iain D. C. – sequence: 11 givenname: Robert G. surname: Newman fullname: Newman, Robert G. – sequence: 12 givenname: Aurelien surname: Corroyer-Dulmont fullname: Corroyer-Dulmont, Aurelien – sequence: 13 givenname: Nadia surname: Falzone fullname: Falzone, Nadia – sequence: 14 givenname: Abul surname: Azad fullname: Azad, Abul – sequence: 15 givenname: Katherine A. surname: Vallis fullname: Vallis, Katherine A. – sequence: 16 givenname: Owen J. surname: Sansom fullname: Sansom, Owen J. – sequence: 17 givenname: Ruth J. surname: Muschel fullname: Muschel, Ruth J. – sequence: 18 givenname: Borivoj surname: Vojnovic fullname: Vojnovic, Borivoj – sequence: 19 givenname: Mark A. surname: Hill fullname: Hill, Mark A. – sequence: 20 givenname: Emmanouil surname: Fokas fullname: Fokas, Emmanouil – sequence: 21 givenname: Sean C. surname: Smart fullname: Smart, Sean C. |
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| Copyright | COPYRIGHT 2017 Public Library of Science 2017 Kersemans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Distributed under a Creative Commons Attribution 4.0 International License 2017 Kersemans et al 2017 Kersemans et al |
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| DOI | 10.1371/journal.pone.0176693 |
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| DocumentTitleAlternate | Efficient and robust MR-IGRT method for abdominal organs and tumours mouse |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 PMCID: PMC5409175 RJM, BV, MAH, EF, and SCS also contributed equally to this work. VK, JSB, SG, PK, PDA, JT, ALG, ZD are joint first authors on this work. RJM, BV, MAH, EF, and SCS are joint senior authors on this work. Conceptualization: VK ALG JSB ACD NF KAV RJM BV MAH EF SCS.Data curation: PDA.Formal analysis: VK ALG JSB PK PDA JT LB ACD NF AA ZDC EF SCS.Funding acquisition: KAV RJM BV MAH SCS.Investigation: VK ALG JSB PK JT LB ACD AA ZDC EF SCS.Methodology: VK ALG JSB ACD NF KAV RJM BV MAH EF SCS.Project administration: VK RJM BV MAH EF SCS.Resources: JSB SG PK PDA IDCT RGN KAV RJM BV MAH EF OJS SCS.Supervision: VK ALG KAV RJM BV MAH EF SCS.Validation: VK ALG JSB PK PDA JT LB ACD NF AA ZDC EF SCS.Visualization: VK PDA JT ALG ZD LB ACD BV EF SCS.Writing – original draft: VK ALG EF SCS.Writing – review & editing: VK JSB SG PK PDA JT ALG ZD LB IDCT RGN ACD NF AA KAV OJS RJM BV MAH EF SCS. Competing Interests: The authors have declared that no competing interests exist. |
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| Snippet | Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was... Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of... IntroductionPreclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of... Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of... |
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| SubjectTerms | Abdomen - diagnostic imaging Abdomen - radiation effects Abdominal cancer Abdominal Neoplasms - diagnostic imaging Abdominal Neoplasms - radiotherapy Adenocarcinoma Adrenal glands Adrenal Glands - diagnostic imaging Adrenal Glands - radiation effects Animals Beams (radiation) Biology and Life Sciences Care and treatment Cell Line, Tumor Charities Cognitive science Computed tomography Contour matching Contouring Dosimetry Glands Health aspects Health risk assessment Health risks House mouse Humans Image contrast Immobilization In vitro methods and tests In vivo methods and tests Magnetic resonance imaging Magnetic Resonance Imaging - instrumentation Magnetic Resonance Imaging - methods Medical research Medicine and Health Sciences Mice, Inbred BALB C Mice, Inbred CBA Mice, Inbred NOD Mice, Nude Mice, Transgenic Motion Motion stability Multimodal Imaging - instrumentation Neoplasm Transplantation Neuroblastoma Neuroscience Organs Pancreas Pancreatic cancer Phantoms, Imaging Radiation Radiation dosage Radiation therapy Radiometry - instrumentation Radiotherapy Radiotherapy Dosage Radiotherapy Planning, Computer-Assisted - instrumentation Radiotherapy Planning, Computer-Assisted - methods Radiotherapy, Image-Guided - instrumentation Radiotherapy, Image-Guided - methods Regression models Research and Analysis Methods Robustness (mathematics) Soft tissues Stability tests Tomography, X-Ray Computed - instrumentation Tomography, X-Ray Computed - methods Tumor Burden Tumors Xenografts Xenotransplantation |
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| Title | An efficient and robust MRI-guided radiotherapy planning approach for targeting abdominal organs and tumours in the mouse |
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