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Collinson F, Royle KL, Swain J, Ralph C, Maraveyas A, Eisen T, Nathan P, Jones R, Meads D, Min Wah T, Martin A, Bestall J, Kelly-Morland C, Linsley C, Oughton J, Chan K, Theodoulou E, Arias-Pinilla G, Kwan A, Daverede L, Handforth C, Trainor S, Salawu A, McCabe C, Goh V, Buckley D, Hewison J, Gregory W, Selby P, Brown J, Brown J. Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT. Health Technol Assess 2024; 28:1-171. [PMID: 39250424 PMCID: PMC11403377 DOI: 10.3310/jwtr4127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2024] Open
Abstract
Background There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
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Affiliation(s)
- Fiona Collinson
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Kara-Louise Royle
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Jayne Swain
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Christy Ralph
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Anthony Maraveyas
- Academic Oncology, Faculty of Health Sciences, Hull York Medical School, Queens Centre Oncology and Haematology, Hull, UK
| | - Tim Eisen
- Department of Oncology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Nathan
- Department of Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Hertfordshire, UK
| | - Robert Jones
- School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - David Meads
- Academic Unit of Health Economics, University of Leeds, Leeds, UK
| | - Tze Min Wah
- Department of Diagnostic and Interventional Radiology, Leeds Teaching Hospitals Trust, Leeds, UK
| | - Adam Martin
- Academic Unit of Health Economics, University of Leeds, Leeds, UK
| | - Janine Bestall
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | | | | | - Jamie Oughton
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Kevin Chan
- Medical Oncology, Weston Park Cancer Hospital, Sheffield, UK
| | - Elisavet Theodoulou
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Gustavo Arias-Pinilla
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Amy Kwan
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK
| | - Luis Daverede
- Department of Clinical Oncology, Austral University Hospital, Buenos Aires, Argentina
| | - Catherine Handforth
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Sebastian Trainor
- St James's Institute of Oncology, St James's University Hospital, Leeds, UK
| | - Abdulazeez Salawu
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK
| | | | - Vicky Goh
- School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
| | - David Buckley
- Faculty of Medicine and Health, School of Medicine, University of Leeds, Leeds, UK
| | - Jenny Hewison
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Walter Gregory
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Peter Selby
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Julia Brown
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Janet Brown
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
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Caruso M, Stanzione A, Prinster A, Pizzuti LM, Brunetti A, Maurea S, Mainenti PP. Role of advanced imaging techniques in the evaluation of oncological therapies in patients with colorectal liver metastases. World J Gastroenterol 2023; 29:521-535. [PMID: 36688023 PMCID: PMC9850941 DOI: 10.3748/wjg.v29.i3.521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/25/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
In patients with colorectal liver metastasis (CRLMs) unsuitable for surgery, oncological treatments, such as chemotherapy and targeted agents, can be performed. Cross-sectional imaging [computed tomography (CT), magnetic resonance imaging (MRI), 18-fluorodexoyglucose positron emission tomography with CT/MRI] evaluates the response of CRLMs to therapy, using post-treatment lesion shrinkage as a qualitative imaging parameter. This point is critical because the risk of toxicity induced by oncological treatments is not always balanced by an effective response to them. Consequently, there is a pressing need to define biomarkers that can predict treatment responses and estimate the likelihood of drug resistance in individual patients. Advanced quantitative imaging (diffusion-weighted imaging, perfusion imaging, molecular imaging) allows the in vivo evaluation of specific biological tissue features described as quantitative parameters. Furthermore, radiomics can represent large amounts of numerical and statistical information buried inside cross-sectional images as quantitative parameters. As a result, parametric analysis (PA) translates the numerical data contained in the voxels of each image into quantitative parameters representative of peculiar neoplastic features such as perfusion, structural heterogeneity, cellularity, oxygenation, and glucose consumption. PA could be a potentially useful imaging marker for predicting CRLMs treatment response. This review describes the role of PA applied to cross-sectional imaging in predicting the response to oncological therapies in patients with CRLMs.
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Affiliation(s)
- Martina Caruso
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Napoli 80131, Italy
| | - Arnaldo Stanzione
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Napoli 80131, Italy
| | - Anna Prinster
- Institute of Biostructures and Bioimaging, National Research Council, Napoli 80131, Italy
| | - Laura Micol Pizzuti
- Institute of Biostructures and Bioimaging, National Research Council, Napoli 80131, Italy
| | - Arturo Brunetti
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Napoli 80131, Italy
| | - Simone Maurea
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Napoli 80131, Italy
| | - Pier Paolo Mainenti
- Institute of Biostructures and Bioimaging, National Research Council, Napoli 80131, Italy
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Posada Calderon L, Eismann L, Reese SW, Reznik E, Hakimi AA. Advances in Imaging-Based Biomarkers in Renal Cell Carcinoma: A Critical Analysis of the Current Literature. Cancers (Basel) 2023; 15:cancers15020354. [PMID: 36672304 PMCID: PMC9856305 DOI: 10.3390/cancers15020354] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/31/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Cross-sectional imaging is the standard diagnostic tool to determine underlying biology in renal masses, which is crucial for subsequent treatment. Currently, standard CT imaging is limited in its ability to differentiate benign from malignant disease. Therefore, various modalities have been investigated to identify imaging-based parameters to improve the noninvasive diagnosis of renal masses and renal cell carcinoma (RCC) subtypes. MRI was reported to predict grading of RCC and to identify RCC subtypes, and has been shown in a small cohort to predict the response to targeted therapy. Dynamic imaging is promising for the staging and diagnosis of RCC. PET/CT radiotracers, such as 18F-fluorodeoxyglucose (FDG), 124I-cG250, radiolabeled prostate-specific membrane antigen (PSMA), and 11C-acetate, have been reported to improve the identification of histology, grading, detection of metastasis, and assessment of response to systemic therapy, and to predict oncological outcomes. Moreover, 99Tc-sestamibi and SPECT scans have shown promising results in distinguishing low-grade RCC from benign lesions. Radiomics has been used to further characterize renal masses based on semantic and textural analyses. In preliminary studies, integrated machine learning algorithms using radiomics proved to be more accurate in distinguishing benign from malignant renal masses compared to radiologists' interpretations. Radiomics and radiogenomics are used to complement risk classification models to predict oncological outcomes. Imaging-based biomarkers hold strong potential in RCC, but require standardization and external validation before integration into clinical routines.
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Affiliation(s)
- Lina Posada Calderon
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lennert Eismann
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Stephen W. Reese
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ed Reznik
- Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Abraham Ari Hakimi
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Correspondence:
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Makihara K, Yamaguchi M, Ito K, Sakaguchi K, Hori Y, Semba T, Funahashi Y, Fujii H, Terada Y. New Cluster Analysis Method for Quantitative Dynamic Contrast-Enhanced MRI Assessing Tumor Heterogeneity Induced by a Tumor-Microenvironmental Ameliorator (E7130) Treatment to a Breast Cancer Mouse Model. J Magn Reson Imaging 2022; 56:1820-1831. [PMID: 35524730 DOI: 10.1002/jmri.28226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide insight into tumor perfusion. However, a method that can quantitatively measure the intra-tumor distribution of tumor voxel clusters with a distinct range of Ktrans and ve values remains insufficiently explored. HYPOTHESIS Two-dimensional cluster analysis may quantify the distribution of a tumor voxel subregion with a distinct range of Ktrans and ve values in human breast cancer xenografts. STUDY TYPE Prospective longitudinal study. ANIMAL MODEL Twenty-two female athymic nude mice with MCF-7 xenograft, treated with E7130, a tumor-microenvironmental ameliorator, or saline. FIELD STRENGTH/SEQUENCE 9.4 Tesla, turbo rapid acquisition with relaxation enhancement, and spoiled gradient-echo sequences. ASSESSMENT We performed two-dimensional k-means clustering to identify tumor voxel clusters with a distinct range of Ktrans and ve values on Days 0, 2, and 5 after treatment, calculated the ratio of the number of tumor voxels in each cluster to the total number of tumor voxels, and measured the normalized distances defined as the ratio of the distance between each tumor voxel and the nearest tumor margin to a tumor radius. STATISTICAL TESTS Unpaired t-tests, Dunnett's multiple comparison tests, and Chi-squared test were used. RESULTS The largest and second largest clusters constituted 44.4% and 27.5% of all tumor voxels with cluster centroid values of Ktrans at 0.040 min-1 and 0.116 min-1 , and ve at 0.131 and 0.201, respectively. At baseline (Day 0), the average normalized distances for the largest and second largest clusters were 0.33 and 0.24, respectively. E7130-treated group showed the normalized distance of the initial largest cluster decreasing to 0.25, while that of the second largest cluster increasing to 0.31. Saline-treated group showed no change. DATA CONCLUSION A two-dimensional cluster analysis might quantify the spatial distribution of a tumor subregion with a distinct range of Ktrans and ve values. LEVEL OF EVIDENCE 1 TECHNICAL EFFICACY: Stage 1.
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Affiliation(s)
- Kazuyuki Makihara
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan.,Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Masayuki Yamaguchi
- Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Ken Ito
- Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Oncology Tsukuba Research Development, Discovery, Medicine Creation, Eisai Co., Ltd., Tsukuba-shi, Japan
| | - Kazuya Sakaguchi
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan.,Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yusaku Hori
- Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Oncology Tsukuba Research Development, Discovery, Medicine Creation, Eisai Co., Ltd., Tsukuba-shi, Japan
| | - Taro Semba
- Oncology Tsukuba Research Development, Discovery, Medicine Creation, Eisai Co., Ltd., Tsukuba-shi, Japan
| | - Yasuhiro Funahashi
- Lenvima Co-Global Lead, Oncology Business Group, Eisai Co., Ltd., Woodcliff Lake, New Jersey, USA
| | - Hirofumi Fujii
- Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yasuhiko Terada
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan.,Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
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5
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Welsh SJ, Thompson N, Warren A, Priest AN, Barrett T, Ursprung S, Gallagher FA, Zaccagna F, Stewart GD, Fife KM, Matakidou A, Machin AJ, Qian W, Ingleson V, Mullin J, Riddick ACP, Armitage JN, Connolly S, Eisen TGQ. Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib. BJU Int 2022; 130:244-253. [PMID: 34549873 DOI: 10.1111/bju.15600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.
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Affiliation(s)
- Sarah J Welsh
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
| | - Nicola Thompson
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Anne Warren
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Andrew N Priest
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Tristan Barrett
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Stephan Ursprung
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Ferdia A Gallagher
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Fulvio Zaccagna
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Grant D Stewart
- Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
| | - Kate M Fife
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
| | - Athena Matakidou
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- GlaxoSmithKline, Brentford, UK
| | - Andrea J Machin
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Wendi Qian
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Victoria Ingleson
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Jean Mullin
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Antony C P Riddick
- Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
| | - James N Armitage
- Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
| | - Stephen Connolly
- Department of Urology, Mater Misericordiae University Hospital, University College Dublin, Dublin 7, Ireland
| | - Timothy G Q Eisen
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Centre Urological Malignancies Programme, University of Cambridge, Cambridge, UK
- Roche, Welwyn Garden City, UK
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Albano D, Bruno F, Agostini A, Angileri SA, Benenati M, Bicchierai G, Cellina M, Chianca V, Cozzi D, Danti G, De Muzio F, Di Meglio L, Gentili F, Giacobbe G, Grazzini G, Grazzini I, Guerriero P, Messina C, Micci G, Palumbo P, Rocco MP, Grassi R, Miele V, Barile A. Dynamic contrast-enhanced (DCE) imaging: state of the art and applications in whole-body imaging. Jpn J Radiol 2022; 40:341-366. [PMID: 34951000 DOI: 10.1007/s11604-021-01223-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022]
Abstract
Dynamic contrast-enhanced (DCE) imaging is a non-invasive technique used for the evaluation of tissue vascularity features through imaging series acquisition after contrast medium administration. Over the years, the study technique and protocols have evolved, seeing a growing application of this method across different imaging modalities for the study of almost all body districts. The main and most consolidated current applications concern MRI imaging for the study of tumors, but an increasing number of studies are evaluating the use of this technique also for inflammatory pathologies and functional studies. Furthermore, the recent advent of artificial intelligence techniques is opening up a vast scenario for the analysis of quantitative information deriving from DCE. The purpose of this article is to provide a comprehensive update on the techniques, protocols, and clinical applications - both established and emerging - of DCE in whole-body imaging.
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Affiliation(s)
- Domenico Albano
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Dipartimento Di Biomedicina, Neuroscienze E Diagnostica Avanzata, Sezione Di Scienze Radiologiche, Università Degli Studi Di Palermo, via Vetoio 1L'Aquila, 67100, Palermo, Italy
| | - Federico Bruno
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy.
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
| | - Andrea Agostini
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Clinical, Special and Dental Sciences, Department of Radiology, University Politecnica delle Marche, University Hospital "Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi", Ancona, Italy
| | - Salvatore Alessio Angileri
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Radiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimo Benenati
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS, Oncologia ed Ematologia, RadioterapiaRome, Italy
| | - Giulia Bicchierai
- Diagnostic Senology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Michaela Cellina
- Department of Radiology, ASST Fatebenefratelli Sacco, Ospedale Fatebenefratelli, Milan, Italy
| | - Vito Chianca
- Ospedale Evangelico Betania, Naples, Italy
- Clinica Di Radiologia, Istituto Imaging Della Svizzera Italiana - Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Diletta Cozzi
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Emergency Radiology, Careggi University Hospital, Florence, Italy
| | - Ginevra Danti
- Department of Emergency Radiology, Careggi University Hospital, Florence, Italy
| | - Federica De Muzio
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | - Letizia Di Meglio
- Postgraduation School in Radiodiagnostics, University of Milan, Milan, Italy
| | - Francesco Gentili
- Unit of Diagnostic Imaging, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Giuliana Giacobbe
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Giulia Grazzini
- Department of Radiology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Irene Grazzini
- Department of Radiology, Section of Neuroradiology, San Donato Hospital, Arezzo, Italy
| | - Pasquale Guerriero
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | | | - Giuseppe Micci
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Dipartimento Di Biomedicina, Neuroscienze E Diagnostica Avanzata, Sezione Di Scienze Radiologiche, Università Degli Studi Di Palermo, via Vetoio 1L'Aquila, 67100, Palermo, Italy
| | - Pierpaolo Palumbo
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Abruzzo Health Unit 1, Department of diagnostic Imaging, Area of Cardiovascular and Interventional Imaging, L'Aquila, Italy
| | - Maria Paola Rocco
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Roberto Grassi
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Vittorio Miele
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Radiology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Antonio Barile
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Milan, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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Bhaduri S, Lesbats C, Sharkey J, Kelly CL, Mukherjee S, Taylor A, Delikatny EJ, Kim SG, Poptani H. Assessing Tumour Haemodynamic Heterogeneity and Response to Choline Kinase Inhibition Using Clustered Dynamic Contrast Enhanced MRI Parameters in Rodent Models of Glioblastoma. Cancers (Basel) 2022; 14:cancers14051223. [PMID: 35267531 PMCID: PMC8909848 DOI: 10.3390/cancers14051223] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/16/2022] [Accepted: 02/23/2022] [Indexed: 12/04/2022] Open
Abstract
To investigate the utility of DCE-MRI derived pharmacokinetic parameters in evaluating tumour haemodynamic heterogeneity and treatment response in rodent models of glioblastoma, imaging was performed on intracranial F98 and GL261 glioblastoma bearing rodents. Clustering of the DCE-MRI-based parametric maps (using Tofts, extended Tofts, shutter speed, two-compartment, and the second generation shutter speed models) was performed using a hierarchical clustering algorithm, resulting in areas with poor fit (reflecting necrosis), low, medium, and high valued pixels representing parameters Ktrans, ve, Kep, vp, τi and Fp. There was a significant increase in the number of necrotic pixels with increasing tumour volume and a significant correlation between ve and tumour volume suggesting increased extracellular volume in larger tumours. In terms of therapeutic response in F98 rat GBMs, a sustained decrease in permeability and perfusion and a reduced cell density was observed during treatment with JAS239 based on Ktrans, Fp and ve as compared to control animals. No significant differences in these parameters were found for the GL261 tumour, indicating that this model may be less sensitive to JAS239 treatment regarding changes in vascular parameters. This study demonstrates that region-based clustered pharmacokinetic parameters derived from DCE-MRI may be useful in assessing tumour haemodynamic heterogeneity with the potential for assessing therapeutic response.
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Affiliation(s)
- Sourav Bhaduri
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
| | - Clémentine Lesbats
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SM2 5NG, UK
| | - Jack Sharkey
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
| | - Claire Louise Kelly
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
| | - Soham Mukherjee
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
| | - Arthur Taylor
- Department of Molecular Physiology & Cell Signalling, University of Liverpool, Liverpool L69 3BX, UK;
| | - Edward J. Delikatny
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Sungheon G. Kim
- Department of Radiology, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Harish Poptani
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK; (S.B.); (C.L.); (J.S.); (C.L.K.); (S.M.)
- Correspondence:
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8
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Takao S, Ushijima Y, Motomura Y, Sakamoto K, Hirakawa M, Nishie A, Mimori K, Yamashita Y, Tsutsumi T, Ishigami K. Radiology- and gene-based risk stratification in small renal cell carcinoma: A preliminary study. PLoS One 2021; 16:e0256471. [PMID: 34492075 PMCID: PMC8423232 DOI: 10.1371/journal.pone.0256471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/06/2021] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Most small renal cell carcinomas (small RCCs) will remain indolent after detection, but some stage I RCCs still metastasize. There are no risk-stratification imaging factors that could be used to identify poor-prognosis patients based on genomic profiling. Here, we evaluated the relationships between imaging parameters and RNA expressions in small RCC and attempted to identify imaging factors that could be used as effective biomarkers. METHODS We acquired biopsy specimens of 18 clear cell carcinomas that had undergone perfusion CT (pCT) and MRI between April 2018 and March 2019. We performed RNA sequencing, assessed RNA expressions, and calculated each tumor's cell-cycle progression (CCP) score, which has prognostic value in predicting metastatic progression. We classified the tumors into two groups: clear cell type A (ccA) and type B (ccB). CcA has better survival compared to ccB. We evaluated the following characteristics of each tumor: tumor size, presence of pseudocapsule, and fat. We used the pCT and MRI to measure each tumor's volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (VE), fractional plasma volume (VP), and apparent diffusion coefficient (ADC). The correlations between these small RCC imaging parameters and the tumor size and RNA expressions were determined. RESULTS The tumor size was significantly correlated with Kep and inversely correlated with VE, VP, ADC, and hallmark angiogenesis. The CCP score was significantly inversely correlated with Ktrans and Kep. The ccA tumors tended to show a pseudocapsule on MRI. CONCLUSION Tumor size was correlated with low perfusion, but not with prognostic factors based on genomic profiling. Imaging parameters (e.g., Ktrans and Kep) and tumor characteristics (e.g., pseudocapsule) may enable gene-based risk stratification in small RCC.
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Affiliation(s)
- Seiichiro Takao
- Department of Radiology, Beppu Hospital, Kyushu University, Beppu, Japan
| | - Yasuhiro Ushijima
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- * E-mail:
| | - Yushi Motomura
- Department of Radiology, Beppu Hospital, Kyushu University, Beppu, Japan
| | - Katsumi Sakamoto
- Department of Radiology, Beppu Hospital, Kyushu University, Beppu, Japan
| | - Masakazu Hirakawa
- Department of Radiology, Beppu Hospital, Kyushu University, Beppu, Japan
| | - Akihiro Nishie
- Department of Advanced Imaging and Interventional Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koshi Mimori
- Department of Surgery, Beppu Hospital, Kyushu University, Beppu, Japan
| | - Yasuo Yamashita
- Department of Medical Technology, Kyushu University Hospital, Fukuoka, Japan
| | | | - Kousei Ishigami
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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9
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Feasibility Study on Using Dynamic Contrast Enhanced MRI to Assess the Effect of Tyrosine Kinase Inhibitor Therapy within the STAR Trial of Metastatic Renal Cell Cancer. Diagnostics (Basel) 2021; 11:diagnostics11071302. [PMID: 34359384 PMCID: PMC8306403 DOI: 10.3390/diagnostics11071302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/06/2021] [Accepted: 07/16/2021] [Indexed: 01/04/2023] Open
Abstract
Objective: To identify dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters predictive of early disease progression in patients with metastatic renal cell cancer (mRCC) treated with anti-angiogenic tyrosine kinase inhibitors (TKI). Methods: The study was linked to a phase II/III randomised control trial. Patients underwent DCE-MRI before, at 4- and 10-weeks after initiation of TKI. DCE-MRI parameters at each time-point were derived from a single-compartment tracer kinetic model, following semi-automated tumour segmentation by two independent readers. Primary endpoint was correlation of DCE-MRI parameters with disease progression at 6-months. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) values were calculated for parameters associated with disease progression at 6 months. Inter-observer agreement was assessed using the intraclass correlation coefficient (ICC). Results: 23 tumours in 14 patients were measurable. Three patients had disease progression at 6 months. The percentage (%) change in perfused tumour volume between baseline and 4-week DCE-MRI (p = 0.016), mean transfer constant Ktrans change (p = 0.038), and % change in extracellular volume (p = 0.009) between 4- and 10-week MRI, correlated with early disease progression (AUC 0.879 for each parameter). Inter-observer agreement was excellent for perfused tumour volume, Ktrans and extracellular volume (ICC: 0.928, 0.949, 0.910 respectively). Conclusions: Early measurement of DCE-MRI biomarkers of tumour perfusion at 4- and 10-weeks predicts disease progression at 6-months following TKI therapy in mRCC.
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10
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Udayakumar D, Zhang Z, Xi Y, Dwivedi DK, Fulkerson M, Haldeman S, McKenzie T, Yousuf Q, Joyce A, Hajibeigi A, Notgrass H, de Leon AD, Yuan Q, Lewis MA, Madhuranthakam AJ, Sibley RC, Elias R, Guo J, Christie A, McKay RM, Cadeddu JA, Bagrodia A, Margulis V, Brugarolas J, Wang T, Kapur P, Pedrosa I. Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform. Clin Cancer Res 2021; 27:4794-4806. [PMID: 34210685 DOI: 10.1158/1078-0432.ccr-21-0706] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/02/2021] [Accepted: 06/24/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. EXPERIMENTAL DESIGN We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. RESULTS DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. CONCLUSIONS These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.
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Affiliation(s)
- Durga Udayakumar
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas.,Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Ze Zhang
- Quantitative Biomedical Research Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Yin Xi
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Durgesh K Dwivedi
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Michael Fulkerson
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Sydney Haldeman
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Tiffani McKenzie
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas
| | - Qurratulain Yousuf
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Allison Joyce
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Asghar Hajibeigi
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Hollis Notgrass
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas
| | | | - Qing Yuan
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Matthew A Lewis
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Ananth J Madhuranthakam
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas.,Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas
| | - Robert C Sibley
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Roy Elias
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Junyu Guo
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Alana Christie
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Renée M McKay
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Jeffrey A Cadeddu
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Aditya Bagrodia
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Vitaly Margulis
- Department of Urology, UT Southwestern Medical Center, Dallas, Texas.,Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - James Brugarolas
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Tao Wang
- Quantitative Biomedical Research Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas.,Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, Texas
| | - Payal Kapur
- Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Ivan Pedrosa
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas. .,Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.,Department of Urology, UT Southwestern Medical Center, Dallas, Texas
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11
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Lee JH, Yoo GS, Yoon YC, Park HC, Kim HS. Diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging after radiation therapy for bone metastases in patients with hepatocellular carcinoma. Sci Rep 2021; 11:10459. [PMID: 34001997 PMCID: PMC8128906 DOI: 10.1038/s41598-021-90065-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 05/04/2021] [Indexed: 12/24/2022] Open
Abstract
The objectives of this study were to assess changes in apparent diffusion coefficient (ADC) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters after radiation therapy (RT) for bone metastases from hepatocellular carcinoma (HCC) and to evaluate their prognostic value. This prospective study was approved by the Institutional Review Board. Fourteen patients with HCC underwent RT (30 Gy in 10 fractions once daily) for bone metastases. The ADC and DCE-MRI parameters and the volume of the target lesions were measured before (baseline) and one month after RT (post-RT). The Wilcoxon signed-rank test was used to compare the parameters between the baseline and post-RT MRI. The parameters were compared between patients with or without disease progression in RT fields using the Mann–Whitney test. Intraclass correlation coefficients were used to evaluate the interobserver agreement. The medians of the ADC, rate constant [kep], and volume fraction of the extravascular extracellular matrix [ve] in the baseline and post-RT MRI were 0.67 (range 0.61–0.72) and 0.75 (range 0.63–1.43) (× 10–3 mm2/s) (P = 0.027), 836.33 (range 301.41–1082.32) and 335.80 (range 21.86–741.87) (× 10–3/min) (P = 0.002), and 161.54 (range 128.38–410.13) and 273.99 (range 181.39–1216.95) (× 10–3) (P = 0.027), respectively. The medians of the percent change in the ADC of post-RT MRI in patients with progressive disease and patients without progressive disease were − 1.35 (range − 6.16 to 6.79) and + 46.71 (range 7.71–112.81) (%) (P = 0.011), respectively. The interobserver agreements for all MRI parameters were excellent (intraclass correlation coefficients > 0.8). In conclusion, the ADC, kep, and ve of bone metastases changed significantly after RT. The percentage change in the ADC was closely related to local tumor progression.
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Affiliation(s)
- Ji Hyun Lee
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Gyu Sang Yoo
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Young Cheol Yoon
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
| | - Hee Chul Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
| | - Hyun Su Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
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12
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Saida Y, Brender JR, Yamamoto K, Mitchell JB, Krishna MC, Kishimoto S. Multimodal Molecular Imaging Detects Early Responses to Immune Checkpoint Blockade. Cancer Res 2021; 81:3693-3705. [PMID: 33837042 DOI: 10.1158/0008-5472.can-20-3182] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/17/2021] [Accepted: 04/08/2021] [Indexed: 01/02/2023]
Abstract
Immune checkpoint blockade (ICB) has become a standard therapy for several cancers, however, the response to ICB is inconsistent and a method for noninvasive assessment has not been established to date. To investigate the capability of multimodal imaging to evaluate treatment response to ICB therapy, hyperpolarized 13C MRI using [1-13C] pyruvate and [1,4-13C2] fumarate and dynamic contrast enhanced (DCE) MRI was evaluated to detect early changes in tumor glycolysis, necrosis, and intratumor perfusion/permeability, respectively. Mouse tumor models served as platforms for high (MC38 colon adenocarcinoma) and low (B16-F10 melanoma) sensitivity to dual ICB of PD-L1 and CTLA4. Glycolytic flux significantly decreased following treatment only in the less sensitive B16-F10 tumors. Imaging [1,4-13C2] fumarate conversion to [1,4-13C2] malate showed a significant increase in necrotic cell death following treatment in the ICB-sensitive MC38 tumors, with essentially no change in B16-F10 tumors. DCE-MRI showed significantly increased perfusion/permeability in MC38-treated tumors, whereas a similar, but statistically nonsignificant, trend was observed in B16-F10 tumors. When tumor volume was also taken into consideration, each imaging biomarker was linearly correlated with future survival in both models. These results suggest that hyperpolarized 13C MRI and DCE MRI may serve as useful noninvasive imaging markers to detect early response to ICB therapy. SIGNIFICANCE: Hyperpolarized 13C MRI and dynamic contrast enhanced MRI in murine tumor models provide useful insight into evaluating early response to immune checkpoint blockade therapy.See related commentary by Cullen and Keshari, p. 3444.
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Affiliation(s)
- Yu Saida
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Jeffrey R Brender
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Kazutoshi Yamamoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - James B Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Murali C Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Shun Kishimoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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13
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Tsai LL, Bhatt RS, Strob MF, Jegede OA, Sun MRM, Alsop DC, Catalano P, McDermott D, Robson PM, Atkins MB, Pedrosa I. Arterial Spin Labeled Perfusion MRI for the Evaluation of Response to Tyrosine Kinase Inhibition Therapy in Metastatic Renal Cell Carcinoma. Radiology 2020; 298:332-340. [PMID: 33258745 DOI: 10.1148/radiol.2020201763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background Tumor perfusion may inform therapeutic response and resistance in metastatic renal cell carcinoma (RCC) treated with antiangiogenic therapy. Purpose To determine if arterial spin labeled (ASL) MRI perfusion changes are associated with tumor response and disease progression in metastatic RCC treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Materials and Methods In this prospective study (ClinicalTrials.gov identifier: NCT00749320), metastatic RCC perfusion was measured with ASL MRI before and during sunitinib or pazopanib therapy between October 2008 and March 2014. Objective response rate (ORR) and progression-free survival (PFS) were calculated. Perfusion was compared between responders and nonresponders at baseline, at week 2, after cycle 2 (12 weeks), after cycle 4 (24 weeks), and at disease progression and compared with the ORR by using the Wilcoxon rank sum test and with PFS by using the log-rank test. Results Seventeen participants received sunitinib (mean age, 59 years ± 7.0 [standard deviation]; 11 men); 11 participants received pazopanib (mean age, 63 years ± 6.6; eight men). Responders had higher baseline tumor perfusion than nonresponders (mean, 404 mL/100 g/min ± 213 vs 199 mL/100 g/min ± 136; P = .02). Perfusion decreased from baseline to week 2 (-53 mL/100 g/min ± 31; P < .001), after cycle 2 (-65 mL/100 g/min ± 25; P < .001), and after cycle 4 (-79 mL/100 g/min ± 15; P = .008). Interval reduction in perfusion at those three time points was not associated with ORR (P = .63, .29, and .27, respectively) or PFS (P = .28, .27, and .32). Perfusion increased from cycle 4 to disease progression (51% ± 11; P < .001). Conclusion Arterial spin labeled perfusion MRI may assist in identifying responders to vascular endothelial growth factor receptor tyrosine kinase inhibitors and may help detect early evidence of disease progression in patients with metastatic renal cell carcinoma. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Goh and De Vita in this issue.
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Affiliation(s)
- Leo L Tsai
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Rupal S Bhatt
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Meaghan F Strob
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Opeyemi A Jegede
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Maryellen R M Sun
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - David C Alsop
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Paul Catalano
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - David McDermott
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Philip M Robson
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Michael B Atkins
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
| | - Ivan Pedrosa
- From the Department of Radiology (L.L.T., M.F.S., D.C.A.) and Division of Hematology/Oncology (R.S.B., D.M.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Mass (O.A.J., P.C.); Department of Radiology, Lowell General Hospital, Lowell, Mass (M.R.M.S.); Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (P.M.R.); Division of Hematology/Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.); and Department of Radiology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390 (I.P.)
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Song Y, Fu Y, Xie Q, Zhu B, Wang J, Zhang B. Anti-angiogenic Agents in Combination With Immune Checkpoint Inhibitors: A Promising Strategy for Cancer Treatment. Front Immunol 2020; 11:1956. [PMID: 32983126 PMCID: PMC7477085 DOI: 10.3389/fimmu.2020.01956] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/20/2020] [Indexed: 12/31/2022] Open
Abstract
Advances in cancer immunity have promoted a major breakthrough in the field of cancer therapy. This is mainly associated with the successful development of immune checkpoint inhibitors (ICIs) for multiple types of human tumors. Blockade with different ICIs, including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, may activate the immune system of the host against malignant cells. However, only a subgroup of patients with cancer would benefit from immune checkpoint blockade. Some patients experience primary resistance to initial immunotherapy, and a majority eventually develop acquired resistance to ICIs. However, the mechanisms involved in the development of drug resistance to immune checkpoint blockade remain unclear. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for overcoming the low efficacy of ICIs. Moreover, through their direct anti-cancer effect by inhibiting tumor growth and metastasis, anti-angiogenic drugs reprogram the tumor milieu from an immunosuppressive to an immune permissive microenvironment. Activated immunity by immune checkpoint blockade also facilitates anti-angiogenesis by downregulating the expression of vascular endothelial growth factor and alleviating hypoxia condition. Many clinical trials showed an improved anti-cancer efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. This review summarizes the current understanding and clinical development of combination therapy with immune checkpoint blockade and anti-angiogenic strategy.
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Affiliation(s)
- Yuxiao Song
- Cancer Center, Hubei Provincial Research Center for Precision Medicine of Cancer, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Fu
- Department of Oncology, Xiangyang Hospital, Hubei University of Chinese Medicine, Xiangyang, China
| | - Qi Xie
- Medical Research Centre, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jun Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Bicheng Zhang
- Cancer Center, Hubei Provincial Research Center for Precision Medicine of Cancer, Renmin Hospital of Wuhan University, Wuhan, China
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15
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Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Tharakan G, Chambers E, Cole T, Lozano-Kuehne JP, Barwick TD, Aboagye EO. [ 18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer. Eur J Nucl Med Mol Imaging 2020; 47:1239-1251. [PMID: 31754793 PMCID: PMC7101300 DOI: 10.1007/s00259-019-04532-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/11/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti-angiogenic response.
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Affiliation(s)
- Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK.
| | - Pablo Oriol Valls
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Marianna Inglese
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
- Department of Computer, Control and Management Engineering Antonio Ruberti, University of Rome "La Sapienza", Rome, Italy
| | - Suraiya Dubash
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Michelle Chen
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Hani Gabra
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
- Clinical Discovery Unit, Early Clinical Development, AstraZeneca, Cambridge, UK
| | - Ana Montes
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Mubarik Arshad
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - George Tharakan
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Ed Chambers
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Tom Cole
- Department of Medicine, Division of Experimental Medicine, NIHR Imperial Clinical Research Facility, Imperial College London, London, UK
| | - Jingky P Lozano-Kuehne
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Tara D Barwick
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
- Department of Radiology, Imperial College Healthcare NHS Trust, London, UK
| | - Eric O Aboagye
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
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16
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Courtney KD, Ma Y, Diaz de Leon A, Christie A, Xie Z, Woolford L, Singla N, Joyce A, Hill H, Madhuranthakam AJ, Yuan Q, Xi Y, Zhang Y, Chang J, Fatunde O, Arriaga Y, Frankel AE, Kalva S, Zhang S, McKenzie T, Reig Torras O, Figlin RA, Rini BI, McKay RM, Kapur P, Wang T, Pedrosa I, Brugarolas J. HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma. Clin Cancer Res 2019; 26:793-803. [PMID: 31727677 DOI: 10.1158/1078-0432.ccr-19-1459] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/16/2019] [Accepted: 11/05/2019] [Indexed: 12/30/2022]
Abstract
PURPOSE The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
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Affiliation(s)
- Kevin D Courtney
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yuanqing Ma
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alberto Diaz de Leon
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alana Christie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Zhiqun Xie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Layton Woolford
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Nirmish Singla
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Allison Joyce
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Haley Hill
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ananth J Madhuranthakam
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Qing Yuan
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yin Xi
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yue Zhang
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jenny Chang
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Oluwatomilade Fatunde
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yull Arriaga
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Arthur E Frankel
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sanjeeva Kalva
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Song Zhang
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tiffani McKenzie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Oscar Reig Torras
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Robert A Figlin
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Brian I Rini
- Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio
| | - Renée M McKay
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Payal Kapur
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tao Wang
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ivan Pedrosa
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. .,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - James Brugarolas
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. .,Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
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17
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Quantitative renal function assessment of atheroembolic renal disease using view-shared compressed sensing based dynamic-contrast enhanced MR imaging: An in vivo study. Magn Reson Imaging 2019; 65:67-74. [PMID: 31654738 DOI: 10.1016/j.mri.2019.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 11/21/2022]
Abstract
Atheroembolic renal disease (AERD) is the major cause of renal insufficiency in the elderly, and particularly, the diagnose of AERD is often delayed and even missed due to its nonspecific presentation and the sudden occurrence of an embolic event. To investigate the feasibility of the view-shared compressed sensing (VCS) based dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in the assessment of AERD in animal models. The reproducibility of VCS DCE-MRI based glomerular filtration rate (GFR) estimation was first evaluated using the three healthy rabbits. Animal models of unilateral AERD were then conducted. All the rabbits underwent VCS DCE-MRI and the GFR maps were estimated by a commonly used cortical-compartment model. The whole kidney and suspicious lesion region GFR values of embolized kidneys were then compared with the corresponding values of normal kidneys. Finally, the suspicious lesion regions were confirmed by the corresponding renal specimens and histological findings. The reproducibility of GFR measurements was analyzed using the coefficient of variation and Bland-Altman analysis. The GFR values of normal and embolized kidneys were compared using the Student t-test. Contrast-enhanced images with sufficient diagnostic quality and reduced motion artifacts are obtained at a temporal resolution of 2.5 s. The Bland-Altman plot indicated close agreement between the GFR values estimated from between-day scans in healthy rabbits. Besides, there existed significant differences between the pixel-wise GFR values of normal and AERD kidneys in region-based comparison(P < 0.0001). The suspicious lesions are consistent well with the renal specimen and histological findings. The preliminary animal study verified the feasibility of VCS DCE-MRI for renal function evaluation, and the strategy could potentially provide a valuable tool to identify AERD.
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18
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Baseline perfusion CT parameters as potential biomarkers in predicting long-term prognosis of localized clear cell renal cell carcinoma. Abdom Radiol (NY) 2019; 44:3370-3376. [PMID: 31399787 DOI: 10.1007/s00261-019-02087-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
PURPOSE We aimed to explore the relationship among baseline perfusion CT parameters, clinical, and pathological factors with post-nephrectomy long-term progression-free survival in localized clear cell renal cell carcinoma. MATERIALS AND METHODS This study retrospectively collected 127 patients from March 2005 to May 2007 who undertook perfusion CT. 61 patients were confirmed of pT1N0M0 or pT2N0M0 ccRCC. The mean follow-up time is 118.8 months (± 13.1 m, range 72-135 m). We compared clinical, pathological factors (gender, T stage, age, Fuhrmann grade, VEGF level, and MVD), and perfusion parameters before treatment [blood flow (BF), blood volume, mean transition time, and permeability surface-area product] between groups with post-nephrectomy metastasis and without metastasis. Association between covariates and progression-free survival (PFS) were analyzed using Cox proportional regression. RESULTS Among 61 patients, 11 developed distant metastasis (10 in the lung, one in the bone). BF in metastatic group [429.1 (233.8, 570.1) ml/min/100 g] was significantly higher than non-metastatic group [214.3 (153.3, 376.5) ml/min/100 g] (p = 0.011). Metastatic group also had more patients with higher Fuhrmann grade. Multi-covariant Cox regression demonstrated T staging, Fuhrmann grade, and BF were significantly associated with PFS [hazard ratio (HR) 3.35, 3.08, and 1.006]. In another model, BF > 230 ml/min/100 g was associated with PFS (HR 12.90), along with T staging and Fuhrmann grade (HR 4.73, 3.69). CONCLUSION Baseline tumor BF is a potential biomarker in prediction long-term metastasis of localized ccRCC and may help screening for higher risk localized ccRCC patients who need personalized surveillance strategy after nephrectomy.
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19
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Comparison of dynamic contrast-enhanced magnetic resonance imaging and contrast-enhanced ultrasound for evaluation of the effects of sorafenib in a rat model of hepatocellular carcinoma. Magn Reson Imaging 2019; 57:156-164. [DOI: 10.1016/j.mri.2018.11.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 10/25/2018] [Accepted: 11/17/2018] [Indexed: 12/11/2022]
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20
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Zhou JY, Wang YC, Zeng CH, Ju SH. Renal Functional MRI and Its Application. J Magn Reson Imaging 2018; 48:863-881. [PMID: 30102436 DOI: 10.1002/jmri.26180] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/10/2018] [Indexed: 12/11/2022] Open
Abstract
Renal function varies according to the nature and stage of diseases. Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for noninvasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging postprocessing algorithms. Function-related imaging markers can be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. This review focuses on the progression and challenges of the main renal fMRI methods, including dynamic contrast-enhanced MRI, blood oxygen level-dependent MRI, diffusion-weighted imaging, diffusion tensor imaging, arterial spin labeling, fat fraction imaging, and their recent clinical applications. LEVEL OF EVIDENCE 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:863-881.
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Affiliation(s)
- Jia-Ying Zhou
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Yuan-Cheng Wang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Chu-Hui Zeng
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Sheng-Hong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
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Abstract
Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.
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22
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Benz MR, Bongartz G, Froehlich JM, Winkel D, Boll DT, Heye T. Acceleration techniques and their impact on arterial input function sampling: Non-accelerated versus view-sharing and compressed sensing sequences. Eur J Radiol 2018; 104:8-13. [PMID: 29857871 DOI: 10.1016/j.ejrad.2018.04.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 04/20/2018] [Accepted: 04/23/2018] [Indexed: 01/25/2023]
Abstract
PURPOSE The aim was to investigate the variation of the arterial input function (AIF) within and between various DCE MRI sequences. MATERIAL AND METHODS A dynamic flow-phantom and steady signal reference were scanned on a 3T MRI using fast low angle shot (FLASH) 2d, FLASH3d (parallel imaging factor (P) = P0, P2, P4), volumetric interpolated breath-hold examination (VIBE) (P = P0, P3, P2 × 2, P2 × 3, P3 × 2), golden-angle radial sparse parallel imaging (GRASP), and time-resolved imaging with stochastic trajectories (TWIST). Signal over time curves were normalized and quantitatively analyzed by full width half maximum (FWHM) measurements to assess variation within and between sequences. RESULTS The coefficient of variation (CV) for the steady signal reference ranged from 0.07-0.8%. The non-accelerated gradient echo FLASH2d, FLASH3d, and VIBE sequences showed low within sequence variation with 2.1%, 1.0%, and 1.6%. The maximum FWHM CV was 3.2% for parallel imaging acceleration (VIBE P2 × 3), 2.7% for GRASP and 9.1% for TWIST. The FWHM CV between sequences ranged from 8.5-14.4% for most non-accelerated/accelerated gradient echo sequences except 6.2% for FLASH3d P0 and 0.3% for FLASH3d P2; GRASP FWHM CV was 9.9% versus 28% for TWIST. CONCLUSION MRI acceleration techniques vary in reproducibility and quantification of the AIF. Incomplete coverage of the k-space with TWIST as a representative of view-sharing techniques showed the highest variation within sequences and might be less suited for reproducible quantification of the AIF.
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Affiliation(s)
- Matthias R Benz
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland.
| | - Georg Bongartz
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | | | - David Winkel
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Daniel T Boll
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Tobias Heye
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
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23
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Morotti M, Dass PH, Harris AL, Lord S. Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients. Eur J Drug Metab Pharmacokinet 2018; 43:137-153. [PMID: 29019020 DOI: 10.1007/s13318-017-0442-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.
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Affiliation(s)
- Matteo Morotti
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
- Department of Gynaecology Oncology, University of Oxford, Oxford, UK.
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK.
| | - Prashanth Hari Dass
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Adrian L Harris
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Simon Lord
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
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24
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Abstract
PURPOSE OF REVIEW Renal cell carcinoma is a heterogeneous disease with a spectrum of subtypes and clinical behavior. Quantitative and qualitative imaging biomarkers are sought to correlate with genetic and histologic features and complement pathologic analysis. RECENT FINDINGS Texture analysis, radiogenomics, and modality-specific advancements have yielded an array of renal cell carcinoma imaging biomarkers in the research domain. Although many techniques are promising, standardization and validation of these procedures are needed prior to implementation into clinical practice. SUMMARY We introduce novel imaging techniques and analytic methods which have been shown to contribute to characterization of renal cell carcinoma and its subtypes, aggressiveness, and responsiveness to therapy, including associated advantages and limitations.
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25
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The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib. Eur Radiol 2018; 28:2281-2290. [DOI: 10.1007/s00330-017-5220-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 11/05/2017] [Accepted: 11/28/2017] [Indexed: 12/20/2022]
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26
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Renal Cell Carcinoma Perfusion before and after Radiofrequency Ablation Measured with Dynamic Contrast Enhanced MRI: A Pilot Study. Diagnostics (Basel) 2018; 8:diagnostics8010003. [PMID: 29316711 PMCID: PMC5871986 DOI: 10.3390/diagnostics8010003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/28/2017] [Accepted: 01/02/2018] [Indexed: 01/31/2023] Open
Abstract
Aim: To investigate if the early treatment effects of radiofrequency ablation (RFA) on renal cell carcinoma (RCC) can be detected with dynamic contrast enhanced (DCE)-MRI and to correlate RCC perfusion with RFA treatment time. Materials and methods: 20 patients undergoing RFA of their 21 RCCs were evaluated with DCE-MRI before and at one month after RFA treatment. Perfusion was estimated using the maximum slope technique at two independent sittings. Total RCC blood flow was correlated with total RFA treatment time, tumour location, size and histology. Results: DCE-MRI examinations were successfully evaluated for 21 RCCs (size from 1.3 to 4 cm). Perfusion of the RCCs decreased significantly (p < 0.0001) from a mean of 203 (±80) mL/min/100 mL before RFA to 8.1 (±3.1) mL/min/100 mL after RFA with low intra-observer variability (r ≥ 0.99, p < 0.0001). There was an excellent correlation (r = 0.95) between time to complete ablation and pre-treatment total RCC blood flow. Tumours with an exophytic location exhibit the lowest mean RFA treatment time. Conclusion: DCE-MRI can detect early treatment effects by measuring RCC perfusion before and after RFA. Perfusion significantly decreases in the zone of ablation, suggesting that it may be useful for the assessment of treatment efficacy. Pre-RFA RCC blood flow may be used to predict RFA treatment time.
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27
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Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 2017; 52:117-124. [PMID: 29229461 DOI: 10.1016/j.semcancer.2017.12.002] [Citation(s) in RCA: 328] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 12/02/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022]
Abstract
The critical role of angiogenesis in promoting tumor growth and metastasis has been well established scientifically, and consequently blocking this pathway as a therapeutic strategy has demonstrated great clinical success for the treatment of cancer. The holy grail however, has been the identification of patients who derive significant survival benefit from this class of agents. Here we attempt to delineate the diverse mechanisms related to anti-VEGF including its role as an anti-vascular, anti-angiogenic or an anti-permeability factor and review the most promising predictive biomarkers interrogated in large clinical trials, that identify patients who may derive significant survival advantage with VEGF inhibition. Lastly, we describe the function of VEGF as an immunomodulator and illustrate the evidence for anti-VEGF in reprogramming the tumor milieu from an immunosuppressive to an immune permissive microenvironment in human cancers, thus elucidating the role of anti-VEGF as an optimal combination partner for immune checkpoint inhibitors.
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Affiliation(s)
- Priti S Hegde
- Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
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28
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Fournier L, Bellucci A, Vano Y, Bouaboula M, Thibault C, Elaidi R, Oudard S, Cuenod C. Imaging Response of Antiangiogenic and Immune-Oncology Drugs in Metastatic Renal Cell Carcinoma (mRCC): Current Status and Future Challenges. KIDNEY CANCER 2017; 1:107-114. [PMID: 30334012 PMCID: PMC6179123 DOI: 10.3233/kca-170011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This report aims to review criteria which have been proposed for treatment evaluation in mRCC under anti-angiogenic and immune-oncologic therapies and discuss future challenges for imagers. RECIST criteria seem to only partially reflect the clinical benefit derived from anti-angiogenic drugs in mRCC. New methods of analysis propose to better evaluate response to these drugs, including a new threshold for size criteria (-10%), attenuation (Choi and modified Choi criteria), functional imaging techniques (perfusion CT, ultrasound or MRI), and new PET radiotracers. Imaging of progression is one of the main future challenges facing imagers. It is progression and not response that will trigger changes in therapy, therefore it is tumour progression that should be identified by imaging techniques to guide the oncologist on the most appropriate time to change therapy. Yet little is known on dynamics of tumour progression, and much data still needs to be accrued to understand it. Finally, as immunotherapies develop, flare or pseudo-progression phenomena are observed. Studies need to be performed to determine whether imaging can distinguish between patients undergoing pseudo-progression for which therapy should be continued, or true progression for which the treatment must be changed.
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Affiliation(s)
- Laure Fournier
- Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Radiology Department, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France
| | - Alexandre Bellucci
- Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Radiology Department, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France
| | - Yann Vano
- Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Oncology Department, Paris, France
| | - Mehdi Bouaboula
- Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Radiology Department, Paris, France
| | - Constance Thibault
- Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Oncology Department, Paris, France
| | - Reza Elaidi
- ARTIC (Association pour la Recherche sur les Thérapeutique Innovantes en Cancérologie), Paris, France
| | - Stephane Oudard
- Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Oncology Department, Paris, France
| | - Charles Cuenod
- Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Radiology Department, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, INSERM UMRS970, Paris, France
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Lebastchi AH, Watson MJ, Russell CM, George AK, Weizer AZ, Turkbey B. Using Imaging to Predict Treatment Response in Genitourinary Malignancies. Eur Urol Focus 2017; 4:804-817. [PMID: 28918178 DOI: 10.1016/j.euf.2017.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/09/2017] [Accepted: 09/01/2017] [Indexed: 02/08/2023]
Abstract
CONTEXT Over the previous2 decades, there have been numerous advancements in the diagnostic evaluation, therapeutic management, and postoperative assessment of genitourinary malignancies. OBJECTIVE To present a review of current and novel imaging modalities and their utility in the assessment of therapeutic response in the systemic management of renal, testicular, and prostate cancers. EVIDENCE ACQUISITION A PubMed/Medline search of the current published literature inclusive of prospective and retrospective original research, systematic reviews, and meta-analyses was conducted evaluating imaging modalities for renal cell carcinoma, prostate cancer, and testicular cancer. All relevant literature was individually reviewed and summarized to provide a concise description of the currently available imaging modalities and their efficacy in assessing treatment response of the genitourinary malignancies targeted in this review. EVIDENCE SYNTHESIS Conventional imaging techniques play a pivotal role in predicting the treatment response of genitourinary malignancies and have, therefore, been incorporated into clinical guidelines. Advancements in imaging technology have led to increased utilization for prognostication of a genitourinary cancer's response to therapy. CONCLUSIONS A good understanding of current recommended imaging techniques to evaluate treatment response in genitourinary malignancies is of paramount importance for today's clinician, who faces increasing treatment modalities. PATIENT SUMMARY In this review, we summarize available imaging modalities in the evaluation of treatment response in kidney, prostate, or testicular tumors. We believe that a good understanding of current imaging modalities is of paramount importance for healthcare providers treating these cancers.
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Affiliation(s)
- Amir H Lebastchi
- Department of Urology, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthew J Watson
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Arvin K George
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Alon Z Weizer
- Department of Urology, University of Michigan, Ann Arbor, Michigan, USA
| | - Baris Turkbey
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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30
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Clinical pharmacology of anti-angiogenic drugs in oncology. Crit Rev Oncol Hematol 2017; 119:75-93. [PMID: 28916378 DOI: 10.1016/j.critrevonc.2017.08.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 08/23/2017] [Accepted: 08/29/2017] [Indexed: 12/14/2022] Open
Abstract
Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.
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31
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Beyond Correlations, Sensitivities, and Specificities: Case Examples of the Evaluation of Advanced Imaging in Oncology Clinical Trials and Cancer Treatment. Acad Radiol 2017; 24:1027-1035. [PMID: 28410912 DOI: 10.1016/j.acra.2016.11.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 12/22/2022]
Abstract
Although advanced imaging is an important component of oncology clinical trials, there has not been a lot of success in advancing its use from a research perspective. One likely reason is the lack of consensus on the methodology used to study advanced imaging in trials, which results in a disconcerted research effort and produces data that are difficult to collate for use in validating the imaging components being studied. Imaging is used in cancer clinical trials for various indications, and the study design needed to evaluate the imaging in a particular indication will vary. Through case examples, this paper will discuss how advanced imaging is currently being investigated in oncology clinical trials, categorized by the potential clinical indication for the imaging tool and offer suggestions on how development should proceed to further evaluate imaging in the given indication. Available National Cancer Institute resources that can assist in this process will also be discussed.
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32
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Robinson SP, Boult JKR, Vasudev NS, Reynolds AR. Monitoring the Vascular Response and Resistance to Sunitinib in Renal Cell Carcinoma In Vivo with Susceptibility Contrast MRI. Cancer Res 2017; 77:4127-4134. [PMID: 28566330 PMCID: PMC6175052 DOI: 10.1158/0008-5472.can-17-0248] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/03/2017] [Accepted: 05/22/2017] [Indexed: 12/25/2022]
Abstract
Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P < 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P < 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P < 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P < 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume. Cancer Res; 77(15); 4127-34. ©2017 AACR.
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Affiliation(s)
- Simon P Robinson
- Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy & Imaging, The Institute of Cancer Research, London, United Kingdom.
| | - Jessica K R Boult
- Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy & Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Naveen S Vasudev
- Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Andrew R Reynolds
- Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
- Early Clinical Development, Innovative Medicines and Early Development, AstraZeneca, Cambridge, United Kingdom
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33
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Shinagare AB, Krajewski KM, Braschi-Amirfarzan M, Ramaiya NH. Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine. Radiology 2017; 284:333-351. [DOI: 10.1148/radiol.2017160343] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Atul B. Shinagare
- From the Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass
| | - Katherine M. Krajewski
- From the Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass
| | - Marta Braschi-Amirfarzan
- From the Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass
| | - Nikhil H. Ramaiya
- From the Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass
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34
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Antiangiogenic tyrosine kinase inhibitors in colorectal cancer: is there a path to making them more effective? Cancer Chemother Pharmacol 2017; 80:661-671. [PMID: 28721456 DOI: 10.1007/s00280-017-3389-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 07/10/2017] [Indexed: 01/07/2023]
Abstract
Antiangiogenic therapy has a proven survival benefit in metastatic colorectal cancer. Inhibition of the VEGF pathway using a variety of extracellular antibody approaches has clear benefit in combination with chemotherapy, while intracellular blockade using tyrosine kinase inhibitors (TKIs) such as sorafenib and regorafenib has had more limited success. Pharmacodynamic modeling using modalities such as DCE-MRI indicates potent antiangiogenic effects of these TKIs, yet numerous combination therapies, primarily with chemotherapy, have failed to demonstrate an additive benefit. The sole comparative study of a single agent TKI against placebo showed a survival benefit of regorafenib in patients with advanced, refractory disease. Preclinical data demonstrate synergy between antiantiogenic TKIs and targeted interventions including autophagy inhibition, and together with a renewed effort to define markers of susceptibility, such combinations may be a way to improve the limited efficacy of this once-promising drug class.
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35
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Kelly-Morland C, Rudman S, Nathan P, Mallett S, Montana G, Cook G, Goh V. Evaluation of treatment response and resistance in metastatic renal cell cancer (mRCC) using integrated 18F-Fluorodeoxyglucose ( 18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI); The REMAP study. BMC Cancer 2017; 17:392. [PMID: 28578690 PMCID: PMC5455133 DOI: 10.1186/s12885-017-3371-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 05/17/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Tyrosine kinase inhibitors are the first line standard of care for treatment of metastatic renal cell carcinoma (RCC). Accurate response assessment in the setting of antiangiogenic therapies remains suboptimal as standard size-related response criteria do not necessarily accurately reflect clinical benefit, as they may be less pronounced or occur later in therapy than devascularisation. The challenge for imaging is providing timely assessment of disease status allowing therapies to be tailored to ensure ongoing clinical benefit. We propose that combined assessment of morphological, physiological and metabolic imaging parameters using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) will better reflect disease behaviour, improving assessment of response/non-response/relapse. METHODS/DESIGN The REMAP study is a single-centre prospective observational study. Eligible patients with metastatic renal cell carcinoma, planned for systemic therapy, with at least 2 lesions will undergo an integrated 18F-FDG PET and MRI whole body imaging with diffusion weighted and contrast-enhanced multiphasic as well as standard anatomical MRI sequences at baseline, 12 weeks and 24 weeks of systemic therapy allowing 18F-FDG standardised uptake value (SUV), apparent diffusion co-efficient (ADC) and normalised signal intensity (SI) parameters to be obtained. Standard of care contrast-enhanced computed tomography CT scans will be performed at equivalent time-points. CT response categorisation will be performed using RECIST 1.1 and alternative (modified)Choi and MASS criteria. The reference standard for disease status will be by consensus panel taking into account clinical, biochemical and conventional imaging parameters. Intra- and inter-tumoural heterogeneity in vascular, diffusion and metabolic response/non-response will be assessed by image texture analysis. Imaging will also inform the development of computational methods for automated disease status categorisation. DISCUSSION The REMAP study will demonstrate the ability of integrated 18F-FDG PET-MRI to provide a more personalised approach to therapy. We suggest that 18F-FDG PET/MRI will provide superior sensitivity and specificity in early response/non-response categorisation when compared to standard CT (using RECIST 1.1 and alternative (modified)Choi or MASS criteria) thus facilitating more timely and better informed treatment decisions. TRIAL REGISTRATION The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 .
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Affiliation(s)
- Christian Kelly-Morland
- Department of Cancer Imaging, King’s College London Division of Imaging Sciences & Biomedical Engineering, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Sarah Rudman
- Department of Medical Oncology, Guy’s Hospital, Great Maze Pond, London, SE1 9RT UK
| | - Paul Nathan
- Department of Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex, HA6 2RN UK
| | - Susan Mallett
- Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, B15 2TT, Birmingham, UK
| | - Giovanni Montana
- Department of Biomedical Engineering, King’s College London Division of Imaging Sciences & Biomedical Engineering, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Gary Cook
- Department of Cancer Imaging, King’s College London Division of Imaging Sciences & Biomedical Engineering, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Vicky Goh
- Department of Cancer Imaging, King’s College London Division of Imaging Sciences & Biomedical Engineering, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
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36
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Molecular Imaging to Predict Response to Targeted Therapies in Renal Cell Carcinoma. CONTRAST MEDIA & MOLECULAR IMAGING 2017; 2017:7498538. [PMID: 29097936 PMCID: PMC5612742 DOI: 10.1155/2017/7498538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 01/26/2017] [Accepted: 03/09/2017] [Indexed: 12/21/2022]
Abstract
Molecular magnetic resonance imaging targeted to an endothelial integrin involved in neoangiogenesis was compared to DCE-US and immunochemistry to assess the early response of three different therapeutic agents in renal cell carcinoma. Human A498 renal cells carcinoma was subcutaneously inoculated into 24 nude mice. Mice received either phosphate-buffered saline solution, sunitinib, everolimus, or bevacizumab during 4 days. DCE-US and molecular MRI targeting αvβ3 were performed at baseline and 4 days after treatment initiation. PI, AUC, relaxation rate variations ΔR2⁎, and percentage of vessels area quantified on CD31-stained microvessels were compared. Significant decreases were observed for PI and AUC parameters measured by DCE-US for bevacizumab group as early as 4 days, whereas molecular αvβ3-targeted MRI was able to detect significant changes in both bevacizumab and everolimus groups. Percentage of CD31-stained microvessels was significantly correlated with DCE-US parameters, PI (R = 0.87, p = 0.0003) and AUC (R = 0.81, p = 0.0013). The percentage of vessel tissue area was significantly reduced (p < 0.01) in both sunitinib and bevacizumab groups. We report an early detection of neoangiogenesis modification after induction of targeted therapies, using DCE-US or αvβ3-targeted MRI. We consider these outcomes should encourage clinical trial developments to further evaluate the potential of this molecular MRI technique.
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37
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Deng J, Wang Y. Quantitative magnetic resonance imaging biomarkers in oncological clinical trials: Current techniques and standardization challenges. Chronic Dis Transl Med 2017; 3:8-20. [PMID: 29063052 PMCID: PMC5627686 DOI: 10.1016/j.cdtm.2017.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Indexed: 12/21/2022] Open
Abstract
Radiological imaging plays an important role in oncological trials to provide imaging biomarkers for disease staging, stratifying patients, defining dose setting, and evaluating the safety and efficacy of new candidate drugs and innovative treatment. This paper reviews the techniques of most commonly used quantitative magnetic resonance imaging (qMRI) biomarkers (dynamic contrast enhanced, dynamic susceptibility contrast, and diffusion weighted imaging) and their applications in oncological trials. Challenges of incorporating qMRI biomarkers in oncological trials are discussed including understanding biological mechanisms revealed by MRI biomarkers, consideration of rigorous trial design and standardized implementation of qMRI protocols.
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Affiliation(s)
- Jie Deng
- Department of Medical Imaging, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.,Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yi Wang
- Department of Radiology, Peking University People's Hospital, Beijing, 100044, China
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Zöllner FG, Gaa T, Zimmer F, Ong MM, Riffel P, Hausmann D, Schoenberg SO, Weis M. [Quantitative perfusion imaging in magnetic resonance imaging]. Radiologe 2016; 56:113-23. [PMID: 26796337 DOI: 10.1007/s00117-015-0068-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
CLINICAL/METHODICAL ISSUE Magnetic resonance imaging (MRI) is recognized for its superior tissue contrast while being non-invasive and free of ionizing radiation. Due to the development of new scanner hardware and fast imaging techniques during the last decades, access to tissue and organ functions became possible. One of these functional imaging techniques is perfusion imaging with which tissue perfusion and capillary permeability can be determined from dynamic imaging data. STANDARD RADIOLOGICAL METHODS Perfusion imaging by MRI can be performed by two approaches, arterial spin labeling (ASL) and dynamic contrast-enhanced (DCE) MRI. While the first method uses magnetically labelled water protons in arterial blood as an endogenous tracer, the latter involves the injection of a contrast agent, usually gadolinium (Gd), as a tracer for calculating hemodynamic parameters. PERFORMANCE Studies have demonstrated the potential of perfusion MRI for diagnostics and also for therapy monitoring. ACHIEVEMENTS The utilization and application of perfusion MRI are still restricted to specialized centers, such as university hospitals. A broad application of the technique has not yet been implemented. PRACTICAL RECOMMENDATIONS The MRI perfusion technique is a valuable tool that might come broadly available after implementation of standards on European and international levels. Such efforts are being promoted by the respective professional bodies.
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Affiliation(s)
- F G Zöllner
- Computerunterstützte Klinische Medizin, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland.
| | - T Gaa
- Computerunterstützte Klinische Medizin, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland
| | - F Zimmer
- Computerunterstützte Klinische Medizin, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland
| | - M M Ong
- Institut für Klinische Radiologie und Nuklearmedizin, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
| | - P Riffel
- Institut für Klinische Radiologie und Nuklearmedizin, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
| | - D Hausmann
- Institut für Klinische Radiologie und Nuklearmedizin, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
| | - S O Schoenberg
- Institut für Klinische Radiologie und Nuklearmedizin, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
| | - M Weis
- Institut für Klinische Radiologie und Nuklearmedizin, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
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Zhang R, Wang ZY, Li YH, Lu YH, Wang S, Yu WX, Zhao H. Usefulness of dynamic contrast-enhanced magnetic resonance imaging for predicting treatment response to vinorelbine-cisplatin with or without recombinant human endostatin in bone metastasis of non-small cell lung cancer. Am J Cancer Res 2016; 6:2890-2900. [PMID: 28042508 PMCID: PMC5199762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/08/2016] [Indexed: 06/06/2023] Open
Abstract
Metastatic bone disease is a frequent complication of advanced non-small cell lung cancer (NSCLC) and causes skeletal-related events, which result in a poor prognosis. Currently, no standard method has been developed to precisely assess the therapeutic response of bone metastases (BM) and the early efficacy of anti-angiogenic therapy, which does not conform to the concept of precision medicine. This study aimed to investigate the usefulness of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for precise evaluation of the response to chemotherapy with anti-angiogenic agents in NSCLC patients with BM. Patients were randomly assigned to a treatment group (vinorelbine + cisplatin [NP] + recombinant human endostatin [rh-endostatin]) or a control group (NP + placebo). All patients were evaluated before treatment and after 2 cycles of treatment using DCE-MRI quantitative analysis technology for BM lesions and chest computed tomography (CT). Correlations between changes in the DCE-MRI quantitative parameters and treatment effect were analyzed. We enrolled 33 patients, of whom 28 were evaluable (20 in the treatment group and 8 in the control group). The results suggested a higher objective response rate (30% vs. 0%), better overall survival (21.44 ± 17.28 months vs. 7.71 ± 4.68 months), and a greater decrease in the transport constant (Ktrans) value (60% vs. 4.4%) in the treatment group than in the control group (P < 0.05). The Ktrans values in the "partial remission plus stable disease (PR + SD)" group were significantly lower after treatment (P < 0.05). Patients with a decrease of > 50% in the Ktrans value showed a significantly better overall survival than those with a decrease of ≤ 50% (13.2 vs. 9.8 months, P < 0.05). Ktrans as a DEC-MRI quantitative parameter could be used for the precise evaluation of BM lesions after anti-angiogenic therapy and as a predictor of survival. In addition, we reconfirmed the anti-angiogenic effect of rh-endostatin in NSCLC patients with BM.
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Affiliation(s)
- Rui Zhang
- Department of Internal Oncology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
| | - Zhi-Yu Wang
- Department of Internal Oncology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
| | - Yue-Hua Li
- Department of Radiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
| | - Yao-Hong Lu
- Department of Clinical Skill Laboratory, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
| | - Shuai Wang
- Department of Internal Oncology, Shanghai Sixth People’s Hospital, Soochow UniversityShanghai 200233, People’s Republic of China
| | - Wen-Xi Yu
- Department of Internal Oncology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
| | - Hui Zhao
- Department of Internal Oncology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 200233, People’s Republic of China
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Abstract
Cancer therapy is mainly based on different combinations of surgery, radiotherapy, and chemotherapy. Additionally, targeted therapies (designed to disrupt specific tumor hallmarks, such as angiogenesis, metabolism, proliferation, invasiveness, and immune evasion), hormonotherapy, immunotherapy, and interventional techniques have emerged as alternative oncologic treatments. Conventional imaging techniques and current response criteria do not always provide the necessary information regarding therapy success particularly to targeted therapies. In this setting, MR imaging offers an attractive combination of anatomic, physiologic, and molecular information, which may surpass these limitations, and is being increasingly used for therapy response assessment.
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Abstract
Multiparametric MR imaging (mpMRI) combine different sequences that, properly tailored, can provide qualitative and quantitative information about the tumor microenvironment beyond traditional tumor size measures and/or morphologic assessments. This article focuses on mpMRI in the evaluation of urogenital tract malignancies by first reviewing technical aspects and then discussing its potential clinical role. This includes insight into histologic subtyping and grading of renal cell carcinoma and assessment of tumor response to targeted therapies. The clinical utility of mpMRI in the staging and grading of ureteral and bladder tumors is presented. Finally, the evolving role of mpMRI in prostate cancer is discussed.
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Abramson RG, Arlinghaus LR, Dula AN, Quarles CC, Stokes AM, Weis JA, Whisenant JG, Chekmenev EY, Zhukov I, Williams JM, Yankeelov TE. MR Imaging Biomarkers in Oncology Clinical Trials. Magn Reson Imaging Clin N Am 2016; 24:11-29. [PMID: 26613873 DOI: 10.1016/j.mric.2015.08.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The authors discuss eight areas of quantitative MR imaging that are currently used (RECIST, DCE-MR imaging, DSC-MR imaging, diffusion MR imaging) in clinical trials or emerging (CEST, elastography, hyperpolarized MR imaging, multiparameter MR imaging) as promising techniques in diagnosing cancer and assessing or predicting response of cancer to therapy. Illustrative applications of the techniques in the clinical setting are summarized before describing the current limitations of the methods.
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Affiliation(s)
- Richard G Abramson
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Lori R Arlinghaus
- Department of Radiology and Radiological Sciences, Vanderbilt University, 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Adrienne N Dula
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - C Chad Quarles
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Biomedical Engineering, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Cancer Biology, Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Ashley M Stokes
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Jared A Weis
- Department of Biomedical Engineering, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Jennifer G Whisenant
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Eduard Y Chekmenev
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Biomedical Engineering, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Biochemistry, Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Igor Zhukov
- National Research Nuclear University MEPhI, Kashirskoye highway, 31, Moscow 115409, Russia
| | - Jason M Williams
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA
| | - Thomas E Yankeelov
- Department of Radiology and Radiological Sciences, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Biomedical Engineering, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Cancer Biology, Institute of Imaging Science, Vanderbilt University, 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA; Department of Physics, Institute of Imaging Science, Vanderbilt University, VUIIS 1161 21st Avenue South, AA 1105 MCN, Nashville, TN 37232-2310, USA.
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Sweis RF, Medved M, Towey S, Karczmar GS, Oto A, Szmulewitz RZ, O'Donnell PH, Fishkin P, Karrison T, Stadler WM. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Pharmacodynamic Biomarker for Pazopanib in Metastatic Renal Carcinoma. Clin Genitourin Cancer 2016; 15:207-212. [PMID: 27634566 DOI: 10.1016/j.clgc.2016.08.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 08/08/2016] [Indexed: 01/18/2023]
Abstract
INTRODUCTION/BACKGROUND Traditional imaging assessment criteria might not correlate well with clinical benefit from vascular endothelial growth factor pathway-directed therapy in metastatic renal cancer. Preclinical data suggest tumor growth is preceded by a rise in Ktrans level, a parameter derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) that reflects vascular permeability. We thus hypothesized that Ktrans might be a predictive biomarker for pazopanib. PATIENTS AND METHODS Patients with metastatic renal cancer were treated with pazopanib at 800 mg oral daily until disease progression. MRI of the abdomen and pelvis with a DCE-MRI sequence was obtained at baseline and every 8 weeks. RESULTS Seventy-three DCE-MRI scans were completed and 66 were technically assessable. Of the 17 patients with at least 1 DCE-MRI scan after the baseline scan, 16 (94%) had a decline in Ktrans level. Changes in Ktrans compared with baseline after 1, 8, 16, and 24 weeks were -49%, -65%, -63%, and -53%, respectively (P = .0052, repeated measures analysis of variance). The median Ktrans nadir occurred at 8 weeks. The median progression-free survival (PFS) was 32.1 weeks. PFS was longer in patients with higher baseline Ktrans values (P = .036, log rank). Baseline Ktrans did not reach significance in a Cox proportional hazard model including clinical prognostic index and previous treatments (P = .083). CONCLUSION We show that Ktrans is a pharmacodynamic biomarker for pazopanib therapy in metastatic renal cancer. Because of the small sample size, the predictive capacity of Ktrans recovery could not be assessed, but baseline Ktrans correlated with PFS.
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Affiliation(s)
- Randy F Sweis
- Department of Medicine, Section of Hematology/Oncology, Comprehensive Cancer Center, University of Chicago, Chicago, IL
| | - Milica Medved
- Department of Radiology, University of Chicago, Chicago, IL
| | - Shannon Towey
- Department of Radiology, University of Chicago, Chicago, IL
| | | | - Aytekin Oto
- Department of Radiology, University of Chicago, Chicago, IL
| | - Russell Z Szmulewitz
- Department of Medicine, Section of Hematology/Oncology, Comprehensive Cancer Center, University of Chicago, Chicago, IL
| | - Peter H O'Donnell
- Department of Medicine, Section of Hematology/Oncology, Comprehensive Cancer Center, University of Chicago, Chicago, IL
| | | | - Theodore Karrison
- Department of Medicine, Section of Hematology/Oncology, Comprehensive Cancer Center, University of Chicago, Chicago, IL
| | - Walter M Stadler
- Department of Medicine, Section of Hematology/Oncology, Comprehensive Cancer Center, University of Chicago, Chicago, IL.
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Dynamic contrast enhanced MR imaging for evaluation of angiogenesis of hepatocellular nodules in liver cirrhosis in N-nitrosodiethylamine induced rat model. Eur Radiol 2016; 27:2086-2094. [PMID: 27488851 DOI: 10.1007/s00330-016-4505-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 04/12/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate whether dynamic contrast -enhanced MRI (DCE-MRI) can distinguish the type of liver nodules in a rat model with N-nitrosodiethylamine- induced cirrhosis. METHODS Liver nodules in cirrhosis were induced in 60 male Wistar rats via 0.01 % N-nitrosodiethylamine in the drinking water for 35-100 days. The nodules were divided into three groups: regenerative nodule (RN), dysplastic nodule (DN), and hepatocellular carcinoma (HCC). DCE-MRI was performed, and parameters including transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume fraction (Ve), and initial area under the contrast concentration versus time curve (iAUC) were measured and compared. RESULTS The highest Ktrans and iAUC values were seen in HCC, followed by DN and RN (all P < 0.05). The area under the receiver operating characteristic curve (AUROC) for DN and HCC were 0.738 and 0.728 for Ktrans and iAUC, respectively. The AUROC for HCC were 0.850 and 0.840 for Ktrans and iAUC, respectively. Ordinal logistic regression analysis showed that Ktrans had a high goodness of fit (0.970, 95 % confidence interval, 13.751-24.958). CONCLUSION DCE-MRI is a promising method to differentiate of liver nodules. Elevated Ktrans suggested that the nodules may be transformed into HCC. KEY POINTS • DCE-MRI is promising for differentiating among RN, DN, and HCC • K trans and iAUC positively correlated with malignancy degree of liver nodules • Elevated K trans suggests that the nodules may be transformed into HCC.
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Abstract
The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. The questions asked in the PhAT should be viewed as a continuum and not used in isolation. Different drug development programmes derive different types of benefit from these questions. The PhAT is critical in making go-no-go decisions in the development of currently studied drugs and will continue to be relevant to discovery and development of future generations of anticancer agents.
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Affiliation(s)
- Udai Banerji
- Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK
| | - Paul Workman
- Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
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Sirous R, Henegan JC, Zhang X, Howard CM, Souza F, Smith AD. Metastatic renal cell carcinoma imaging evaluation in the era of anti-angiogenic therapies. Abdom Radiol (NY) 2016; 41:1086-99. [PMID: 27193601 DOI: 10.1007/s00261-016-0742-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
During the last decade, the arsenal of anti-angiogenic (AAG) agents used to treat metastatic renal cell carcinoma (RCC) has grown and revolutionized the treatment of metastatic RCC, leading to improved overall survival compared to conventional chemotherapy and traditional immunotherapy agents. AAG agents include inhibitors of vascular endothelial growth factor receptor signaling pathways and mammalian target of rapamycin inhibitors. Both of these classes of targeted agents are considered cytostatic rather than cytotoxic, inducing tumor stabilization rather than marked tumor shrinkage. As a result, decreases in tumor size alone are often minimal and/or occur late in the course of successful AAG therapy, while tumor devascularization is a distinct feature of AAG therapy. In successful AAG therapy, tumor devascularization manifests on computed tomography images as a composite of a decrease in tumor size, a decrease in tumor attenuation, and the development of tumor necrosis. In this article, we review Response Evaluation Criteria in Solid Tumors (RECIST)-the current standard of care for tumor treatment response assessment which is based merely on changes in tumor length-and its assessment of metastatic RCC tumor response in the era of AAG therapies. We then review the features of an ideal tumor imaging biomarker for predicting metastatic RCC response to a particular AAG agent and serving as a longitudinal tumor response assessment tool. Finally, a discussion of the more recently proposed imaging response criteria and new imaging trends in metastatic RCC response assessment will be reviewed.
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Affiliation(s)
- Reza Sirous
- Department of Radiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - John C Henegan
- Department of Hematology/Oncology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Xu Zhang
- Center for Biostatistics and Bioinformatics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Candace M Howard
- Department of Radiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Frederico Souza
- Department of Radiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Andrew D Smith
- Department of Radiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.
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Kim YE, Joo B, Park MS, Shin SJ, Ahn JB, Kim MJ. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Surrogate Biomarker for Bevacizumab in Colorectal Cancer Liver Metastasis: A Single-Arm, Exploratory Trial. Cancer Res Treat 2016; 48:1210-1221. [PMID: 26987390 PMCID: PMC5080817 DOI: 10.4143/crt.2015.374] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 03/08/2016] [Indexed: 12/16/2022] Open
Abstract
Purpose The purpose of this study is to investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma cytokines and angiogenic factors (CAFs) as pharmacodynamic and prognostic biomarkers of bevacizumab monotherapy in colorectal cancer with liver metastasis (CRCLM). Materials and Methods From July 2011 to March 2012, 28 patients with histologically confirmed CRCLM received bevacizumab monotherapy followed by combined FOLFOX therapy. The mean age of the patients was 57 years (range, 30 to 77 years). DCE-MRI (Ktransand IAUC60) was performed at baseline, first follow-up (3 days after bevacizumab monotherapy), and second follow-up (3 days after combined therapy). CAF levels (vascular endothelial growth factor [VEGF], placental growth factor [PlGF], and interleukin-8) were assessed on the same days. Progression-free survival (PFS) time distributions were summarized using the Kaplan-Meier method and compared using log-rank tests. Results The median PFS period was 11.2 months. Ktrans, IAUC60, VEGF, and PlGF values on the first follow-up day were significantly different compared with baseline values. No differences were observed on the second follow-up day. A > 40% decrease in Ktrans from baseline to first follow-up was associated with a longer PFS (hazard ratio, 0.349; 95% confidence interval, 0.133 to 0.912; p=0.032). Changes in CAFs did not show correlation with PFS time. Conclusion DCE-MRI parameters and CAFs are pharmacodynamic biomarkers of bevacizumab for CRCLM. In our study, change in Ktrans at 3 days after bevacizumab monotherapy was a favorable prognostic factor; however, the value of CAFs as a prognostic biomarker was not found.
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Affiliation(s)
- Yeo-Eun Kim
- Department of Diagnostic Radiology, Seoul Medical Center, Seoul, Korea.,Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Bio Joo
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Suk Park
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Joon Shin
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Joong Bae Ahn
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Myeong-Jin Kim
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Atri M, Hudson JM, Sinaei M, Williams R, Milot L, Moshonov H, Burns PN, Bjarnason GA. Impact of Acquisition Method and Region of Interest Placement on Inter-observer Agreement and Measurement of Tumor Response to Targeted Therapy Using Dynamic Contrast-Enhanced Ultrasound. ULTRASOUND IN MEDICINE & BIOLOGY 2016; 42:763-768. [PMID: 26712416 DOI: 10.1016/j.ultrasmedbio.2015.11.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 09/06/2015] [Accepted: 11/07/2015] [Indexed: 06/05/2023]
Abstract
This study evaluated the impact of different acquisition methods, user-directed region of interest placement and post-processing steps on the quantification of dynamic contrast-enhanced ultrasound measurements of blood volume in 29 patients with renal cancer, pre- and post-treatment. Specifically, we compared tumor quantification using multiple planes versus a single plane, breathhold versus free breathing and large region of interest versus a region targeting the area of highest vascularity. Performance was evaluated using area under the receiver operating characteristic curves to identify the method that best predicts progression-free survival. The intra-class correlation coefficient was also used to investigate how the same parameters affect inter-observer agreement. Of the different methods used to quantify blood volume in this study, the combination that had the highest level of inter-observer agreement (intra-class correlation coefficient = 0.8-0.97) and was the best predictor of progression-free survival was the change in blood volume measured (area under receiver operating characteristic curve = 0.77, p = 0.04) by a multiplane average, acquired during quiet breathing, quantified using a region of interest that encompassed the entire tumor.
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Affiliation(s)
- Mostafa Atri
- Division of Abdominal Imaging, Department of Medical Imaging, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.
| | - John M Hudson
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Mehrdad Sinaei
- Division of Abdominal Imaging, Department of Medical Imaging, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
| | - Ross Williams
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Laurent Milot
- Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Hadas Moshonov
- Division of Abdominal Imaging, Department of Medical Imaging, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
| | - Peter N Burns
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Georg A Bjarnason
- Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
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Sung YS, Park B, Choi Y, Lim HS, Woo DC, Kim KW, Kim JK. Dynamic contrast-enhanced MRI for oncology drug development. J Magn Reson Imaging 2016; 44:251-64. [PMID: 26854494 DOI: 10.1002/jmri.25173] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 01/15/2016] [Indexed: 12/17/2022] Open
Abstract
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature-derived, functional, and quantitative parameters. To implement DCE-MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular-disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE-MRI parameters for evaluating treatment-driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE-MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE-MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics-oriented meaning of individual DCE-MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE-MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE-MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE-MRI. J. Magn. Reson. Imaging 2016;44:251-264.
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Affiliation(s)
- Yu Sub Sung
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Bumwoo Park
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoonseok Choi
- Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyeong-Seok Lim
- Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Dong-Cheol Woo
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyung Won Kim
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jeong Kon Kim
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Center for Bioimaging of New Drug Development, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Shen FU, Lu J, Chen L, Wang Z, Chen Y. Diagnostic value of dynamic contrast-enhanced magnetic resonance imaging in rectal cancer and its correlation with tumor differentiation. Mol Clin Oncol 2016; 4:500-506. [PMID: 27073650 DOI: 10.3892/mco.2016.762] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 01/22/2016] [Indexed: 12/12/2022] Open
Abstract
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a novel imaging modality that can be used to reflect the microcirculation, although its value in diagnosing rectal cancer is unknown. The present study aimed to explore the clinical application of DCE-MRI in the preoperative diagnosis of rectal cancer, and its correlation with tumor differentiation. To achieve this, 40 pathologically confirmed patients with rectal cancer and 15 controls were scanned using DCE-MRI. The Tofts model was applied to obtain the perfusion parameters, including the plasma to extravascular volume transfer (Ktrans), the extravascular to plasma volume transfer (Kep), the extravascular fluid volume (Ve) and the initial area under the enhancement curve (iAUC). Receiver-operating characteristic (ROC) curves were plotted to determine the diagnostic value. The results demonstrated that the time-signal intensity curve of the rectal cancer lesion exhibited an outflow pattern. The Ktrans, Kep, Ve, and iAUC values were higher in the cancer patients compared with controls (P<0.05). The intraclass correlation coefficients of Ktrans, Kep, Ve and iAUC, as measured by two independent radiologists, were 0.991, 0.988, 0.972 and 0.984, respectively (all P<0.001), indicating a good consistency. The areas under the ROC curves for Ktrans and iAUC were both >0.9, resulting in a sensitivity and specificity of 100% and 93.3% for Ktrans, and of 92.5%, and 93.3% or 100%, for iAUC, respectively. In the 40 rectal cancer cases, there was a moderate correlation between Ktrans and iAUC, and pathological differentiation (0.3<r<0.8, all P<0.05). In conclusion, Ktrans and iAUC were associated with the presence of rectal cancer and differentiation, and therefore may provide novel insights into the preoperative diagnosis of rectal cancer.
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Affiliation(s)
- F U Shen
- Department of Radiology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Jianping Lu
- Department of Radiology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Luguang Chen
- Department of Radiology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Zhen Wang
- Department of Radiology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Yukun Chen
- Department of Radiology, Changhai Hospital, Shanghai 200433, P.R. China
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