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Nai R, Wang K, Ma S, Xi Z, Zhang Y, Zhang X, Wang X. Using apparent diffusion coefficient maps and radiomics to predict pathological grade in upper urinary tract urothelial carcinoma. BMC Med Imaging 2024; 24:355. [PMID: 39736546 DOI: 10.1186/s12880-024-01540-w] [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] [Received: 10/07/2024] [Accepted: 12/18/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND The apparent diffusion coefficient (ADC) has been reported as a quantitative biomarker for assessing the aggressiveness of upper urinary tract urothelial carcinoma (UTUC), but it has typically been used only with mean ADC values. This study aims to develop a radiomics model using ADC maps to differentiate UTUC grades by incorporating texture features and to compare its performance with that of mean ADC values. METHODS A total of 215 patients with histopathologically confirmed UTUC were enrolled retrospectively and divided into training and test sets. The optimum cutoff value for the mean ADC was derived using the receiver operating characteristic (ROC) curve. Radiomics features based on ADC maps were extracted and screened, and then a radiomics model was constructed. Both mean ADC values and the radiomics model were tested on the training and test sets. ROC curve and DeLong test were used to assess the diagnostic performance. RESULTS The training set consisted of 151 patients (median age: 68.0, IQR: [63.0, 75.0] years; 80 males), whereas the test set consisted of 64 patients (median age: 68.0, IQR: [61.0, 72.3] years; 31 males). The ADC values were significantly lower in high-grade versus low-grade UTUC (1310 × 10- 6mm2/s vs. 1480 × 10- 6mm2/s, p < 0.001). The area under the curve (AUC) values of the mean ADC values in the training and test sets were 0.698 [95% confidence interval [CI]: 0.625-0.772] and 0.628 [95% CI: 0.474-0.782], respectively. Compared with the mean ADC values, the ADC-based radiomics model, which incorporates features such as log-sigma-1-0-mm-3D_glcm_ClusterProminence and wavelet-LLL_firstorder_10Percentile, obtained a significantly greater AUC in the training set (AUC: 1.000, 95% CI: 1.000-1.000, p < 0.001), and a trend towards statistical significance in the test set (AUC: 0.786, 95% CI: 0.651-0.921, p = 0.071). CONCLUSIONS The ADC-based radiomics model showed promising potential in predicting the pathological grade of UTUC, outperforming the mean ADC values in classification accuracy. Further studies with larger sample sizes and external validation are necessary to confirm its clinical utility and generalizability. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Rile Nai
- Department of Radiology, Peking University First Hospital, 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Kexin Wang
- School of Basic Medical Sciences, Capital Medical University, 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China
| | - Shuai Ma
- Department of Radiology, Peking University First Hospital, 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Zuqiang Xi
- Beijing Smart Tree Medical Technology Co., Ltd., 24, Huangsi Avenue, Xicheng District, Beijing, 100035, China
| | - Yaofeng Zhang
- Beijing Smart Tree Medical Technology Co., Ltd., 24, Huangsi Avenue, Xicheng District, Beijing, 100035, China
| | - Xiaodong Zhang
- Department of Radiology, Peking University First Hospital, 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Xiaoying Wang
- Department of Radiology, Peking University First Hospital, 8, Xishiku Street, Xicheng District, Beijing, 100034, China.
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Gerwing M, Krähling T, Schliemann C, Harrach S, Schwöppe C, Berdel AF, Klein S, Hartmann W, Wardelmann E, Heindel WL, Lenz G, Berdel WE, Wildgruber M. Multiparametric Magnetic Resonance Imaging for Immediate Target Hit Assessment of CD13-Targeted Tissue Factor tTF-NGR in Advanced Malignant Disease. Cancers (Basel) 2021; 13:cancers13235880. [PMID: 34884988 PMCID: PMC8657298 DOI: 10.3390/cancers13235880] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/17/2021] [Accepted: 11/21/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Since the knowledge of tumor biology has advanced, a variety of targeted therapies has been developed. These do not immediately affect the tumor size, so optimized oncological imaging is needed. In this phase I study of patients with advanced malignant disease, a multiparametric imaging approach was used to assess changes in tumor perfusion after vessel-occluding therapy with the CD13 targeted truncated tissue factor with a C-terminal NGR-peptide. It comprises different sequences and the use of two different contrast media, ferucarbotran and gadobutrol. This multiparametric MRI protocol enables assessing the therapy effectiveness as early as five hours after therapy initiation. Abstract Early assessment of target hit in anti-cancer therapies is a major task in oncologic imaging. In this study, immediate target hit and effectiveness of CD13-targeted tissue factor tTF-NGR in patients with advanced malignant disease enrolled in a phase I trial was assessed using a multiparametric MRI protocol. Seventeen patients with advanced solid malignancies were enrolled in the trial and received tTF-NGR for at least one cycle of five daily infusions. Tumor target lesions were imaged with multiparametric MRI before therapy initiation, five hours after the first infusion and after five days. The imaging protocol comprised ADC, calculated from DWI, and DCE imaging and vascular volume fraction (VVF) assessment. DCE and VVF values decreased within 5 h after therapy initiation, indicating early target hit with a subsequent decrease in tumor perfusion due to selective tumor vessel occlusion and thrombosis induced by tTF-NGR. Simultaneously, ADC values increased at five hours after tTF-NGR administration. In four patients, treatment had to be stopped due to an increase in troponin T hs, with subsequent anticoagulation. In these patients, a reversed effect, with DCE and VVF values increasing and ADC values decreasing, was observed after anticoagulation. Changes in imaging parameters were independent of the mean vessel density determined by immunohistochemistry. By using a multiparametric imaging approach, changes in tumor perfusion after initiation of a tumor vessel occluding therapy can be evaluated as early as five hours after therapy initiation, enabling early assessment of target hit.
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Affiliation(s)
- Mirjam Gerwing
- Clinic of Radiology, University Hospital Muenster, D-48149 Muenster, Germany; (T.K.); (W.L.H.); (M.W.)
- Correspondence:
| | - Tobias Krähling
- Clinic of Radiology, University Hospital Muenster, D-48149 Muenster, Germany; (T.K.); (W.L.H.); (M.W.)
| | - Christoph Schliemann
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Saliha Harrach
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Christian Schwöppe
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Andrew F. Berdel
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Sebastian Klein
- Gerhard-Domagk-Institute for Pathology, University of Muenster, D-48149 Muenster, Germany; (S.K.); (W.H.); (E.W.)
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute for Pathology, University of Muenster, D-48149 Muenster, Germany; (S.K.); (W.H.); (E.W.)
| | - Eva Wardelmann
- Gerhard-Domagk-Institute for Pathology, University of Muenster, D-48149 Muenster, Germany; (S.K.); (W.H.); (E.W.)
| | - Walter L. Heindel
- Clinic of Radiology, University Hospital Muenster, D-48149 Muenster, Germany; (T.K.); (W.L.H.); (M.W.)
| | - Georg Lenz
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Wolfgang E. Berdel
- Department of Medicine A, Hematology, Hemostaseology, Oncology and Pulmonology, University Hospital Muenster, D-48149 Muenster, Germany; (C.S.); (S.H.); (C.S.); (A.F.B.); (G.L.); (W.E.B.)
| | - Moritz Wildgruber
- Clinic of Radiology, University Hospital Muenster, D-48149 Muenster, Germany; (T.K.); (W.L.H.); (M.W.)
- Department of Radiology, University Hospital, LMU Munich, D-81377 Munich, Germany
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Doleschel D, Hoff S, Koletnik S, Rix A, Zopf D, Kiessling F, Lederle W. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:288. [PMID: 34517894 PMCID: PMC8436536 DOI: 10.1186/s13046-021-02043-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/14/2021] [Indexed: 01/10/2023]
Abstract
Background Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Methods Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. Results In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. Conclusions This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02043-0.
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Affiliation(s)
- Dennis Doleschel
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sabine Hoff
- Research and Development, Preclinical Research Oncology, Bayer AG, Berlin, Germany
| | - Susanne Koletnik
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Anne Rix
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Dieter Zopf
- Research and Development, Preclinical Research Oncology, Bayer AG, Berlin, Germany.
| | - Fabian Kiessling
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.,Fraunhofer Institute for Digital Medicine MEVIS, Bremen, Germany
| | - Wiltrud Lederle
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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Reichardt W, von Elverfeldt D. Preclinical Applications of Magnetic Resonance Imaging in Oncology. Recent Results Cancer Res 2020; 216:405-437. [PMID: 32594394 DOI: 10.1007/978-3-030-42618-7_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The evolving possibilities of molecular imaging (MI) are fundamentally changing the way we look at cancer, with imaging paradigms now shifting away from basic morphological measures toward the longitudinal assessment of functional, metabolic, cellular, and molecular information in vivo. Recent developments of imaging methodology and probe molecules utilizing the vast number of novel animal models of human cancers have enhanced our ability to non-invasively characterize neoplastic tissue and follow anticancer treatments. While preclinical molecular imaging offers a whole palette of excellent methodology to choose from, we will focus on magnetic resonance imaging (MRI) techniques, since they provide excellent molecular imaging capabilities and bear high potential for clinical translation. Prerequisites and consequences of using animal models as surrogates of human cancers in preclinical molecular imaging are outlined. We present physical principles, values, and limitations of MRI as molecular imaging modality and comment on its high potential to non-invasively assess information on metabolism, hypoxia, angiogenesis, and cell trafficking in preclinical cancer research.
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Affiliation(s)
- Wilfried Reichardt
- Medical Physics, Department of Radiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. .,German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. .,German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Dominik von Elverfeldt
- Medical Physics, Department of Radiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Wang Y, Song L, Guo J, Xian J. Value of quantitative multiparametric MRI in differentiating pleomorphic adenomas from malignant epithelial tumors in lacrimal gland. Neuroradiology 2020; 62:1141-1147. [PMID: 32430642 DOI: 10.1007/s00234-020-02455-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 05/05/2020] [Indexed: 02/02/2023]
Abstract
PURPOSE To evaluate the diagnostic performance of the quantitative parameters derived from diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI in differentiating lacrimal gland pleomorphic adenomas (LGPAs) from lacrimal gland malignant epithelial tumors (LGMETs). METHODS Seventy-seven cases with LG epithelial tumors confirmed by histopathology (47 LGPAs and 30 LGMETs) underwent DWI and DCE-MRI. The quantitative parameters including the apparent diffusion coefficient (ADC), the volume transfer constant (Ktrans), the efflux rate constant from the extravascular extracellular space (EES) to blood plasma (Kep), and the extravascular extracellular volume fraction (Ve) were used to differentiate LGPAs from LGMETs. Independent-samples t test was conducted to compare these parameters. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS Compared with LGPAs, LGMETs had significantly lower ADC value (1.090 ± 0.169mm2/s) (P < 0.001), higher Ktrans value (0.892 ± 0.517/min) (P = 0.001), and Kep value (1.300 ± 1.131/min) (P = 0.002). ADC as a diagnostic index showed a better diagnostic efficacy in predicting malignant tumors (AUC 0.914, sensitivity 90.0%, specificity 85.1%, and accuracy 87.0%) than Ktrans and Kep alone. The combination of ADC and Ktrans presented the optimal diagnostic performance for the differentiation (AUC 0.938, sensitivity 93.3%, specificity 87.2%, accuracy 89.6%). CONCLUSION The quantitative parameters including ADC, Ktrans, and Kep derived from DWI and DCE-MRI might be potential imaging biomarkers in differentiating LGPAs from LGMETs. The combination of ADC and Ktrans is superior to other quantitative parameters in distinguishing LGPAs from LGMETs.
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Affiliation(s)
- Yongzhe Wang
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, China.,Clinical Center for Eye Tumors, Capital Medical University, Beijing, China
| | - Liyuan Song
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, China.,Clinical Center for Eye Tumors, Capital Medical University, Beijing, China
| | - Jian Guo
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, China.,Clinical Center for Eye Tumors, Capital Medical University, Beijing, China
| | - Junfang Xian
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, China. .,Clinical Center for Eye Tumors, Capital Medical University, Beijing, China.
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Fiegle E, Doleschel D, Koletnik S, Rix A, Weiskirchen R, Borkham-Kamphorst E, Kiessling F, Lederle W. Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer. Neoplasia 2019; 21:932-944. [PMID: 31412307 PMCID: PMC6700499 DOI: 10.1016/j.neo.2019.07.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 07/17/2019] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint inhibitors have shown clinical benefit in several cancer entities including metastatic microsatellite instable colorectal carcinomas. However, for the majority of metastatic colorectal carcinomas the potential and limitations of immune checkpoint inhibition is not fully understood. In this study, the effects of sole and dual CTLA-4 and PD-L1 blockade were investigated in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer. Dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis. Sole CTLA-4 and PD-L1 inhibition only moderately reduced metastatic spread of the colon cancer cells, though CTLA-4 blockade being superior to PD-L1 inhibition. Dual immune checkpoint blockade and sole CTLA-4 inhibition significantly increased intratumoral CD8+ and CD4+ T cells and reduced FOXP3+/CD4+ Treg cells. This was associated with increased expression levels of the pro-inflammatory Th1/M1-related cytokines IFN-γ, IL-1α, IL-2, and IL-12. Moreover, tumors treated with combined immune checkpoint blockade showed the strongest increase in intratumoral iNOS+ macrophages, reduction of PD-L1+ and Tie2+ macrophages and the lowest expression of M2/Th2-related IL-4, TARC and COX-2. The assessment of further microenvironmental changes by DCE-MRI and immunohistology revealed no alterations in functional tumor vascularization upon combined immune checkpoint blockade, but a significant increase in intratumoral fibroblasts and collagen I deposition. Thus, the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. This was accompanied by pronounced fibroblast activation highlighting the interconnection between immunogenicity and desmoplasia.
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Affiliation(s)
- E Fiegle
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany
| | - D Doleschel
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany
| | - S Koletnik
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany
| | - A Rix
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany
| | - R Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany
| | - E Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany
| | - F Kiessling
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany
| | - W Lederle
- Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany.
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Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: a comparative study of pharmacokinetic models and correlation with mRECIST criteria. Cancer Imaging 2019; 19:10. [PMID: 30813957 PMCID: PMC6391827 DOI: 10.1186/s40644-019-0189-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 01/16/2019] [Indexed: 12/29/2022] Open
Abstract
Background Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic malignancy that is difficult to cure. Dynamic contrast-enhanced (DCE) MRI is a functional imaging technique used to analyze tumor microvascular properties and to monitor therapy response. Purpose of this study was to compare two tracer kinetic models, the extended Tofts (ET) and the adiabatic approximation tissue homogeneity model (AATH) for analysis of DCE-MRI and examine the value of the DCE parameters to predict response to chemotherapy in patients with MPM. Method This prospective, longitudinal, single tertiary radiology center study was conducted between October 2013 and July 2015. Patient underwent DCE-MRI studies at three time points: prior to therapy, during and after cisplatin-based chemotherapy. The images were analyzed using ET and AATH models. In short-term follow-up, the patients were classified as having disease control or progressive disease according to modified response evaluation criteria in solid tumors (mRECIST) criteria. Receiver operating characteristic curve analysis was used to examine specificity and sensitivity of DCE parameters for predicting response to therapy. Comparison tests were used to analyze whether derived parameters are interchangeable between the two models. Results Nineteen patients form the study population. The results indicate that the derived parameters are not interchangeable between the models. Significant correlation with response to therapy was found for AATH-calculated median pre-treatment efflux rate (kep) showing sensitivity of 83% and specificity of 100% (AUC 0.9). ET-calculated maximal pre-treatment kep showed 100% sensitivity and specificity for predicting treatment response during the early phase of the therapy and reached a favorable trend to significant prognostic value post-therapy. Conclusion Both models show potential in predicting response to therapy in MPM. High pre-treatment kep values suggest MPM disease control post-chemotherapy. Electronic supplementary material The online version of this article (10.1186/s40644-019-0189-5) contains supplementary material, which is available to authorized users.
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Deng Z, Li X, Xue Z, Jiang M, Li Y, Zeng S, Liu H. A high performance Sc-based nanoprobe for through-skull fluorescence imaging of brain vessels beyond 1500 nm. NANOSCALE 2018; 10:9393-9400. [PMID: 29741177 DOI: 10.1039/c8nr00305j] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Optical bioimaging that works in the second near infrared region (NIR-II, 1000-1700 nm) has emerged as a next generation imaging technique with superior imaging sensitivity and spatial resolution compared to traditional optical imaging utilizing visible and near-infrared lights (below 900 nm). Herein, a new Sc-based NIR-II probe was explored for high performance NIR-II in vivo bioimaging and optical imaging-guided non-invasive brain blood vessel visualization. The lanthanide doped Sc-based probes (KSc2F7:Yb3+/Er3+) possess a pure orthorhombic phase structure with size control by adjusting the F- ion content. These probes present a dominant red upconversion (UC) emission, which is significantly different from the traditional NaYF4:Yb/Er host, which usually has a green UC emission. More importantly, apart from the dominant red UC emission, these probes also possess a strong NIR-II downconversion (DC) emission centered at 1525 nm, which is usually ignored for bioimaging applications. In vivo NIR-II imaging reveals that our explored Sc-based nanorods are promising probes for highly sensitive optical imaging. Moreover, non-invasive through-skull fluorescence bioimaging of brain vessels with high spatial resolution was demonstrated. Therefore, it is expected that Sc-based nanomaterials with unique dominant red UC and DC NIR-II emissions beyond 1500 nm are ideal probes for bio-applications.
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Affiliation(s)
- Zhiming Deng
- School of Physics and Electronics, and Key Laboratory of Low-dimensional Quantum Structures and Quantum Control of the Ministry of Education, and Synergetic Innovation Center for Quantum Effects and Applications, Hunan Normal University, Changsha 410081, Hunan, China.
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Teodori L, Crupi A, Costa A, Diaspro A, Melzer S, Tarnok A. Three-dimensional imaging technologies: a priority for the advancement of tissue engineering and a challenge for the imaging community. JOURNAL OF BIOPHOTONICS 2017; 10:24-45. [PMID: 27110674 DOI: 10.1002/jbio.201600049] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/04/2016] [Accepted: 04/05/2016] [Indexed: 06/05/2023]
Abstract
Tissue engineering/regenerative medicine (TERM) is an interdisciplinary field that applies the principle of engineering and life sciences to restore/replace damaged tissues/organs with in vitro artificially-created ones. Research on TERM quickly moves forward. Today newest technologies and discoveries, such as 3D-/bio-printing, allow in vitro fabrication of ex-novo made tissues/organs, opening the door to wide and probably never-ending application possibilities, from organ transplant to drug discovery, high content screening and replacement of laboratory animals. Imaging techniques are fundamental tools for the characterization of tissue engineering (TE) products at any stage, from biomaterial/scaffold to construct/organ analysis. Indeed, tissue engineers need versatile imaging methods capable of monitoring not only morphological but also functional and molecular features, allowing three-dimensional (3D) and time-lapse in vivo analysis, in a non-destructive, quantitative, multidimensional analysis of TE constructs, to analyze their pre-implantation quality assessment and their fate after implantation. This review focuses on the newest developments in imaging technologies and applications in the context of requirements of the different steps of the TERM field, describing strengths and weaknesses of the current imaging approaches.
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Affiliation(s)
- Laura Teodori
- Diagnostics and Metrology Laboratory FSN-TECFIS-DIM ENEA CR Frascati, Via Enrico Fermi 44, 00044, Rome, Italy
| | - Annunziata Crupi
- Diagnostics and Metrology Laboratory FSN-TECFIS-DIM ENEA CR Frascati, Via Enrico Fermi 44, 00044, Rome, Italy
- Fondazione San Raffaele, S.S. Ceglie San Michele km 1200, 72013, Ceglie Messapica, Italy
| | - Alessandra Costa
- University of Pittsburgh McGowan Institute, 3550 Terrace St 5606, Pittsburgh, PA 15261, USA
| | - Alberto Diaspro
- Department of Nanophysics, Istituto Italiano di Tecnologia, Genova, Italy
- Dipartimento di Fisica, Università degli Studi di Genova, Genova, Italy
- Nikon Imaging Center, Genova, Italy, www.nic.iit.it
| | - Susanne Melzer
- Sächsische Inkubator für klinische Translation (SIKT), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103, Leipzig, Germany
- Department of Pediatric Cardiology, HELIOS Heart Center Leipzig, University of Leipzig, Strümpellstraße 39, 04289, Leipzig, Germany
| | - Attila Tarnok
- Sächsische Inkubator für klinische Translation (SIKT), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103, Leipzig, Germany
- Department of Pediatric Cardiology, HELIOS Heart Center Leipzig, University of Leipzig, Strümpellstraße 39, 04289, Leipzig, Germany
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Cidon EU, Alonso P, Masters B. Markers of Response to Antiangiogenic Therapies in Colorectal Cancer: Where Are We Now and What Should Be Next? Clin Med Insights Oncol 2016; 10:41-55. [PMID: 27147901 PMCID: PMC4849423 DOI: 10.4137/cmo.s34542] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/15/2016] [Accepted: 03/13/2016] [Indexed: 12/17/2022] Open
Abstract
Despite advances in the treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the Western world. Angiogenesis is a complex process that involves the formation of new blood vessels from preexisting vessels. It is essential for promoting cancer survival, growth, and dissemination. The inhibition of angiogenesis has been shown to prevent tumor progression experimentally, and several chemotherapeutic targets of tumor angiogenesis have been identified. These include anti-vascular endothelial growth factor (VEGF) treatments, such as bevacizumab (a VEGF-specific binding antibody) and anti-VEGF receptor tyrosine kinase inhibitors, although antiangiogenic therapy has been shown to be effective in the treatment of several cancers, including CRC. However, it is also associated with its own side effects and financial costs. Therefore, the identification of biomarkers that are able to identify patients who are more likely to benefit from antiangiogenic treatment is very important. This article intends to be a concise summary of the potential biomarkers that can predict or prognosticate the benefit of antiangiogenic treatments in CRC, and also what we can expect in the near future.
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Affiliation(s)
- E. Una Cidon
- Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK
| | - P. Alonso
- Department of Clinical Oncology, Clinical University Hospital, Valladolid, Spain
| | - B. Masters
- Department of Oncology, Nottingham City Hospital, Nottingham, UK
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11
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Consolino L, Longo DL, Dastrù W, Cutrin JC, Dettori D, Lanzardo S, Oliviero S, Cavallo F, Aime S. Functional imaging of the angiogenic switch in a transgenic mouse model of human breast cancer by dynamic contrast enhanced magnetic resonance imaging. Int J Cancer 2016; 139:404-13. [PMID: 26941084 DOI: 10.1002/ijc.30073] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 02/24/2016] [Indexed: 01/16/2023]
Abstract
Tumour progression depends on several sequential events that include the microenvironment remodelling processes and the switch to the angiogenic phenotype, leading to new blood vessels recruitment. Non-invasive imaging techniques allow the monitoring of functional alterations in tumour vascularity and cellularity. The aim of this work was to detect functional changes in vascularisation and cellularity through Dynamic Contrast Enhanced (DCE) and Diffusion Weighted (DW) Magnetic Resonance Imaging (MRI) modalities during breast cancer initiation and progression of a transgenic mouse model (BALB-neuT mice). Histological examination showed that BALB-neuT mammary glands undergo a slow neoplastic progression from simple hyperplasia to invasive carcinoma, still preserving normal parts of mammary glands. DCE-MRI results highlighted marked functional changes in terms of vessel permeability (K(trans) , volume transfer constant) and vascularisation (vp , vascular volume fraction) in BALB-neuT hyperplastic mammary glands if compared to BALB/c ones. When breast tissue progressed from simple to atypical hyperplasia, a strong increase in DCE-MRI biomarkers was observed in BALB-neuT in comparison to BALB/c mice (K(trans) = 5.3 ± 0.7E-4 and 3.1 ± 0.5E-4; vp = 7.4 ± 0.8E-2 and 4.7 ± 0.6E-2 for BALB-neuT and BALB/c, respectively) that remained constant during the successive steps of the neoplastic transformation. Consistent with DCE-MRI observations, microvessel counting revealed a significant increase in tumour vessels. Our study showed that DCE-MRI estimates can accurately detect the angiogenic switch at early step of breast cancer carcinogenesis. These results support the view that this imaging approach is an excellent tool to characterize microvasculature changes, despite only small portions of the mammary glands developed neoplastic lesions in a transgenic mouse model.
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Affiliation(s)
- Lorena Consolino
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy
| | - Dario Livio Longo
- (CNR) c/o Molecular Biotechnologies Center, Istituto di Biostrutture e Bioimmagini, via Nizza 52, Torino, 10126, Italy.,Molecular Imaging Center, University of Torino, via Nizza 52, Torino, 10126, Italy
| | - Walter Dastrù
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy.,Molecular Imaging Center, University of Torino, via Nizza 52, Torino, 10126, Italy
| | - Juan Carlos Cutrin
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy
| | - Daniela Dettori
- Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy
| | - Stefania Lanzardo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy
| | | | - Federica Cavallo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy
| | - Silvio Aime
- Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, 10126, Italy.,Molecular Imaging Center, University of Torino, via Nizza 52, Torino, 10126, Italy
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12
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Characterization of orbital masses by multiparametric MRI. Eur J Radiol 2015; 85:324-36. [PMID: 26781137 DOI: 10.1016/j.ejrad.2015.11.041] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 11/25/2015] [Accepted: 11/30/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVES DWI and dynamic contrast enhanced (DCE) MR imaging are techniques that allow insight to tumor vascularity and cellularity. We evaluated the diagnostic performance of multiparametric MRI (mp-MRI) in distinguishing benign from malignant orbital masses using standard anatomic imaging (sAI), DWI and DCE. MATERIALS AND METHODS This prospective IRB approved study with written informed consent included 65 patients. mp-MRI at 3 Tesla including DWI and DCE was performed in all patients. Parametric maps were generated for obtaining the perfusion parameters including K(trans), kep, ve and iAUC and time-signal intensity curves were recorded to determine the curve pattern. Two radiologists rated the likelihood of malignancy on a five-point scale in three separate, randomized reading sessions (initially only sAI, afterwards sAI+either DWI or DCE and finally sAI+DWI+DCE). Data was statistically analyzed. RESULTS 33 Patients had malignant orbital masses and 32 patients had benign orbital masses (reference standard histopathology in 35 cases and clinical follow-up in 30 patients). The mean ADC of malignant masses differed significantly from the mean (SD) ADC of benign masses (0.825 [0.437]×10(-3)mm(2)/s and 1.257 [0.576]×10(-3)mm(2)/s, respectively) (p=0.001). K(trans), kep and iAUC were significantly higher in malignant masses (p<0.01). The reading of sAI only resulted in a moderate specificity but poor sensitivity in differentiating benign from malignant lesions. Adding DWI and DCE images improved specificity and sensitivity considerably, being the highest for the combined reading of all sequences. CONCLUSION mp-MRI is a helpful tool in differentiating malignant orbital lesions from benign masses and should therefore be included in the routine diagnostic protocol for orbital imaging.
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Longo DL, Arena F, Consolino L, Minazzi P, Geninatti-Crich S, Giovenzana GB, Aime S. Gd-AAZTA-MADEC, an improved blood pool agent for DCE-MRI studies on mice on 1 T scanners. Biomaterials 2015; 75:47-57. [PMID: 26480471 DOI: 10.1016/j.biomaterials.2015.10.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 09/30/2015] [Accepted: 10/05/2015] [Indexed: 10/22/2022]
Abstract
A novel MRI blood-pool contrast agent (Gd-AAZTA-MADEC) has been compared with established blood pool agents for tumor contrast enhanced images and angiography. Synthesis, relaxometric properties, albumin binding affinity and pharmacokinetic profiles are reported. For in vivo studies, angiographic images and tumor contrast enhanced images were acquired on mice with benchtop 1T-MRI scanners and compared with MS-325, B22956/1 and B25716/1. The design of this contrast agent involved the elongation of the spacer between the targeting deoxycholic acid moiety and the Gd-AAZTA imaging reporting unit that drastically changed either the binding affinity to albumin (KA(HSA) = 8.3 × 10(5) M(-1)) and the hydration state of the Gd ion (q = 2) in comparison to the recently reported B25716/1. The very markedly high binding affinity towards mouse and human serum albumins resulted in peculiar pharmacokinetics and relaxometric properties. The NMRD profiles clearly indicated that maximum efficiency is attainable at magnetic field strength of 1 T. In vivo studies showed high enhancement of the vasculature and a prolonged accumulation inside tumor. The herein reported pre-clinical imaging studies show that a great benefit arises from the combination of a benchtop MRI scanner operating at 1 T and the albumin-binding Gd-AAZTA-MADEC complex, for pursuing enhanced angiography and improved characterization of tumor vascular microenvironment.
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Affiliation(s)
- Dario Livio Longo
- Istituto di Biostrutture e Bioimmagini (CNR) c/o Molecular Biotechnology Center, Via Nizza 52, 10126, Torino, Italy; Molecular Imaging Center, University of Torino, Via Nizza 52, 10126, Torino, Italy.
| | - Francesca Arena
- Molecular Imaging Center, University of Torino, Via Nizza 52, 10126, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Lorena Consolino
- Molecular Imaging Center, University of Torino, Via Nizza 52, 10126, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy; CAGE Chemicals Srl, Via Bovio 6, 28100, Novara, Italy
| | - Paolo Minazzi
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale "A. Avogadro" Largo Donegani 2/3, 28100, Novara, Italy; CAGE Chemicals Srl, Via Bovio 6, 28100, Novara, Italy
| | - Simonetta Geninatti-Crich
- Molecular Imaging Center, University of Torino, Via Nizza 52, 10126, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Giovanni Battista Giovenzana
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale "A. Avogadro" Largo Donegani 2/3, 28100, Novara, Italy; CAGE Chemicals Srl, Via Bovio 6, 28100, Novara, Italy
| | - Silvio Aime
- Istituto di Biostrutture e Bioimmagini (CNR) c/o Molecular Biotechnology Center, Via Nizza 52, 10126, Torino, Italy; Molecular Imaging Center, University of Torino, Via Nizza 52, 10126, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
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Laufer S, Mazuz A, Nachmansson N, Fellig Y, Corn BW, Bokstein F, Bashat DB, Abramovitch R. Monitoring brain tumor vascular heamodynamic following anti-angiogenic therapy with advanced magnetic resonance imaging in mice. PLoS One 2014; 9:e115093. [PMID: 25506833 PMCID: PMC4266643 DOI: 10.1371/journal.pone.0115093] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 11/18/2014] [Indexed: 11/18/2022] Open
Abstract
Advanced MR imaging methods have an essential role in classification, grading, follow-up and therapeutic management in patients with brain tumors. With the introduction of new therapeutic options, the challenge for better tissue characterization and diagnosis increase, calling for new reliable non-invasive imaging methods. In the current study we evaluated the added value of a combined protocol of blood oxygen level dependent (BOLD) imaging during hyperoxic challenge (termed hemodynamic response imaging (HRI)) in an orthotopic mouse model for glioblastoma under anti-angiogenic treatment with B20-4.1.1, an anti-VEGF antibody. In glioblastoma tumors, the elevated HRI indicated progressive angiogenesis as further confirmed by histology. In the current glioblastoma model, B20-treatment caused delayed tumor progression with no significant changes in HRI yet with slightly reduced tumor vascularity as indicated by histology. Furthermore, fewer apoptotic cells and higher proliferation index were detected in the B20-treated tumors compared to control-treated tumors. In conclusion, HRI provides an easy, safe and contrast agent free method for the assessment of the brain hemodynamic function, an additionally important clinical information.
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Affiliation(s)
- Shlomi Laufer
- The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ahinoam Mazuz
- The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Nathalie Nachmansson
- The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Yakov Fellig
- Pathology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - Felix Bokstein
- Neuro-Oncology Service. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Dafna Ben Bashat
- The Functional Brain Center, The Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Rinat Abramovitch
- The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- * E-mail:
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Kording F, Weidensteiner C, Zwick S, Osterberg N, Weyerbrock A, Staszewski O, von Elverfeldt D, Reichardt W. Simultaneous assessment of vessel size index, relative blood volume, and vessel permeability in a mouse brain tumor model using a combined spin echo gradient echo echo-planar imaging sequence and viable tumor analysis. J Magn Reson Imaging 2014; 40:1310-8. [PMID: 24390982 DOI: 10.1002/jmri.24513] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 10/02/2013] [Indexed: 01/18/2023] Open
Abstract
PURPOSE Combining multiple imaging biomarkers in one magnetic resonance imaging (MRI) session would be beneficial to gain more data pertaining to tumor vasculature under therapy. Therefore, simultaneous measurement of perfusion, permeability, and vessel size imaging (VSI) using a gradient echo spin echo (GE-SE) sequence with injection of a clinically approved gadolinium (Gd)-based contrast agent was assessed in an orthotopic glioma model. MATERIALS AND METHODS A combined spin echo gradient echo echo-planar imaging sequence was implemented using a single contrast agent Gd diethylenetriaminepentaacetic acid (Gd-DTPA). This sequence was tested in a mouse brain tumor model (U87_MG), also under treatment with an antiangiogenic agent (bevacizumab). T2 maps and the apparent diffusion coefficient (ADC) were used to differentiate regions of cell death and viable tumor tissue. RESULTS In viable tumor tissue regional blood volume was 5.7 ± 0.6% in controls and 5.2 ± 0.3% in treated mice. Vessel size was 18.1 ± 2.4 μm in controls and 12.8 ± 2.0 μm in treated mice, which correlated with results from immunohistochemistry. Permeability (K(trans) ) was close to zero in treated viable tumor tissue and 0.062 ± 0.024 min(-1) in controls. CONCLUSION Our MRI method allows simultaneous assessment of several physiological and morphological parameters and extraction of MRI biomarkers for vasculature. These could be used for treatment monitoring of novel therapeutic agents such as antiangiogenic drugs.
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Affiliation(s)
- Fabian Kording
- Department of Radiology Medical Physics, University Medical Center, Freiburg, Germany
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16
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Lollert A, Junginger T, Schimanski CC, Biesterfeld S, Gockel I, Düber C, Oberholzer K. Rectal cancer: dynamic contrast-enhanced MRI correlates with lymph node status and epidermal growth factor receptor expression. J Magn Reson Imaging 2013; 39:1436-42. [PMID: 24127411 DOI: 10.1002/jmri.24301] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 05/31/2013] [Indexed: 12/16/2022] Open
Abstract
PURPOSE To evaluate correlations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinicopathologic data as well as immunostaining of the markers of angiogenesis epidermal growth factor receptor (EGFR) and CXC-motif chemokine receptor 4 (CXCR4) in patients with rectal cancer. MATERIALS AND METHODS Presurgical DCE-MRI was performed in 41 patients according to a standardized protocol. Two quantitative parameters (k21 , A) were derived from a pharmacokinetic two-compartment model, and one semiquantitative parameter (TTP) was assessed. Standardized surgery and histopathologic examinations were performed in all patients. Immunostaining for EGFR and CXCR4 was performed and evaluated with a standardized scoring system. RESULTS DCE-MRI parameter A correlated significantly with the N category (P = 0.048) and k21 with the occurrence of synchronous and metachronous distant metastases (P = 0.029). A trend was shown toward a correlation between k21 and EGFR expression (P = 0.107). A significant correlation was found between DCE-MRI parameter TTP and the expression of EGFR (P = 0.044). DCE-MRI data did not correlate with CXCR4 expression. CONCLUSION DCE-MRI is a noninvasive method which can characterize microcirculation in rectal cancer and correlates with EGFR expression. Given the relationship between the dynamic parameters and the clinicopathologic data, DCE-MRI data may constitute a prognostic indicator for lymph node and distant metastases in patients with rectal cancer.
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Affiliation(s)
- André Lollert
- Department of Radiology, University of Mainz, Germany
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Sourbron SP, Buckley DL. Classic models for dynamic contrast-enhanced MRI. NMR IN BIOMEDICINE 2013; 26:1004-1027. [PMID: 23674304 DOI: 10.1002/nbm.2940] [Citation(s) in RCA: 290] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Revised: 02/12/2013] [Accepted: 02/12/2013] [Indexed: 06/02/2023]
Abstract
Dynamic contrast-enhanced MRI (DCE-MRI) is a functional MRI method where T1 -weighted MR images are acquired dynamically after bolus injection of a contrast agent. The data can be interpreted in terms of physiological tissue characteristics by applying the principles of tracer-kinetic modelling. In the brain, DCE-MRI enables measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), blood-brain barrier (BBB) permeability-surface area product (PS) and the volume of the interstitium (ve ). These parameters can be combined to form others such as the volume-transfer constant K(trans) , the extraction fraction E and the contrast-agent mean transit times through the intra- and extravascular spaces. A first generation of tracer-kinetic models for DCE-MRI was developed in the early 1990s and has become a standard in many applications. Subsequent improvements in DCE-MRI data quality have driven the development of a second generation of more complex models. They are increasingly used, but it is not always clear how they relate to the models of the first generation or to the model-free deconvolution methods for tissues with intact BBB. This lack of understanding is leading to increasing confusion on when to use which model and how to interpret the parameters. The purpose of this review is to clarify the relation between models of the first and second generations and between model-based and model-free methods. All quantities are defined using a generic terminology to ensure the widest possible scope and to reveal the link between applications in the brain and in other organs.
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18
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Abou-Elkacem L, Arns S, Brix G, Gremse F, Zopf D, Kiessling F, Lederle W. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther 2013; 12:1322-31. [PMID: 23619301 DOI: 10.1158/1535-7163.mct-12-1162] [Citation(s) in RCA: 203] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The combination of target-specific drugs like bevacizumab with chemotherapeutics has improved treatment efficacy in advanced colorectal cancer (CRC). However, the clinical prognosis of metastatic CRCs is still poor, and novel drugs are currently assessed with respect to their efficacies in patients with CRCs. In a phase III study, the multikinase inhibitor regorafenib (BAY 73-4506) has recently been shown to prolong survival of patients with CRCs after standard therapies failed. In the present study, the activity of regorafenib was investigated in comparison with the angiogenesis inhibitor DC101 in the highly aggressive, murine CT26 metastatic colon cancer model. While a treatment for 10 days with DC101 given at a dose of 34 mg/kg every third day significantly delayed tumor growth compared with vehicle-treated animals, regorafenib completely suppressed tumor growth at a daily oral dose of 30 mg/kg. Regorafenib also induced a stronger reduction in tumor vascularization, as longitudinally assessed in vivo by dynamic contrast-enhanced MRI (DCE-MRI) and confirmed by immunohistochemistry. In addition, regorafenib inhibited the angiogenic activity more strongly and induced a three times higher apoptosis rate than DC101. Even more important, regorafenib completely prevented the formation of liver metastases, whereas in DC101-treated animals, the metastatic rate was only reduced by 33% compared with the vehicle group. In addition, regorafenib significantly reduced the amount of infiltrating macrophages. These data show that the multikinase inhibitor regorafenib exerts strong antiangiogenic, antitumorigenic, and even antimetastatic effects on highly aggressive colon carcinomas indicative for its high potential in the treatment of advanced CRCs.
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Affiliation(s)
- Lotfi Abou-Elkacem
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, D-52074 Aachen, Germany
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Peungjesada S, Chuang HH, Prasad SR, Choi H, Loyer EM, Bronstein Y. Evaluation of cancer treatment in the abdomen: Trends and advances. World J Radiol 2013; 5:126-42. [PMID: 23671749 PMCID: PMC3650203 DOI: 10.4329/wjr.v5.i3.126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Revised: 01/24/2013] [Accepted: 01/31/2013] [Indexed: 02/06/2023] Open
Abstract
Response evaluation in Oncology has relied primarily on change in tumor size. Inconsistent results in the prediction of clinical outcome when size based criteria are used and the increasing role of targeted and loco-regional therapies have led to the development of new methods of response evaluation that are unrelated to change in tumor size. The goals of this review are to expose briefly the size based criteria and to present the non-size based approaches that are currently applicable in the clinical setting. Other paths that are still being explored are not discussed in details.
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Nathan P, Vinayan A. Imaging techniques as predictive and prognostic biomarkers in renal cell carcinoma. Ther Adv Med Oncol 2013; 5:119-31. [PMID: 23450112 PMCID: PMC3556873 DOI: 10.1177/1758834012463624] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
A number of imaging modalities are showing promise as predictive and prognostic biomarkers in advanced renal cell carcinoma. This review discusses progress to date in this exciting area and identifies areas of future promise.
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Affiliation(s)
- Paul Nathan
- Mount Vernon Cancer Centre - Medical Oncology, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK
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Liu Y, Cao L, Hillengass J, Delorme S, Schlewitz G, Govindarajan P, Schnettler R, Heiß C, Bäuerle T. Quantitative assessment of microcirculation and diffusion in the bone marrow of osteoporotic rats using VCT, DCE-MRI, DW-MRI, and histology. Acta Radiol 2013; 54:205-13. [PMID: 23319721 DOI: 10.1258/ar.2012.120508] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Etiologic and pathophysiologic role of functional bone marrow processes is not fully understood especially in the case of osteoporosis. PURPOSE To investigate the role of vascularization and diffusion in rat models of osteoporosis through a cross-correlation between non-invasive in-vivo imaging and invasive ex-vivo imaging of bone, bone marrow, and in particular of microcirculation. MATERIAL AND METHODS Osteoporosis was induced in rats by combining ovariectomy (OVX) with calcium and Vitamin D3 deficiency, or with glucocorticoid (dexamethasone). For comparison, controls underwent a sham surgery. In in-vivo investigations, animals (n = 36) were examined by volumetric CT (VCT) and MRI at 1, 3, or 12 months post surgery. Using VCT, bone morphology was monitored and relative bone density r within pelvis was extracted. With DCE-MRI and DW-MRI, parameters A (amplitude), Kep (exchange rate constant), and ADC (apparent diffusion coefficient) were acquired for regions of lumbar vertebrae, pelvis, and femur. In ex-vivo investigations, selective histological sections of pelvis were either stained with hematoxylin and eosin (HE stain) for quantifying vessel size and density or immunostained for collagen IV and α-smooth muscle actin to assess vessel maturity (SMA/collagen IV ratio). RESULTS After 12 months, decrease in DCE-MRI parameter Kep was found in all locations of osteoporotic rats (strongest in femur and lumbar vertebrae) while no significant differences were seen for parameter A and DW-MRI parameter ADC. Furthermore, vessel rarefication and maturation were observed on the histological level in animals with osteoporotic phenotype. In particular in the pelvis, the osteoporotic individuals (irrespective of the osteoporosis inducers applied) exhibited decreased Kep, significantly reduced vessel density, significantly increased vessel maturity, as well as statistically unaltered A, ADC, and vessel diameter. CONCLUSION Changes in microcirculation but not diffusion in the bone marrow of osteoporotic rats are detected by DCE-MRI and DW-MRI due to vessel rarefication and maturation.
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Affiliation(s)
- Yifei Liu
- Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg
| | - Liji Cao
- Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg
| | - Jens Hillengass
- Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg
- Department of Radiology, German Cancer Research Center, Heidelberg
| | - Stefan Delorme
- Department of Radiology, German Cancer Research Center, Heidelberg
| | - Gudrun Schlewitz
- Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen
- Laboratory of Experimental Trauma Surgery, Justus-Liebig-University, Giessen, Germany
| | | | - Reinhard Schnettler
- Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen
- Laboratory of Experimental Trauma Surgery, Justus-Liebig-University, Giessen, Germany
| | - Christian Heiß
- Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen
- Laboratory of Experimental Trauma Surgery, Justus-Liebig-University, Giessen, Germany
| | - Tobias Bäuerle
- Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg
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Ehling J, Lammers T, Kiessling F. Non-invasive imaging for studying anti-angiogenic therapy effects. Thromb Haemost 2013; 109:375-90. [PMID: 23407722 DOI: 10.1160/th12-10-0721] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 12/28/2012] [Indexed: 12/14/2022]
Abstract
Noninvasive imaging plays an emerging role in preclinical and clinical cancer research and has high potential to improve clinical translation of new drugs. This article summarises and discusses tools and methods to image tumour angiogenesis and monitor anti-angiogenic therapy effects. In this context, micro-computed tomography (µCT) is recommended to visualise and quantify the micro-architecture of functional tumour vessels. Contrast-enhanced ultrasound (US) and magnetic resonance imaging (MRI) are favourable tools to assess functional vascular parameters, such as perfusion and relative blood volume. These functional parameters have been shown to indicate anti-angiogenic therapy response at an early stage, before changes in tumour size appear. For tumour characterisation, the imaging of the molecular characteristics of tumour blood vessels, such as receptor expression, might have an even higher diagnostic potential and has been shown to be highly suitable for therapy monitoring as well. In this context, US using targeted microbubbles is currently evaluated in clinical trials as an important tool for the molecular characterisation of the angiogenic endothelium. Other modalities, being preferably used for molecular imaging of vessels and their surrounding stroma, are photoacoustic imaging (PAI), near-infrared fluorescence optical imaging (OI), MRI, positron emission tomography (PET) and single photon emission computed tomography (SPECT). The latter two are particularly useful if very high sensitivity is needed, and/or if the molecular target is difficult to access. Carefully considering the pros and cons of different imaging modalities in a multimodal imaging setup enables a comprehensive longitudinal assessment of the (micro)morphology, function and molecular regulation of tumour vessels.
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Affiliation(s)
- Josef Ehling
- Department of Experimental Molecular Imaging, Medical Faculty and Helmholtz Institute for Biomedical Engineering, Pauwelsstraße 30, 52074 Aachen, Germany
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Abstract
Molecular imaging fundamentally changes the way we look at cancer. Imaging paradigms are now shifting away from classical morphological measures towards the assessment of functional, metabolic, cellular, and molecular information in vivo. Interdisciplinary driven developments of imaging methodology and probe molecules utilizing animal models of human cancers have enhanced our ability to non-invasively characterize neoplastic tissue and follow anti-cancer treatments. Preclinical molecular imaging offers a whole palette of excellent methodology to choose from. We will focus on positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques, since they provide excellent and complementary molecular imaging capabilities and bear high potential for clinical translation. Prerequisites and consequences of using animal models as surrogates of human cancers in preclinical molecular imaging are outlined. We present physical principles, values and limitations of PET and MRI as molecular imaging modalities and comment on their high potential to non-invasively assess information on hypoxia, angiogenesis, apoptosis, gene expression, metabolism, and cell trafficking in preclinical cancer research.
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Affiliation(s)
- Gunter Wolf
- University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
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Brix G, Griebel J, Delorme S. [Dynamic contrast-enhanced computed tomography. Tracer kinetics and radiation hygienic principles]. Radiologe 2012; 52:277-94; quiz 295-6. [PMID: 22476707 DOI: 10.1007/s00117-011-2277-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Technical innovations in multislice computed tomography (CT) allow for larger volume coverage in ever shorter scan times. This progress has stimulated the clinical application of dynamic contrast-enhanced (DCE) CT techniques, which offer the possibility to noninvasively characterize tissue microcirculation in terms of well-defined physiological quantities. This educational review imparts to radiologists the essential physiological terms and definitions as well as the basic tracer kinetic concepts required for the analysis of DCE-CT data. In particular, four different approaches are presented and exemplified by the analysis of representative DCE data: the steepest-gradient method, model-free algebraic deconvolution in combination with the indicator-dilution theory, two-compartment modelling and the so-called adiabatic approximation to the homogeneity model. Even though DCE-CT offers substantial methodological and practical advantages as compared to DCE-MRI (magnetic resonance imaging), there are also two serious and interconnected shortcomings: the low contrast enhancement in relation to the noise level and the high exposure of patients to ionizing radiation. These limiting aspects are considered in detail from a radiation hygienic point of view, emphasizing the basic principles of justification and optimization. Clinically established as well as potential future applications of DCE-CT will be presented in a subsequent paper.
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Affiliation(s)
- G Brix
- Abteilung für Medizinischen und Beruflichen Strahlenschutz, Fachbereich Strahlenschutz und Gesundheit, Bundesamt für Strahlenschutz, Ingolstädter Landstr. 1, 85764 Neuherberg.
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25
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Chen F, Feng Y, Zheng K, De Keyzer F, Li J, Feng Y, Cona MM, Wang H, Jiang Y, Yu J, Marchal G, Verfaillie C, De Geest B, Oyen R, Ni Y. Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI. PLoS One 2012; 7:e41140. [PMID: 22815943 PMCID: PMC3399789 DOI: 10.1371/journal.pone.0041140] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 06/17/2012] [Indexed: 12/16/2022] Open
Abstract
A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.
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Affiliation(s)
- Feng Chen
- Theragnostic Laboratory, Department of Imaging and Pathology, University Hospital, University of Leuven, Leuven, Belgium.
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IRM fonctionnelle : nouvel outil pour prédire la réponse des cancers du col utérin à la chimioradiothérapie concomitante ? IMAGERIE DE LA FEMME 2011. [DOI: 10.1016/j.femme.2011.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Remmele S, Ring J, Sénégas J, Heindel W, Mesters RM, Bremer C, Persigehl T. Concurrent MR blood volume and vessel size estimation in tumors by robust and simultaneous ΔR2 and ΔR2* quantification. Magn Reson Med 2011; 66:144-53. [PMID: 21305604 DOI: 10.1002/mrm.22810] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2010] [Revised: 11/30/2010] [Accepted: 12/10/2010] [Indexed: 11/09/2022]
Abstract
This work presents a novel method for concurrent estimation of the fractional blood volume and the mean vessel size of tumors based on a multi-gradient-echo-multi-spin-echo sequence and the injection of a super-paramagnetic blood-pool agent. The approach further comprises a post-processing technique for simultaneous estimation of changes in the transverse relaxation rates R(2) and R(2)*, which is robust against global B(0) and B(1) field inhomogeneities and slice imperfections. The accuracy of the simultaneous ΔR(2) and ΔR(2)* quantification approach is evaluated in a phantom. The simultaneous blood volume and vessel size estimates, obtained with MR, compare well to the immunohistological findings in a preclinical experiment (HT1080 cells, implanted in nude mice). Clinical translation is achieved in a patient with a pleomorphic sarcoma in the left pubic bone. The latter demonstrates the robustness of the technique against changes in the contrast agent concentration in blood during washout.
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Tracer kinetic modelling of tumour angiogenesis based on dynamic contrast-enhanced CT and MRI measurements. Eur J Nucl Med Mol Imaging 2010; 37 Suppl 1:S30-51. [PMID: 20503049 DOI: 10.1007/s00259-010-1448-7] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Technical developments in both magnetic resonance imaging (MRI) and computed tomography (CT) have helped to reduce scan times and expedited the development of dynamic contrast-enhanced (DCE) imaging techniques. Since the temporal change of the image signal following the administration of a diffusible, extracellular contrast agent (CA) is related to the local blood supply and the extravasation of the CA into the interstitial space, DCE imaging can be used to assess tissue microvasculature and microcirculation. It is the aim of this review to summarize the biophysical and tracer kinetic principles underlying this emerging imaging technique offering great potential for non-invasive characterization of tumour angiogenesis. METHODS In the first part, the relevant contrast mechanisms are presented that form the basis to relate signal variations measured by serial CT and MRI to local tissue concentrations of the administered CA. In the second part, the concepts most widely used for tracer kinetic modelling of concentration-time courses derived from measured DCE image data sets are described in a consistent and unified manner to highlight their particular structure and assumptions as well as the relationships among them. Finally, the concepts presented are exemplified by the analysis of representative DCE data as well as discussed with respect to present and future applications in cancer diagnosis and therapy. RESULTS Depending on the specific protocol used for the acquisition of DCE image data and the particular model applied for tracer kinetic analysis of the derived concentration-time courses, different aspects of tumour angiogenesis can be quantified in terms of well-defined physiological tissue parameters. CONCLUSIONS DCE imaging offers promising prospects for improved tumour diagnosis, individualization of cancer treatment as well as the evaluation of novel therapeutic concepts in preclinical and early-stage clinical trials.
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Merz M, Komljenovic D, Zwick S, Semmler W, Bäuerle T. Sorafenib tosylate and paclitaxel induce anti-angiogenic, anti-tumour and anti-resorptive effects in experimental breast cancer bone metastases. Eur J Cancer 2010; 47:277-86. [PMID: 20863686 DOI: 10.1016/j.ejca.2010.08.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 08/19/2010] [Accepted: 08/24/2010] [Indexed: 01/07/2023]
Abstract
PURPOSE In this study we investigated sorafenib tosylate and paclitaxel as single and combination therapies regarding their effects on tumour growth and vasculature as well as their potency to inhibit osteolysis in experimental breast cancer bone metastases. EXPERIMENTAL DESIGN Nude rats bearing breast cancer bone metastases were treated with sorafenib tosylate (7 mg/kg, n=11), paclitaxel (5mg/kg, n=11) or the combination of both (n=10) and were compared to untreated controls (n=11). In a longitudinal study, volumes of osteolyses and respective soft tissue tumours were measured in these groups by MRI and volume CT, while changes in cellularity within bone metastases were assessed by diffusion-weighted imaging. Dynamic contrast-enhanced MRI and vessel size imaging was performed to determine changes of tumour vasculature within osseous lesions non-invasively. RESULTS Animals treated with sorafenib tosylate or paclitaxel showed significantly reduced growth of both, the osteolytic lesions and the soft tissue tumours as well as a decreased cellularity in bone metastases compared to control rats. Effects on the tumour vasculature of these drugs included significantly reduced blood volume as well as significant changes of the vessel permeability and the mean vessel calibers. When combining sorafenib tosylate with paclitaxel for the treatment of bone metastases positive combination effects were observed, particularly on reducing vessel permeability in these lesions. CONCLUSION The application of sorafenib tosylate monotherapy or in combination with paclitaxel is effective against experimental breast cancer bone metastases resulting in anti-angiogenic, anti-tumour and anti-resorptive effects.
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Affiliation(s)
- Maximilian Merz
- Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Persigehl T, Wall A, Kellert J, Ring J, Remmele S, Heindel W, Dahnke H, Bremer C. Tumor blood volume determination by using susceptibility-corrected DeltaR2* multiecho MR. Radiology 2010; 255:781-9. [PMID: 20501715 DOI: 10.1148/radiol.10090832] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. MATERIALS AND METHODS All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. RESULTS For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. CONCLUSION Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.
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Affiliation(s)
- Thorsten Persigehl
- Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany.
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Palmowski M, Lederle W, Gaetjens J, Socher M, Hauff P, Bzyl J, Semmler W, Günther RW, Kiessling F. Comparison of conventional time–intensity curves vs. maximum intensity over time for post-processing of dynamic contrast-enhanced ultrasound. Eur J Radiol 2010; 75:e149-53. [DOI: 10.1016/j.ejrad.2009.10.030] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Revised: 10/26/2009] [Accepted: 10/30/2009] [Indexed: 11/26/2022]
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Bäuerle T, Merz M, Komljenovic D, Zwick S, Semmler W. Drug-induced vessel remodeling in bone metastases as assessed by dynamic contrast enhanced magnetic resonance imaging and vessel size imaging: a longitudinal in vivo study. Clin Cancer Res 2010; 16:3215-25. [PMID: 20530698 DOI: 10.1158/1078-0432.ccr-09-2932] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The aim of this study was to assess the antiangiogenic treatment effects of zoledronic acid (ZA) and sunitinib malate (SM) noninvasively in experimental breast cancer bone metastases by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging. EXPERIMENTAL DESIGN Nude rats bearing bone metastases after inoculation of MDA-MB-231 breast cancer cells were treated with ZA (40 microg/kg weekly; n = 8 rats), SM (20 mg/kg daily; n = 8 rats), or their combination (ZA and SM; n = 8 rats) and compared with sham-treated controls (n = 10 rats). Vascular changes in bone metastases were longitudinally imaged in vivo using DCE-MRI [amplitude (A) and exchange rate coefficient (k(ep))] and vessel size imaging [blood volume (BV) and vessel size index (VI)]. In addition, antiresorptive and antitumor changes were assessed in these lesions by flat-panel volumetric computed tomography as well as morphologic MRI and diffusion-weighted imaging. RESULTS In bone metastases, significant changes in A, k(ep), BV, and VI in accordance with decreased blood volume and vessel permeability as well as with increased mean vessel diameters were observed after application of ZA and SM as compared with controls. In this longitudinal study, antiangiogenic changes preceded the inhibition of osteolysis and antitumor effects after treatment. CONCLUSIONS These results indicate vessel remodeling in breast cancer bone metastases on ZA and SM treatment and implicate substantial effects on imaging and treatment of malignant bone lesions.
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Affiliation(s)
- Tobias Bäuerle
- Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany.
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Tumor perfusion assessed by dynamic contrast-enhanced MRI correlates to the grading of renal cell carcinoma: Initial results. Eur J Radiol 2010; 74:e176-80. [DOI: 10.1016/j.ejrad.2009.05.042] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Revised: 04/28/2009] [Accepted: 05/25/2009] [Indexed: 02/06/2023]
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Sourbron S. Technical aspects of MR perfusion. Eur J Radiol 2010; 76:304-13. [PMID: 20363574 DOI: 10.1016/j.ejrad.2010.02.017] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 02/23/2010] [Indexed: 12/15/2022]
Abstract
The most common methods for measuring perfusion with MRI are arterial spin labelling (ASL), dynamic susceptibility contrast (DSC-MRI), and T(1)-weighted dynamic contrast enhancement (DCE-MRI). This review focuses on the latter approach, which is by far the most common in the body and produces measures of capillary permeability as well. The aim is to present a concise but complete overview of the technical issues involved in DCE-MRI data acquisition and analysis. For details the reader is referred to the references. The presentation of the topic is essentially generic and focuses on technical aspects that are common to all DCE-MRI measurements. For organ-specific problems and illustrations, we refer to the other papers in this issue. In Section 1 "Theory" the basic quantities are defined, and the physical mechanisms are presented that provide a relation between the hemodynamic parameters and the DCE-MRI signal. Section 2 "Data acquisition" discusses the issues involved in the design of an optimal measurement protocol. Section 3 "Data analysis" summarizes the steps that need to be taken to determine the hemodynamic parameters from the measured data.
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Affiliation(s)
- Steven Sourbron
- Division of Medical Physics, University of Leeds, Worsley Building, Clarendon Way, LS2 9JT Leeds, UK.
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35
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Abramyuk A, Tokalov SV. Distribution of fluorescent microspheres in vascular space and parenchymal organs of intact nude rats. Int J Radiat Biol 2009; 85:781-6. [PMID: 19657864 DOI: 10.1080/09553000903090035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
PURPOSE To assess kinetics of elimination of different sized microspheres (MS) from the blood pool and tendency of their distribution in parenchymal organs of intact nude rats. MATERIALS AND METHODS A mixture of 1 microm and 3 microm MS in phosphate-buffered saline was injected intravenously into eight rats under intraperitoneal anaesthesia. Blood samples were collected before, just after and in 2, 5 and 10 min after MS injection. Dynamics of MS elimination from blood pool was evaluated with flow cytometry. After euthanasia, histological sections were prepared and distributions of MS through the liver, spleen, kidney and lung were analysed with fluorescence microscopy and flow cytometry. RESULTS The number of microspheres registered in the intravascular space showed a marked exponential decrease over time independent of MS size. Different amounts and proportions of 1 microm and 3 microm MS were revealed in lung, liver, spleen and kidneys of the rats. Most of 1 microm MS were localised in liver and spleen. In contrast, 3 microm MS were detected predominantly in lung. CONCLUSION 1 microm and 3 microm MS may be assumed as free circulating particles only for a short period of time after injection. Their elimination kinetics seems to be tightly linked to specific tissue properties such a pulmonary vasoconstriction and phagocytosis.
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Affiliation(s)
- Andrij Abramyuk
- OncoRay-Center for Radiation Research in Oncology, Dresden University of Technology, Dresden, Germany.
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Kelm BM, Menze BH, Nix O, Zechmann CM, Hamprecht FA. Estimating kinetic parameter maps from dynamic contrast-enhanced MRI using spatial prior knowledge. IEEE TRANSACTIONS ON MEDICAL IMAGING 2009; 28:1534-47. [PMID: 19369150 DOI: 10.1109/tmi.2009.2019957] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
Dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging can be used to study microvascular structure in vivo by monitoring the abundance of an injected diffusible contrast agent over time. The resulting spatially resolved intensity-time curves are usually interpreted in terms of kinetic parameters obtained by fitting a pharmacokinetic model to the observed data. Least squares estimates of the highly nonlinear model parameters, however, can exhibit high variance and can be severely biased. As a remedy, we bring to bear spatial prior knowledge by means of a generalized Gaussian Markov random field (GGMRF). By using information from neighboring voxels and computing the maximum a posteriori solution for entire parameter maps at once, both bias and variance of the parameter estimates can be reduced thus leading to smaller root mean square error (RMSE). Since the number of variables gets very big for common image resolutions, sparse solvers have to be employed. To this end, we propose a generalized iterated conditional modes (ICM) algorithm operating on blocks instead of sites which is shown to converge considerably faster than the conventional ICM algorithm. Results on simulated DCE-MR images show a clear reduction of RMSE and variance as well as, in some cases, reduced estimation bias. The mean residual bias (MRB) is reduced on the simulated data as well as for all 37 patients of a prostate DCE-MRI dataset. Using the proposed algorithm, average computation times only increase by a factor of 1.18 (871 ms per voxel) for a Gaussian prior and 1.51 (1.12 s per voxel) for an edge-preserving prior compared to the single voxel approach (740 ms per voxel).
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IRM fonctionnelle : nouvel outil pour prédire la réponse des cancers du col utérin à la chimioradiothérapie concomitante ? Cancer Radiother 2009; 13:511-4. [DOI: 10.1016/j.canrad.2009.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Revised: 06/23/2009] [Accepted: 07/07/2009] [Indexed: 11/18/2022]
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Sauerbier S, Palmowski M, Vogeler M, Nagursky H, Al-Ahmad A, Fisch D, Hennig J, Schmelzeisen R, Gutwald R, Fasol U. Onset and Maintenance of Angiogenesis in Biomaterials: In Vivo Assessment by Dynamic Contrast-Enhanced MRI. Tissue Eng Part C Methods 2009; 15:455-62. [DOI: 10.1089/ten.tec.2008.0626] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Sebastian Sauerbier
- Department of Oral and Craniomaxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Moritz Palmowski
- Department of Diagnostic Radiology and Institute of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany
| | - Michael Vogeler
- Department of Oral and Craniomaxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Heiner Nagursky
- Hard Tissue Research Laboratory, Department for Oral- and Maxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Ali Al-Ahmad
- Cell Laboratory, Department of Operative Dentistry, University Hospital Freiburg, Freiburg, Germany
| | - Dagmar Fisch
- Department of Diagnostic Radiology, Medical Physics, University Hospital Freiburg, Freiburg, Germany
| | - Jürgen Hennig
- Department of Diagnostic Radiology, Medical Physics, University Hospital Freiburg, Freiburg, Germany
| | - Rainer Schmelzeisen
- Department of Oral and Craniomaxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Ralf Gutwald
- Department of Oral and Craniomaxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Ulrike Fasol
- Department of Diagnostic Radiology, Medical Physics, University Hospital Freiburg, Freiburg, Germany
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Razek AAKA, Elsorogy LG, Soliman NY, Nada N. Dynamic susceptibility contrast perfusion MR imaging in distinguishing malignant from benign head and neck tumors: a pilot study. Eur J Radiol 2009; 77:73-9. [PMID: 19695805 DOI: 10.1016/j.ejrad.2009.07.022] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2009] [Revised: 07/16/2009] [Accepted: 07/16/2009] [Indexed: 01/21/2023]
Abstract
PURPOSE To preliminarily investigate the utility of dynamic susceptibility contrast perfusion MR imaging in distinguishing malignant from benign head and neck tumors. MATERIAL AND METHODS Seventy eight patients with head and neck masses underwent single shot dynamic susceptibility contrast T2*-weighted perfusion weighted MR imaging after bolus infusion of gadolinium-DTPA was administrated. The signal intensity time curve of the lesion was created. Dynamic susceptibility contrast percentage (DSC%) was calculated and correlated with pathological findings. RESULTS The mean DSC% of malignant tumor (n=40) was 39.3±9.6% and of benign lesions (n=38) was 24.3±10.3%. There was a statistically significant difference of the DSC% between benign and malignant tumors (P=0.001) and within benign tumors (P=0.001). When DSC% of 30.7% was used as a threshold for differentiating malignant from benign tumors, the best results were obtained: accuracy of 84.6%, sensitivity of 80% and specificity of 89.2%. CONCLUSION Dynamic susceptibility contrast perfusion weighted MR imaging is a non-invasive imaging technique that can play a role in differentiation between malignant and benign head and neck tumors.
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Oostendorp M, Post MJ, Backes WH. Vessel growth and function: depiction with contrast-enhanced MR imaging. Radiology 2009; 251:317-35. [PMID: 19401568 DOI: 10.1148/radiol.2512080485] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Magnetic resonance (MR) imaging is a versatile noninvasive diagnostic tool that can be applied to the entire human body to revealing morphologic, functional, and metabolic information. The authors review how MR imaging can depict both the established and the developing vasculature with techniques involving intravenously administered contrast agents. In addition to macrovascular morphology and flow, MR imaging is able to exploit microvascular properties, including vessel size distribution, hyperpermeability, flow heterogeneity, and possibly also upregulation of endothelial biomarkers. For each MR method, the basic principles, potential acquisition and interpretation pitfalls, solutions, and applications are described. Furthermore, discussion includes current shortcomings and the impact of future developments (eg, higher magnetic field strength systems, targeted macromolecular contrast agents) on the visualization of blood vessel growth and function with contrast-enhanced MR imaging.
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Affiliation(s)
- Marlies Oostendorp
- Department of Radiology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands
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Bäuerle T, Semmler W. Imaging response to systemic therapy for bone metastases. Eur Radiol 2009; 19:2495-507. [PMID: 19468736 DOI: 10.1007/s00330-009-1443-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2008] [Revised: 03/14/2009] [Accepted: 04/20/2009] [Indexed: 12/15/2022]
Abstract
In patients with osteotropic primary tumours such as breast and prostate cancer, imaging treatment response of bone metastases is essential for the clinical management. After treatment of skeletal metastases, morphological changes, in particular of bone structure, occur relatively late and are difficult to quantify using conventional X-rays, CT or MRI. Early treatment response in these lesions can be assessed from functional imaging techniques such as dynamic contrast-enhanced techniques by MRI or CT and by diffusion-weighted MRI, which are quantifiable. Among the techniques within nuclear medicine, PET offers the acquisition of quantifiable parameters for response evaluation. PET, therefore, especially in combination with CT and MRI using hybrid techniques, holds great promise for early and quantifiable assessment of treatment response in bone metastases. This review summarises the classification systems and the use of imaging techniques for evaluation of treatment response and suggests parameters for the early detection and quantification of response to systemic therapy.
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Affiliation(s)
- Tobias Bäuerle
- Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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Zwick S, Strecker R, Kiselev V, Gall P, Huppert J, Palmowski M, Lederle W, Woenne EC, Hengerer A, Taupitz M, Semmler W, Kiessling F. Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging. J Magn Reson Imaging 2009; 29:1125-33. [DOI: 10.1002/jmri.21710] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Khalil A, Thomassin-Naggara I, Gounant V, Nedelcu N, Marsault C, Carette MF. [Perfusion and diffusion-weighted MR imaging in the early staging and the follow-up of patients with lung cancer]. REVUE DE PNEUMOLOGIE CLINIQUE 2009; 65:40-48. [PMID: 19306784 DOI: 10.1016/j.pneumo.2008.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2008] [Accepted: 08/23/2008] [Indexed: 05/27/2023]
Abstract
Tissue characterization is a major and ultimate goal of imaging, whether morphological (Computed Tomography, Magnetic Resonance Imaging) or metabolic (PET-FDG-[18F]). Functional imaging, using the MRI, began several years ago with the perfusion of lung nodules and very recently with diffusion-weighted imaging applied to the lung cancer. The authors review the interest and the place of diffusion-weighted and perfusion MR imaging in the diagnosis, early staging and follow-up of patients with lung cancer.
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Affiliation(s)
- A Khalil
- Service de radiologie, hôpital Tenon, AP-HP, 4, rue de la Chine, 75020 Paris, France.
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Abstract
Diseases caused by cancer have become more common due to an increase in life-expectation, but the probability of reaching an old age with or without a tumor disease is still increasing. According to the statistics of the German Cancer register, at present more than half of cancer patients survive for at least 5 years after cancer has been diagnosed. Many tumors can be cured using innovative neoadjuvant and adjuvant therapy regimes, but the options for palliative therapy have also been improved. This leads to an increasing importance of the evaluation of the tumor response using imaging techniques. Classically, tumor response is measured by imaging using the RECIST (response evaluation criteria in solid tumors) criteria, which define the changes in size of the tumor during therapy. However, there is increasingly more evidence that RECIST as the only measure of tumor response, does not document tumor response for all tumor entities and especially not for many medications known as targeted therapy. This article gives a review of the principles and mode of effect of various therapy regimes as well as the clinical demands on imaging techniques.
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Abstract
Magnetic resonance imaging (MRI) is a mainstay in oncological imaging with respect to tumor detection, characterization and treatment monitoring. Besides quantifying metric changes of tumor tissue, a wide range of different other surrogate parameters of therapy response can be imaged and quantified by MRI. Early monitoring of treatment success is critical both for medical and economical reasons specifically with more expensive target-specific drugs entering the clinical arena. Dynamic contrast-enhanced (DCE) and steady state MRI can help to assess tumor perfusion and vessel permeability. The cellular state of tissue can be measured by diffusion-weighted imaging (DWI) and metabolic changes can be monitored by MR spectroscopy (MRS). New target-specific contrast agents potentially allow selective imaging of apoptotic events.This review aims to give a brief overview of new MR-based imaging approaches to assess tumor response to new target-specific therapy regimes, with special emphasis on anti-angiogenic and antivascular treatment effects.
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Oberholzer K, Pohlmann A, Schreiber W, Mildenberger P, Kunz P, Schmidberger H, Junginger T, Düber C. Assessment of tumor microcirculation with dynamic contrast-enhanced MRI in patients with esophageal cancer: initial experience. J Magn Reson Imaging 2008; 27:1296-301. [PMID: 18504749 DOI: 10.1002/jmri.21305] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
PURPOSE To investigate the feasibility and impact of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on tumor characterization and response to radiochemotherapy (RCT) in patients with esophageal cancer. MATERIALS AND METHODS A total of 48 patients underwent DCE-MRI to assess tumor microcirculation based on a two-compartment model function. Effects of RCT on kinetic parameters were studied in 12 patients with squamous cell carcinoma. RESULTS Tumor microcirculation differs with respect to histological subtype: squamous cell carcinomas showed lower values of amplitude A (leakage space, P = 0.015) and higher contrast agent exchange rates (k(21), P = 0.225) compared with adenocarcinomas. RCT led to a significant decrease of the contrast agent exchange rate (P = 0.005), while amplitude A increased moderately after therapy (P = 0.136). CONCLUSION DCE-MRI is feasible in patients with esophageal cancer, reveals therapeutic effects, and may thus be useful in therapy management and monitoring.
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Affiliation(s)
- Katja Oberholzer
- Department of Diagnostic and Interventional Radiology, Johannes Gutenberg University Mainz, Mainz, Germany
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Marcus CD, Ladam-Marcus V, Cucu C, Bouché O, Lucas L, Hoeffel C. Imaging techniques to evaluate the response to treatment in oncology: current standards and perspectives. Crit Rev Oncol Hematol 2008; 72:217-38. [PMID: 18760935 DOI: 10.1016/j.critrevonc.2008.07.012] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 07/04/2008] [Accepted: 07/17/2008] [Indexed: 02/07/2023] Open
Abstract
Response evaluation in solid tumours currently uses radiological imaging techniques to measure changes under treatment. Imaging requires a well-defined anatomical lesion to be viewed and relies on the measurement of a reduction in tumour size during treatment as the basis for presumed clinical benefit. However, with the development of anti-angiogenesis agents, anatomical imaging has became inappropriate as certain tumours would not reduce in size. Functional studies are therefore necessary and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), DCE-computed tomography (CT) and DCE-ultrasonography (US) are currently being evaluated for monitoring treatments. Diffusion-weighted MR imaging (DW-MRI) and magnetic resonance spectroscopy (MRS) are also capable of detecting changes in cell density and metabolite content within tumours. In this article, we review anatomical and functional criteria currently used for monitoring therapy. We review the published data on DCE-MRI, DCE-CT, DCE-US, DW-MRI and MRS. This literature review covers the following area: basic principles of the technique, clinical studies, reproducibility and repeatability, limits and perspectives in monitoring therapy. Anatomical criteria such as response evaluation criteria in solid tumours (RECIST) will require adaptation to employ not only new tools but also different complementary techniques such as functional imaging in order to monitor therapeutic effects of conventional and new anti-cancer agents.
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Affiliation(s)
- C D Marcus
- Department of Radiology, Robert-Debre Hospital, University of Reims, France.
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Palmowski M, Huppert J, Hauff P, Reinhardt M, Schreiner K, Socher MA, Hallscheidt P, Kauffmann GW, Semmler W, Kiessling F. Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment. Cancer Res 2008; 68:7042-9. [DOI: 10.1158/0008-5472.can-08-0285] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI. Neoplasia 2008; 10:511-20. [PMID: 18472968 DOI: 10.1593/neo.08220] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2008] [Revised: 02/18/2008] [Accepted: 02/20/2008] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer bone metastasis and to monitor osteolysis, soft tissue tumor, and angiogenesis in bone metastasis noninvasively by volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). After inoculation of MDA-MB-231 human breast cancer cells into nude rats, bone metastasis was monitored with contrast-enhanced VCT and MRI from day 30 to day 70 after tumor cell inoculation, respectively. Thereby, animals of the treatment group (10 mg/kg bevacizumab IV weekly, n = 15) were compared with sham-treated animals (n = 17). Treatment with bevacizumab resulted in a significant difference versus control in osteolytic as well as soft tissue lesion sizes (days 50 to 70 and 40 to 70 after tumor cell inoculation, respectively; P < .05). This observation was paralleled with significantly reduced vascularization in the treatment group as shown by reduced increase in relative signal intensity in dynamic contrast-enhanced MRI from days 40 to 70 (P < .05). Contrast-enhanced VCT and histology confirmed decreased angiogenesis as well as new bone formation after application of bevacizumab. In conclusion, bevacizumab significantly inhibited osteolysis, surrounding soft tissue tumor growth, and angiogenesis in an experimental model of breast cancer bone metastasis as visualized by VCT and MRI.
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Palmowski M, Huppert J, Ladewig G, Hauff P, Reinhardt M, Mueller MM, Woenne EC, Jenne JW, Maurer M, Kauffmann GW, Semmler W, Kiessling F. Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects. Mol Cancer Ther 2008; 7:101-9. [PMID: 18202013 DOI: 10.1158/1535-7163.mct-07-0409] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alphavbeta3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alphavbeta3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alphavbeta3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alphavbeta3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.
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Affiliation(s)
- Moritz Palmowski
- Department of Diagnostic Radiology, Ruprecht-Karls University, Heidelberg, Germany
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