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PURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Imageamento por Ressonância Magnética Multiparamétrica , Sunitinibe/uso terapêutico , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Resultado do TratamentoRESUMO
Hyperpolarized 13C-MRI is an emerging tool for probing tissue metabolism by measuring 13C-label exchange between intravenously injected hyperpolarized [1-13C]pyruvate and endogenous tissue lactate. Here, we demonstrate that hyperpolarized 13C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1H-MRI and hyperpolarized 13C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of approximately 20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1 and lactate dehydrogenase A (LDHA), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of approximately 2,000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX was associated with reduced relapse-free and overall survival. Hyperpolarized 13C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential. SIGNIFICANCE: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7-11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Isótopos de Carbono/análise , Imageamento por Ressonância Magnética/métodos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Taxa de SobrevidaRESUMO
RATIONALE: The recent development of hyperpolarized 13C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time. OBJECTIVE: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. METHODS AND RESULTS: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-magnetic resonance spectroscopy), and lipid content (1H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via PDH (pyruvate dehydrogenase, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate), and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P<0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort. CONCLUSIONS: This work represents the first demonstration of the ability of hyperpolarized 13C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.
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Diabetes Mellitus Tipo 2/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Miocárdio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Jejum/metabolismo , Feminino , Glucose/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Complexo Piruvato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismoRESUMO
PURPOSE: This prospective study evaluated the use of vascular, extracellular and restricted diffusion for cytometry in tumours (VERDICT) MRI to investigate the tissue microstructure in glioma. VERDICT-derived parameters were correlated with both histological features and tumour subtype and were also used to explore the peritumoural region. METHODS: Fourteen consecutive treatment-naïve patients (43.5 years ± 15.1 years, six males, eight females) with suspected glioma underwent diffusion-weighted imaging including VERDICT modelling. Tumour cell radius and intracellular and combined extracellular/vascular volumes were estimated using a framework based on linearisation and convex optimisation. An experienced neuroradiologist outlined the peritumoural oedema, enhancing tumour and necrosis on T2-weighted imaging and contrast-enhanced T1-weighted imaging. The same regions of interest were applied to the co-registered VERDICT maps to calculate the microstructure parameters. Pathology sections were analysed with semi-automated software to measure cellularity and cell size. RESULTS: VERDICT parameters were successfully calculated in all patients. The imaging-derived results showed a larger intracellular volume fraction in high-grade glioma compared to low-grade glioma (0.13 ± 0.07 vs. 0.08 ± 0.02, respectively; p = 0.05) and a trend towards a smaller extracellular/vascular volume fraction (0.88 ± 0.07 vs. 0.92 ± 0.04, respectively; p = 0.10). The conventional apparent diffusion coefficient was higher in low-grade gliomas compared to high-grade gliomas, but this difference was not statistically significant (1.22 ± 0.13 × 10-3 mm2/s vs. 0.98 ± 0.38 × 10-3 mm2/s, respectively; p = 0.18). CONCLUSION: This feasibility study demonstrated that VERDICT MRI can be used to explore the tissue microstructure of glioma using an abbreviated protocol. The VERDICT parameters of tissue structure correlated with those derived on histology. The method shows promise as a potential test for diagnostic stratification and treatment response monitoring in the future. KEY POINTS: ⢠VERDICT MRI is an advanced diffusion technique which has been correlated with histopathological findings obtained at surgery from patients with glioma in this study. ⢠The intracellular volume fraction measured with VERDICT was larger in high-grade tumours compared to that in low-grade tumours. ⢠The results were complementary to measurements from conventional diffusion-weighted imaging, and the technique could be performed in a clinically feasible timescale.
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Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Adulto , Idoso , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Viabilidade , Feminino , Glioma/patologia , Humanos , Angiografia por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
PURPOSE: To determine whether, in patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), [18F]FDG PET/MR can capture treatment effects within the first week after treatment initiation, and whether changes in glucose metabolism and cell density occur simultaneously. METHODS: Patients with histologically proven HL or NHL were included in this prospective IRB-approved study. Patients underwent [18F]FDG PET/MR before, and then 48-72 h after (follow-up 1, FU-1) and 1 week after (FU-2) initiation of the first cycle of their respective standard chemotherapy (for HL) or immunochemotherapy (for NHL). Standardized [18F]FDG uptake values (SUVmax, SUVmean) and apparent diffusion coefficients (ADCmin, ADCmean) based on diffusion-weighted MRI, and metabolic and morphological tumour volumes (MTV, VOL) were assessed at each time-point. Multilevel analyses with an unstructured covariance matrix, and pair-wise post-hoc tests were used to test for significant changes in SUVs, ADCs, MTVs and VOLs between the three time-points. RESULTS: A total of 58 patients (11 with HL and 47 with NHL) with 166 lesions were analysed. Lesion-based mean rates of change in SUVmax, SUVmean, ADCmin, ADCmean, MTV and VOL between baseline and FU-1 were -46.8%, -33.3%, +20.3%, +14%, -46% and -12.8%, respectively, and between baseline and FU-2 were -65.1%, -49%, +50.7%, +32.4%, -61.1% and -24.2%, respectively. These changes were statistically significant (P < 0.01) except for the change in VOL between baseline and FU-1 (P = 0.079). CONCLUSION: In lymphoma patients, [18F]FDG PET/MR can capture treatment-induced changes in glucose metabolism and cell density as early as 48-72 h after treatment initiation.
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Doença de Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Contagem de Células , Feminino , Fluordesoxiglucose F18 , Alemanha , Glucose , Humanos , Gravidez , Estudos Prospectivos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios XRESUMO
Hyperpolarized MRI with 13C-labelled compounds is an emerging clinical technique allowing in vivo metabolic processes to be characterized non-invasively. Accurate quantification of 13C data, both for clinical and research purposes, typically relies on the use of region-of-interest analysis to detect and compare regions of altered metabolism. However, it is not clear how this should be determined from the five-dimensional data produced and most standard methodologies are unable to exploit the multidimensional nature of the data. Here we propose a solution to the novel problem of 13C image segmentation using a hybrid Markov random field model with continuous fuzzy logic. The algorithm fully utilizes the multi-dimensional data format in order to classify each voxel into one of six distinct classes based on its metabolic characteristics. Bayesian priors fully incorporate spatial, temporal and ratiometric contextual information whilst image contrast from multiple spectral dimensions are considered concurrently by using an analogy from color image segmentation. Performance of the algorithm is demonstrated on in silico data, where the superiority of the approach over a reference thresholding method is consistently observed. Application to in vivo animal data from a pre-clinical subcutaneous tumor model illustrates the ability of the MRF algorithm to successfully detect tumor location whilst avoiding image artifacts. This work has the potential to assist the analysis of human hyperpolarized 13C data in the future.
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Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Aprendizado de Máquina não Supervisionado , Algoritmos , Animais , Isótopos de Carbono/química , Simulação por Computador , Meios de Contraste , Lógica Fuzzy , Cadeias de Markov , Modelos Estatísticos , Neoplasias Experimentais/diagnóstico por imagem , Imagens de Fantasmas , RatosRESUMO
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.
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Biomarcadores Tumorais , Neoplasias/diagnóstico , Tomada de Decisão Clínica , Análise Custo-Benefício , Fluordesoxiglucose F18 , Ácido Fólico/análogos & derivados , Humanos , Neoplasias/economia , Compostos de Organotecnécio , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Projetos de Pesquisa/normas , Viés de SeleçãoRESUMO
OBJECTIVE: The purpose of this study was to prospectively evaluate the value of diffusion-weighted MRI (DWI) for the assessment of extracapsular extension (ECE) in patients with prostate cancer. SUBJECTS AND METHODS: Between November 2010 and April 2012, 40 patients with intermediate- to high-risk prostate cancer were prospectively recruited. MR images were obtained at 3 T with a phased-array coil. Two independent readers scored the T2-weighted images alone and then in combination with DW images. ROIs were drawn on the apparent diffusion coefficient (ADC) maps, and histogram-derived values were calculated. Whole-mount histopathologic examination was the standard of reference. Reader performance was analyzed, and differences in patient characteristics and histogram-based ADC values, according to ECE status, were evaluated. RESULTS: ECE was present in 23 of 40 (58%) patients and 23 of 43 (53%) tumors. The sensitivity for side-specific ECE detection significantly increased, from 0.22 to 0.44 for reader 1 and 0.33 to 0.82 for reader 2 (both p < 0.05) without a significant change in specificity for either reader with the addition of DWI and ADC mapping. The positive and negative predictive values for both readers also increased. The ADC parameters of median and 10th and 25th centiles showed a statistically significant difference between tumors with and those without ECE (p < 0.05). CONCLUSION: The addition of DWI and ADC mapping to T2-weighted MRI improved the accuracy of preoperative detection of ECE. Median and 10th and 25th centile ADC values were significantly associated with the presence of ECE and may be useful in the pretreatment assessment of patients with prostate cancer.
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Imagem de Difusão por Ressonância Magnética/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Humanos , Masculino , Invasividade Neoplásica , Variações Dependentes do Observador , Cuidados Pré-Operatórios/métodos , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Cirurgia Assistida por Computador/métodos , Resultado do TratamentoRESUMO
Dynamic nuclear polarization (DNP) is an emerging technique for dramatically increasing the sensitivity of magnetic resonance spectroscopy (MRS). This review evaluates the potential strengths and weaknesses of DNP-enhanced (13)C magnetic resonance spectroscopic imaging (DNP-MRSI) as a clinical imaging technique in comparison to PET. The major advantage of MRS is chemical shift, which enables the injected molecule to be observed separately from its metabolites, whereas the major advantage of PET is its high sensitivity. Factors such as spatial and temporal resolution and potential risks and costs of the two techniques will be discussed. PET tracers and (13)C-labeled molecules that can be used in oncology will be reviewed with reference to the biologic processes they detect. Because DNP-MRSI and PET are, in principle, similar techniques for assessing tumor metabolism, the experiences gained during the development of PET may help to accelerate translation of DNP-MRSI into routine patient imaging.