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Parametric response mapping (PRM) of inspiration and expiration computed tomography (CT) images improves the radiological phenotyping of chronic obstructive pulmonary disease (COPD). PRM classifies individual voxels of lung parenchyma as normal, emphysematous, or nonemphysematous air trapping. In this study, bias and noise characteristics of the PRM methodology to CT and clinical procedures were evaluated to determine best practices for this quantitative technique. Twenty patients of varying COPD status with paired volumetric inspiration and expiration CT scans of the lungs were identified from the baseline COPD-Gene cohort. The impact of CT scanner manufacturer and reconstruction kernels were evaluated as potential sources of variability in PRM measurements along with simulations to quantify the impact of inspiration/expiration lung volume levels, misregistration, and image spacing on PRM measurements. Negligible variation in PRM metrics was observed when CT scanner type and reconstruction were consistent and inspiration/expiration lung volume levels were near target volumes. CT scanner Hounsfield unit drift occurred but remained difficult to ameliorate. Increasing levels of image misregistration and CT slice spacing were found to have a minor effect on PRM measurements. PRM-derived values were found to be most sensitive to lung volume levels and mismatched reconstruction kernels. As with other quantitative imaging techniques, reliable PRM measurements are attainable when consistent clinical and CT protocols are implemented.
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Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease.
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Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Imagen Multimodal/métodos , Neoplasias de la Próstata/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Densidad Ósea , Neoplasias Óseas/terapia , Imagen de Difusión por Resonancia Magnética , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Modelos Animales de Enfermedad , Docetaxel , Humanos , Masculino , Ratones , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteólisis/diagnóstico , Taxoides/farmacología , Taxoides/uso terapéutico , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiaciónRESUMEN
Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. Increased abundance of phosphorylated FADD in patient-derived tumor samples predicts poor clinical outcome. Using immunohistochemistry analysis and in vivo imaging of conditional mouse models of KRAS(G12D)-driven lung cancer, we found that the deletion of the gene encoding FADD suppressed tumor growth, reduced the proliferative index of cells, and decreased the activation of downstream effectors of the RAS-MAPK (mitogen-activated protein kinase) pathway that promote the cell cycle, including retinoblastoma (RB) and cyclin D1. In mouse embryonic fibroblasts, the induction of mitosis upon activation of KRAS required FADD and the phosphorylation of FADD by CK1α (casein kinase 1α). Deleting the gene encoding CK1α in KRAS mutant mice abrogated the phosphorylation of FADD and suppressed lung cancer development. Phosphorylated FADD was most abundant during the G2/M phase of the cell cycle, and mass spectrometry revealed that phosphorylated FADD interacted with kinases that mediate the G2/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A), and BUB1 (budding uninhibited by benzimidazoles 1). This interaction was decreased in cells treated with a CKI-7, a CK1α inhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1α may be a therapeutic target for KRAS-driven lung cancer.
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Caseína Quinasa Ialfa/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Neoplasias Pulmonares/genética , Mutación Missense/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Aurora Quinasa A/metabolismo , Western Blotting , Proteínas de Ciclo Celular/metabolismo , Cartilla de ADN/genética , Genotipo , Técnicas Histológicas , Inmunoprecipitación , Mediciones Luminiscentes , Espectrometría de Masas , Ratones , Fosforilación , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Microtomografía por Rayos X , Quinasa Tipo Polo 1RESUMEN
RATIONALE AND OBJECTIVES: The longitudinal relationship between regional air trapping and emphysema remains unexplored. We have sought to demonstrate the utility of parametric response mapping (PRM), a computed tomography (CT)-based biomarker, for monitoring regional disease progression in chronic obstructive pulmonary disease (COPD) patients, linking expiratory- and inspiratory-based CT metrics over time. MATERIALS AND METHODS: Inspiratory and expiratory lung CT scans were acquired from 89 COPD subjects with varying Global Initiative for Chronic Obstructive Lung Disease (GOLD) status at 30 days (n = 13) or 1 year (n = 76) from baseline as part of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) clinical trial. PRMs of CT data were used to quantify the relative volumes of normal parenchyma (PRM(Normal)), emphysema (PRM(Emph)), and functional small airways disease (PRM(fSAD)). PRM measurement variability was assessed using the 30-day interval data. Changes in PRM metrics over a 1-year period were correlated to pulmonary function (forced expiratory volume at 1 second [FEV1]). A theoretical model that simulates PRM changes from COPD was compared to experimental findings. RESULTS: PRM metrics varied by â¼6.5% of total lung volume for PRM(Normal) and PRM(fSAD) and 1% for PRM(Emph) when testing 30-day repeatability. Over a 1-year interval, only PRM(Emph) in severe COPD subjects produced significant change (19%-21%). However, 11 of 76 subjects showed changes in PRM(fSAD) greater than variations observed from analysis of 30-day data. Mathematical model simulations agreed with experimental PRM results, suggesting fSAD is a transitional phase from normal parenchyma to emphysema. CONCLUSIONS: PRM of lung CT scans in COPD patients provides an opportunity to more precisely characterize underlying disease phenotypes, with the potential to monitor disease status and therapy response.
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Pulmón/diagnóstico por imagen , Reconocimiento de Normas Patrones Automatizadas/métodos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Técnica de Sustracción , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Intensificación de Imagen Radiográfica/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The management of bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation presents many challenges, both diagnostically and therapeutically. We developed a computed tomography (CT) voxel-wise methodology termed parametric response mapping (PRM) that quantifies normal parenchyma, functional small airway disease (PRM(fSAD)), emphysema, and parenchymal disease as relative lung volumes. We now investigate the use of PRM as an imaging biomarker in the diagnosis of BOS. PRM was applied to CT data from 4 patient cohorts: acute infection (n = 11), BOS at onset (n = 34), BOS plus infection (n = 9), and age-matched, nontransplant control subjects (n = 23). Pulmonary function tests and bronchoalveolar lavage were used for group classification. Mean values for PRM(fSAD) were significantly greater in patients with BOS (38% ± 2%) when compared with those with infection alone (17% ± 4%, P < .0001) and age-matched control subjects (8.4% ± 1%, P < .0001). Patients with BOS had similar PRM(fSAD) profiles, whether a concurrent infection was present or not. An optimal cut-point for PRM(fSAD) of 28% of the total lung volume was identified, with values >28% highly indicative of BOS occurrence. PRM may provide a major advance in our ability to identify the small airway obstruction that characterizes BOS, even in the presence of concurrent infection.
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Bronquiolitis Obliterante/diagnóstico por imagen , Neoplasias Hematológicas/diagnóstico por imagen , Trasplante de Células Madre Hematopoyéticas , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/inmunología , Bronquiolitis Obliterante/microbiología , Líquido del Lavado Bronquioalveolar/microbiología , Estudios de Casos y Controles , Niño , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/microbiología , Humanos , Pulmón/inmunología , Pulmón/microbiología , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Estudios Prospectivos , Pruebas de Función Respiratoria , Síndrome , Trasplante HomólogoRESUMEN
Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy.
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RATIONALE: Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model. EXPERIMENTAL DESIGN: Twenty-four genetically engineered murine GBM models [Ink4a-Arf(-/-)/Pten(loxp/loxp)/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation. RESULTS: Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R (2) = 0.88). CONCLUSION: This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.
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Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers is urgently needed to enable individualized treatment, thus improving patient outcome. We adapted the parametric response map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole-lung computed tomography (CT) scans acquired at inspiration and expiration of 194 individuals with COPD from the COPDGene study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype while providing detailed spatial information of disease distribution and location. PRM's ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients, complementing standard clinical techniques.
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Diagnóstico Diferencial , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Tomografía Computarizada de Emisión , Biomarcadores , Progresión de la Enfermedad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/fisiopatología , Fumar/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
Loss of bone mass due to disease, such as osteoporosis and metastatic cancer to the bone, is a leading cause of orthopedic complications and hospitalization. Onset of bone loss resulting from disease increases the risk of incurring fractures and subsequent pain, increasing medical expenses while reducing quality of life. Although current standard CT-based protocols provide adequate prognostic information for assessing bone loss, many of the techniques for evaluating CT scans rely on measures based on whole-bone summary statistics. This reduces the sensitivity at identifying local regions of bone resorption, as well as formation. In this study, we evaluate the effectiveness of a voxel-based image post-processing technique, called the Parametric Response Map (PRM), for identifying local changes in bone mass in weight-bearing bones on CT scans using an established animal model of osteoporosis. Serial CT scans were evaluated weekly using PRM subsequent to ovariectomy or sham surgeries over the period of one month. For comparison, bone volume fraction and mineral density measurements were acquired and found to significantly differ between groups starting 3 weeks post-surgery. High resolution ex vivo measurements acquired four weeks post-surgery validated the extent of bone loss in the surgical groups. In contrast to standard methodologies for assessing bone loss, PRM results were capable of identifying local decreases in bone mineral by week 2, which were found to be significant between groups. This study concludes that PRM is able to detect changes in bone mineral with higher sensitivity and spatial differentiation than conventional techniques for evaluating CT scans, which may aid in clinical decision making for patients suffering from bone loss.