Craig J. Galbán

The Impact of Sources of Variability on Parametric Response Mapping of Lung CT Scans.

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 COPDGene 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.

MRI-Guided Stereotactic Biopsy of Murine GBM for Spatiotemporal Molecular Genomic Assessment

Brain tumor biopsies that are routinely performed in clinical settings significantly aid in diagnosis and staging. The aim of this study is to develop and evaluate a methodological image-guided approach that would allow for routine sampling of glioma tissue from orthotopic mouse brain tumor models. A magnetic resonance imaging-guided biopsy method is presented to allow for spatially precise stereotaxic sampling of a murine glioma coupled with genome-scale technology to provide unbiased characterization of intra- and intertumoral clonal heterogeneity. Longitudinal and multiregional sampling of intracranial tumors allows for successful collection of tumor biopsy samples, thus allowing for a pathway-enrichment analysis and a transcriptional profiling of RNA sequencing data. Spatiotemporal gene expression pattern variations revealing genomic heterogeneity were found.

A Pilot Study of Quantitative MRI Parametric Response Mapping of Bone Marrow Fat for Treatment Assessment in Myelofibrosis.

Myelofibrosis (MF) is a hematologic neoplasm arising as a primary disease or secondary to other blood malignancies. Both primary and secondary MF develop progressive fibrosis of bone marrow, displacing normal hematopoietic cells to other organs and disrupting normal production of mature blood cells. Activation of JAK2 signaling in hematopoietic stem cells commonly causes MF, and ruxolitinib, a drug targeting this pathway, is the preferred treatment for many patients. However, current measures of disease status in MF do not necessarily predict response to treatment with ruxolitinib or other drugs. Bone marrow biopsies are invasive and prone to sampling error, while measurements of spleen volume only indirectly reflect status of bone marrow. Toward the goal of developing an imaging biomarker for treatment response in MF, we present preliminary results from a prospective clinical study evaluating parametric response mapping (PRM) of quantitative Dixon MRI bone marrow fat fraction maps in four MF patients treated with ruxolitinib. PRM allows voxel-wise identification of temporal changes in quantitative imaging readouts, in this case bone marrow fat. We identified heterogeneous responses of bone marrow fat among patients and within different bone marrow sites in the same patient. Changes in bone marrow fat fraction also were discordant with reductions in spleen volume, the standard imaging metric for treatment response. This study provides initial support for PRM analysis of quantitative MRI of bone marrow fat to monitor therapy in MF, setting the stage for larger studies to further develop and validate this method as a complementary imaging biomarker.

Potential for Early Fracture Risk Assessment in Patients with Metastatic Bone Disease using Parametric Response Mapping of CT Images.

Pathologic vertebral compression fractures (PVCFs) cause significant morbidity in patients with metastatic bone disease. Limitations in existing clinical biomarkers leave clinicians without reliable metrics for predicting PVCF, thus impeding efforts to prevent this severe complication. To establish the feasibility of a new method for defining the risk of a PVCF, we retrospectively analyzed serial computed tomography (CT) scans from 5 breast cancer patients using parametric response mapping (PRM) to quantify dynamic bone miniral density (BMD) changes that preceded an event. Vertebrae segmented from each scan were registered to the same spatial frame and voxel classification was accomplished using a predetermined threshold of change in Hounsfield units (HU), resulting in relative volumes of increased (PRMHU+), decreased (PRMHU−), or unchanged (PRMHU0) attenuation. A total of 7 PVCFs were compared to undiseased vertebrae in each patient serving as controls. A receiver operator curve (ROC) analysis identified optimal imaging times for group stratification. BMD changes were apparent by an elevated PRMHU+ as early as 1 year before fracture. ROC analysis showed poor performance of PRMHU− in stratifying PVCFs versus controls. As early as 6 months before PVCF, PRMHU+ was significantly larger (12.9 ± 11.6%) than control vertebrae (2.3 ± 2.5%), with an area under the curve of 0.918 from an ROC analysis. Mean HU changes were also significant between PVCF (26.8 ± 26.9%) and control (−2.2 ± 22.0%) over the same period. A PRM analysis of BMD changes using standard CT imaging was sensitive for spatially resolving changes that preceded structural failure in these patients.

DW-MRI Assessment of Cancer Response to Chemoradiation

MR imaging is widely used in the radiological diagnosis of oncology patients as it provides excellent soft tissue differentiation using routine anatomical MR imaging. A variety of MR acquisition sequences are available which can yield images of biophysical, physiological, metabolic, or functional properties of tissues. Imaging of response to oncological treatments has traditionally used single or multidirectional measurements of tumour dimensions following completion of therapy. Development of an MR imaging biomarker that would allow for early prediction of tumour response to therapeutic intervention would be a significant achievement as it could individualize clinical management of cancer patients in a timely fashion and improve outcome. This goal is very important as standard risk factors currently used in patient assessment cannot account for the variable and unpredictable treatment responses encountered by patients with similar risk profiles. This chapter will overview the use of diffusion-weighted MR imaging (DW-MRI) as a method of providing a potentially early surrogate marker of response to therapy in oncological imaging.