The purposes of this study were: 1) to show bone marrow (BM) functional heterogeneity, 2) to demo... more The purposes of this study were: 1) to show bone marrow (BM) functional heterogeneity, 2) to demonstrate site-dependent responses of BM to cancer treatment utilizing whole body FDG-PET/CT and 3) to identify correlations between FDG uptake in different bone sites and long term complete blood count (CBC). Thirty two patients who had pre- and post-treatment FDG-PET/CT scans were selected retrospectively. Each patient received either head and neck radiation for cancer of the tongue, or pelvic radiation for rectal or cervical cancer with chemotherapy. Patients had FDG-PET/CT performed prior to the first radiation therapy session and at least one FDG-PET/CT after completion of the prescribed radiation therapy. FDG uptake before radiotherapy was significantly different among bone regions (p < 0.01). This heterogeneity was felt to reflect site-dependent amounts of BM contents possibly due to structural and functional requirements. FDG uptake in the irradiated regions was significantly decreased on the first and second follow-ups after radiation. Feasibly, this could be due to a reduction in the number of active BM cells following intensive radiation in addition to concurrent chemotherapy. Overall, CBC significantly decreased after treatment. Correlation values of each hematological parameter with FDG uptake varied among skeletal regions and scan time points. FDG uptake in sacrum and lumbar regions had better correlation with white blood cells and neutrophils. Longitudinal FDG-PET revealed a regional functional heterogeneity of the BM site-dependent response to treatment. Patients experienced immediate and prolonged marrow metabolic damage that correlates with hematological parameters. FDG-PET/CT may provide additional capabilities to assess BM health.
Recent studies have proven that skeleton-wide functional assessment is essential to comprehensive... more Recent studies have proven that skeleton-wide functional assessment is essential to comprehensively understand physiological aspects of the skeletal system. Therefore, in contrast to regional imaging studies utilizing a multiple-animal holder (mouse hotel), we attempted to develop and characterize a multiple-mouse imaging system with micro-PET/CT for high-throughput whole-skeleton assessment. Using items found in a laboratory, a simple mouse hotel that houses four mice linked with gas anesthesia was constructed. A mouse-simulating phantom was used to measure uniformity in a cross sectional area and flatness (Amax/Amin*100) along the axial, radial and tangential directions, where Amax and Amin are maximum and minimum activity concentration in the profile, respectively. Fourteen mice were used for single- or multiple-micro-PET/CT scans. NaF uptake was measured at eight skeletal sites (skull to tibia). Skeletal (18)F activities measured with mice in the mouse hotel were within 1.6 ± 4% (mean ± standard deviation) of those measured with mice in the single-mouse holder. Single-holder scanning yields slightly better uniformity and flatness over the hotel. Compared to use of the single-mouse holder, scanning with the mouse hotel reduced study time (by 65%), decreased the number of scans (four-fold), reduced cost, required less computer storage space (40%), and maximized (18)F usage. The mouse hotel allows high-throughput, quantitatively equivalent scanning compared to the single-mouse holder for micro-PET/CT imaging for whole-skeleton assessment of mice.
To assess skeletal wide fracture location and time of fracture after cancer treatment Study Desig... more To assess skeletal wide fracture location and time of fracture after cancer treatment Study Design: One hundred thirty-nine women diagnosed with breast or gynecologic cancer between 2003 and 2012 that subsequently had a radiologic diagnosis of fracture were identified retrospectively using electronic medical records. RESULTS were compared with skeletal fracture pattern previously reported for a general population. Skeletal fractures in cancer patients occur throughout the entire skeleton similar to general population. The most common sites were vertebrae (16%), feet and toes (15%), ribs (12%), hands and fingers (10%), and pelvis (8%). Fracture incidence was observed starting within the first year of survivorship, and continued to after five years. The median time from cancer diagnosis to fracture varied by age (p<0.01), from a high of 3.2 years for ages 50-59 to a low of 1.2 years for patients older than 70. The pattern of skeletal fracture is similar between cancer survivor and general population. Contrary to general assumption, survivors can experience skeletal fracture early after cancer treatment, especially at an older age. Thus, cancer survivorship care should include assessment of early time points with improved management of cancer treatment related bone injury.
The objective of this study is to determine the optimal physical parameters of a rotating gantry ... more The objective of this study is to determine the optimal physical parameters of a rotating gantry micro-CT system to assess in vivo changes to the trabecular bone of mice. Magnification, binning, peak kilovoltage, beam filtration, and tissue thickness are examined on a commercially available micro-CT system. The X-ray source and detector geometry provides 1.3×, 1.8×, or 3.3× magnification. Binning is examined from no binning to 2 to 4. Energy is varied from 40 to 80 kVp in 10 kVp increments and filter thickness is increased from no filtration to 1.5 mmAl in 0.5 mmAl increments. Mice are imaged at different magnifications and binning combinations to evaluate changes to image quality and microstructure estimation. Increasing magnification from 1.3× to 3.3× and lowering binning from 4 to 1 varies the spatial resolution from 2.5 to 11.8 lp/mm. Increasing the beam energy or filtration thickness decreases Hounsfield unit (HU) estimation, with a maximum rate of change being -286 HU/kVp for 80 kVp. Images for murine trabecular bone are blurred at effective pixel sizes above 60 μm. By comparing resolution, signal-to-noise ratio, and radiation dose, we find that a 3.3× magnification, binning of 2.80 kVp beam with a 0.5 mmAl filter comprises the optimal parameters to evaluate murine trabecular bone for this rotating gantry micro-CT.
To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes ... more To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.
High-resolution large datasets were acquired to improve the understanding of murine bone physiolo... more High-resolution large datasets were acquired to improve the understanding of murine bone physiology. The purpose of this work is to present the challenges and solutions in segmenting and visualizing bone in such large datasets acquired using micro-CT scan of mice. The analyzed dataset is more than 50 GB in size with more than 6,000 2,048 × 2,048 slices. The study was performed to automatically measure the bone mineral density (BMD) of the entire skeleton. A global Renyi entropy (GREP) method was initially used for bone segmentation. This method consistently oversegmented skeletal region. A new method called adaptive local Renyi entropy (ALREP) is proposed to improve the segmentation results. To study the efficacy of the ALREP, manual segmentation was performed. Finally, a specialized high-end remote visualization system along with the software, VirtualGL, was used to perform remote rendering of this large dataset. It was determined that GREP overestimated the bone cross-section by around 30 % compared with ALREP. The manual segmentation process took 6,300 min for 6,300 slices while ALREP took only 150 min for segmentation. Automatic image processing with ALREP method may facilitate BMD measurement of the entire skeleton in a significantly reduced time, compared with manual process.
Cancer survivors are at an increased risk for fractures, but lack of effective and economical bio... more Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both…
The purposes of this study were: 1) to show bone marrow (BM) functional heterogeneity, 2) to demo... more The purposes of this study were: 1) to show bone marrow (BM) functional heterogeneity, 2) to demonstrate site-dependent responses of BM to cancer treatment utilizing whole body FDG-PET/CT and 3) to identify correlations between FDG uptake in different bone sites and long term complete blood count (CBC). Thirty two patients who had pre- and post-treatment FDG-PET/CT scans were selected retrospectively. Each patient received either head and neck radiation for cancer of the tongue, or pelvic radiation for rectal or cervical cancer with chemotherapy. Patients had FDG-PET/CT performed prior to the first radiation therapy session and at least one FDG-PET/CT after completion of the prescribed radiation therapy. FDG uptake before radiotherapy was significantly different among bone regions (p < 0.01). This heterogeneity was felt to reflect site-dependent amounts of BM contents possibly due to structural and functional requirements. FDG uptake in the irradiated regions was significantly decreased on the first and second follow-ups after radiation. Feasibly, this could be due to a reduction in the number of active BM cells following intensive radiation in addition to concurrent chemotherapy. Overall, CBC significantly decreased after treatment. Correlation values of each hematological parameter with FDG uptake varied among skeletal regions and scan time points. FDG uptake in sacrum and lumbar regions had better correlation with white blood cells and neutrophils. Longitudinal FDG-PET revealed a regional functional heterogeneity of the BM site-dependent response to treatment. Patients experienced immediate and prolonged marrow metabolic damage that correlates with hematological parameters. FDG-PET/CT may provide additional capabilities to assess BM health.
Recent studies have proven that skeleton-wide functional assessment is essential to comprehensive... more Recent studies have proven that skeleton-wide functional assessment is essential to comprehensively understand physiological aspects of the skeletal system. Therefore, in contrast to regional imaging studies utilizing a multiple-animal holder (mouse hotel), we attempted to develop and characterize a multiple-mouse imaging system with micro-PET/CT for high-throughput whole-skeleton assessment. Using items found in a laboratory, a simple mouse hotel that houses four mice linked with gas anesthesia was constructed. A mouse-simulating phantom was used to measure uniformity in a cross sectional area and flatness (Amax/Amin*100) along the axial, radial and tangential directions, where Amax and Amin are maximum and minimum activity concentration in the profile, respectively. Fourteen mice were used for single- or multiple-micro-PET/CT scans. NaF uptake was measured at eight skeletal sites (skull to tibia). Skeletal (18)F activities measured with mice in the mouse hotel were within 1.6 ± 4% (mean ± standard deviation) of those measured with mice in the single-mouse holder. Single-holder scanning yields slightly better uniformity and flatness over the hotel. Compared to use of the single-mouse holder, scanning with the mouse hotel reduced study time (by 65%), decreased the number of scans (four-fold), reduced cost, required less computer storage space (40%), and maximized (18)F usage. The mouse hotel allows high-throughput, quantitatively equivalent scanning compared to the single-mouse holder for micro-PET/CT imaging for whole-skeleton assessment of mice.
To assess skeletal wide fracture location and time of fracture after cancer treatment Study Desig... more To assess skeletal wide fracture location and time of fracture after cancer treatment Study Design: One hundred thirty-nine women diagnosed with breast or gynecologic cancer between 2003 and 2012 that subsequently had a radiologic diagnosis of fracture were identified retrospectively using electronic medical records. RESULTS were compared with skeletal fracture pattern previously reported for a general population. Skeletal fractures in cancer patients occur throughout the entire skeleton similar to general population. The most common sites were vertebrae (16%), feet and toes (15%), ribs (12%), hands and fingers (10%), and pelvis (8%). Fracture incidence was observed starting within the first year of survivorship, and continued to after five years. The median time from cancer diagnosis to fracture varied by age (p<0.01), from a high of 3.2 years for ages 50-59 to a low of 1.2 years for patients older than 70. The pattern of skeletal fracture is similar between cancer survivor and general population. Contrary to general assumption, survivors can experience skeletal fracture early after cancer treatment, especially at an older age. Thus, cancer survivorship care should include assessment of early time points with improved management of cancer treatment related bone injury.
The objective of this study is to determine the optimal physical parameters of a rotating gantry ... more The objective of this study is to determine the optimal physical parameters of a rotating gantry micro-CT system to assess in vivo changes to the trabecular bone of mice. Magnification, binning, peak kilovoltage, beam filtration, and tissue thickness are examined on a commercially available micro-CT system. The X-ray source and detector geometry provides 1.3×, 1.8×, or 3.3× magnification. Binning is examined from no binning to 2 to 4. Energy is varied from 40 to 80 kVp in 10 kVp increments and filter thickness is increased from no filtration to 1.5 mmAl in 0.5 mmAl increments. Mice are imaged at different magnifications and binning combinations to evaluate changes to image quality and microstructure estimation. Increasing magnification from 1.3× to 3.3× and lowering binning from 4 to 1 varies the spatial resolution from 2.5 to 11.8 lp/mm. Increasing the beam energy or filtration thickness decreases Hounsfield unit (HU) estimation, with a maximum rate of change being -286 HU/kVp for 80 kVp. Images for murine trabecular bone are blurred at effective pixel sizes above 60 μm. By comparing resolution, signal-to-noise ratio, and radiation dose, we find that a 3.3× magnification, binning of 2.80 kVp beam with a 0.5 mmAl filter comprises the optimal parameters to evaluate murine trabecular bone for this rotating gantry micro-CT.
To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes ... more To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.
High-resolution large datasets were acquired to improve the understanding of murine bone physiolo... more High-resolution large datasets were acquired to improve the understanding of murine bone physiology. The purpose of this work is to present the challenges and solutions in segmenting and visualizing bone in such large datasets acquired using micro-CT scan of mice. The analyzed dataset is more than 50 GB in size with more than 6,000 2,048 × 2,048 slices. The study was performed to automatically measure the bone mineral density (BMD) of the entire skeleton. A global Renyi entropy (GREP) method was initially used for bone segmentation. This method consistently oversegmented skeletal region. A new method called adaptive local Renyi entropy (ALREP) is proposed to improve the segmentation results. To study the efficacy of the ALREP, manual segmentation was performed. Finally, a specialized high-end remote visualization system along with the software, VirtualGL, was used to perform remote rendering of this large dataset. It was determined that GREP overestimated the bone cross-section by around 30 % compared with ALREP. The manual segmentation process took 6,300 min for 6,300 slices while ALREP took only 150 min for segmentation. Automatic image processing with ALREP method may facilitate BMD measurement of the entire skeleton in a significantly reduced time, compared with manual process.
Cancer survivors are at an increased risk for fractures, but lack of effective and economical bio... more Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both…
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