Publications by authors named "Susanta K Hui"

44 Publications

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

3-D Cell Culture Systems in Bone Marrow Tissue and Organoid Engineering, and BM Phantoms as In Vitro Models of Hematological Cancer Therapeutics-A Review.

Materials (Basel) 2020 Dec 9;13(24). Epub 2020 Dec 9.

Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.

We review the state-of-the-art in bone and marrow tissue engineering (BMTE) and hematological cancer tissue engineering (HCTE) in light of the recent interest in bone marrow environment and pathophysiology of hematological cancers. This review focuses on engineered BM tissue and organoids as in vitro models of hematological cancer therapeutics, along with identification of BM components and their integration as synthetically engineered BM mimetic scaffolds. In addition, the review details interaction dynamics of various BM and hematologic cancer (HC) cell types in co-culture systems of engineered BM tissues/phantoms as well as their relation to drug resistance and cytotoxicity. Interaction between hematological cancer cells and their niche, and the difference with respect to the healthy niche microenvironment narrated. Future perspectives of BMTE for in vitro disease models, BM regeneration and large scale ex vivo expansion of hematopoietic and mesenchymal stem cells for transplantation and therapy are explained. We conclude by overviewing the clinical application of biomaterials in BM and HC pathophysiology and its challenges and opportunities.
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http://dx.doi.org/10.3390/ma13245609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763362PMC
December 2020

Biophysical Characterization of the Leukemic Bone Marrow Vasculature Reveals Benefits of Neoadjuvant Low-Dose Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 01 22;109(1):60-72. Epub 2020 Aug 22.

Department of Radiation Oncology, City of Hope, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California. Electronic address:

Purpose: Although vascular alterations in solid tumor malignancies are known to decrease therapeutic delivery, the effects of leukemia-induced bone marrow vasculature (BMV) alterations on therapeutic delivery are not well known. Additionally, functional quantitative measurements of the leukemic BMV during chemotherapy and radiation therapy are limited, largely due to a lack of high-resolution imaging techniques available preclinically. This study develops a murine model using compartmental modeling for quantitative multiphoton microscopy (QMPM) to characterize the malignant BMV before and during treatment.

Methods And Materials: Using QMPM, live time-lapsed images of dextran leakage from the local BMV to the surrounding bone marrow of mice bearing acute lymphoblastic leukemia (ALL) were taken and fit to a 2-compartment model to measure the transfer rate (K), fractional extracellular extravascular space (ν), and vascular permeability parameters, as well as functional single-vessel characteristics. In response to leukemia-induced BMV alterations, the effects of 2 to 4 Gy low-dose radiation therapy (LDRT) on the BMV, drug delivery, and mouse survival were assessed post-treatment to determine whether neoadjuvant LDRT before chemotherapy improves treatment outcome.

Results: Mice bearing ALL had significantly altered K, increased ν, and increased permeability compared with healthy mice. Angiogenesis, decreased single-vessel perfusion, and decreased vessel diameter were observed. BMV alterations resulted in disease-dependent reductions in cellular uptake of Hoechst dye. LDRT to mice bearing ALL dilated BMV, increased single-vessel perfusion, and increased daunorubicin uptake by ALL cells. Consequently, LDRT administered to mice before receiving nilotinib significantly increased survival compared with mice receiving LDRT after nilotinib, demonstrating the importance of LDRT conditioning before therapeutic administration.

Conclusion: The developed QMPM enables single-platform assessments of the pharmacokinetics of fluorescent agents and characterization of the BMV. Initial results suggest BMV alterations after neoadjuvant LDRT may contribute to enhanced drug delivery and increased treatment efficacy for ALL. The developed QMPM enables observations of the BMV for use in ALL treatment optimization.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736317PMC
January 2021

Automated in vivo Assessment of Vascular Response to Radiation using a Hybrid Theranostic X-ray Irradiator/Fluorescence Molecular Imaging System.

IEEE Access 2020 15;8:93663-93670. Epub 2020 May 15.

Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010 USA.

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5±16.1% P=0.0405 Paired t-test n=4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P=0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.
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http://dx.doi.org/10.1109/access.2020.2994943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295127PMC
May 2020

ImmunoPET, [Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model.

Clin Cancer Res 2019 12 23;25(24):7463-7474. Epub 2019 Sep 23.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California.

Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.

Experimental Design: We evaluated whether [Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody-drug conjugate (ADC) and radioimmunotherapy (RIT).

Results: [Cu]Cu-DOTA-anti-CD33-based PET-CT imaging detected CD33 AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33 PET activity was significantly higher in specific skeletal niches [femur ( < 0.00001), tibia ( = 0.0001), humerus ( = 0.0014), and lumber spine ( < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC ( = 0.02) and [Ac]Ac-anti-CD33-RIT ( < 0.00001) significantly reduced disease burden over that of respective controls.

Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT-based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911626PMC
December 2019

SMC1A is associated with radioresistance in prostate cancer and acts by regulating epithelial-mesenchymal transition and cancer stem-like properties.

Mol Carcinog 2019 01 5;58(1):113-125. Epub 2018 Oct 5.

Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California.

Prostate cancer is one of the most commonly diagnosed cancers and a pressing health challenge in men worldwide. Radiation therapy (RT) is widely considered a standard therapy for advanced as well as localized prostate cancer. Although this primary therapy is associated with high cancer control rates, up to one-third of patients undergoing radiation therapy becomes radio-resistant and/or has tumor-relapse/recurrence. Therefore, focus on new molecular targets and pathways is essential to develop novel radio-sensitizing agents for the effective and safe treatment of prostate cancer. Here, we describe functional studies that were performed to investigate the role of structural maintenance of chromosome-1 (SMC1A) in radioresistance of metastatic prostate cancer cells. Short hairpin RNA (shRNA) was used to suppress SMC1A in metastatic castration-resistant prostate cancer cells, DU145 and PC3. Clonogenic survival assays, Western blot, RT-PCR, and γ-H2AX staining were used to assess the effect of SMC1A knockdown on radiation sensitivity of these prostate cancer cells. We demonstrate that SMC1A is overexpressed in human prostate tumors compared to the normal adjacent tissue. SMC1A knockdown limits the clonogenic potential, epithelial-mesenchymal transition (EMT), and cancer stem-like cell (CSC) properties of DU145 and PC3 cells and enhanced efficacy of RT in these cells. Targeted inhibition of SMC1A not only plays a critical role in overcoming radio-resistance in prostate cancer cells, but also suppresses self-renewal and the tumor-propagating potential of x-irradiated cancer cells. We propose that SMC1A could be a potential molecular target for the development of novel radio-sensitizing therapeutic agents for management of radio-resistant metastatic prostate cancer.
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http://dx.doi.org/10.1002/mc.22913DOI Listing
January 2019

Whole-Body Distribution of Leukemia and Functional Total Marrow Irradiation Based on FLT-PET and Dual-Energy CT.

Mol Imaging 2017 Jan-Dec;16:1536012117732203

2 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

This report describes a multimodal whole-body 3'-deoxy-3'[(18)F]-fluorothymidine positron emission tomography (FLT-PET) and dual-energy computed tomography (DECT) method to identify leukemia distribution within the bone marrow environment (BME) and to develop disease- and/or BME-specific radiation strategies. A control participant and a newly diagnosed patient with acute myeloid leukemia prior to induction chemotherapy were scanned with FLT-PET and DECT. The red marrow (RM) and yellow marrow (YM) of the BME were segmented from DECT using a basis material decomposition method. Functional total marrow irradiation (fTMI) treatment planning simulations were performed combining FLT-PET and DECT imaging to differentially target irradiation to the leukemia niche and the rest of the skeleton. Leukemia colonized both RM and YM regions, adheres to the cortical bone in the spine, and has enhanced activity in the proximal/distal femur, suggesting a potential association of leukemia with the BME. The planning target volume was reduced significantly in fTMI compared with conventional TMI. The dose to active disease (standardized uptake value >4) was increased by 2-fold, while maintaining doses to critical organs similar to those in conventional TMI. In conclusion, a hybrid system of functional-anatomical-physiological imaging can identify the spatial distribution of leukemia and will be useful to both help understand the leukemia niche and develop targeted radiation strategies.
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http://dx.doi.org/10.1177/1536012117732203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624344PMC
July 2018

Megavoltage 2D topographic imaging: An attractive alternative to megavoltage CT for the localization of breast cancer patients treated with TomoDirect.

Phys Med 2017 Jul 20;39:33-38. Epub 2017 Jun 20.

ICube-UMR 7357, Strasbourg, France.

Purpose: To show the usefulness of topographic 2D megavoltage images (MV2D) for the localization of breast cancer patients treated with TomoDirect (TD), a radiotherapy treatment technique with fixed-angle beams performed on a TomoTherapy system.

Methods: A method was developed to quickly localize breast cancer patients treated with TD by registering the MV2D images produced before a TD treatment with reference images reconstructed from a kilovoltage CT simulation scanner and by using the projection of the beam-eye-view TD treatment field. Dose and image quality measurements were performed to determine the optimal parameters for acquiring MV2D images. A TD treatment was simulated on a chest phantom equipped with a breast attachment. MVCT and MV2D images were performed for 7 different shifted positions of the phantom and registered by 10 different operators with the simulation kilovoltage CT images.

Results: Compared to MVCT, MV2D imaging reduces the dose by a factor of up to 45 and the acquisition time by a factor of up to 49. Comparing the registration shift values obtained for the phantom images obtained with MVCT in the coarse mode to those obtained with MV2D, the mean difference is 1.0±1.1mm, -1.1mm±1.1, and -0.1±2.2mm, respectively, in the lateral, longitudinal, and vertical directions.

Conclusions: With dual advantages (very fast imaging and a potentially reduced dose to the heart and contralateral organs), MV2D topographic images may be an attractive alternative to MVCT for the localization of breast cancer patients treated with TomoDirect.
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http://dx.doi.org/10.1016/j.ejmp.2017.06.015DOI Listing
July 2017

Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance.

PLoS Comput Biol 2017 Jul 6;13(7):e1005482. Epub 2017 Jul 6.

Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota, United States of America.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.
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http://dx.doi.org/10.1371/journal.pcbi.1005482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500007PMC
July 2017

Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density.

J Bone Miner Metab 2017 Jul 9;35(4):428-436. Epub 2016 Dec 9.

Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.

Temporal and spatial variations in bone marrow adipose tissue (MAT) can be indicative of several pathologies and confound current methods of assessing immediate changes in bone mineral remodeling. We present a novel dual-energy computed tomography (DECT) method to monitor MAT and marrow-corrected volumetric BMD (mcvBMD) throughout the body. Twenty-three cancellous skeletal sites in 20 adult female cadavers aged 40-80 years old were measured using DECT (80 and 140 kVp). vBMD was simultaneous recorded using QCT. MAT was further sampled using MRI. Thirteen lumbar vertebrae were then excised from the MRI-imaged donors and examined by microCT. After MAT correction throughout the skeleton, significant differences (p < 0.05) were found between QCT-derived vBMD and DECT-derived mcvBMD results. McvBMD was highly heterogeneous with a maximum at the posterior skull and minimum in the proximal humerus (574 and 0.7 mg/cc, respectively). BV/TV and BMC have a nearly significant correlation with mcvBMD (r = 0.545, p = 0.057 and r = 0.539, p = 0.061, respectively). MAT assessed by DECT showed a significant correlation with MRI MAT results (r = 0.881, p < 0.0001). Both DECT- and MRI-derived MAT had a significant influence on uncorrected vBMD (r = -0.86 and r = -0.818, p ≤ 0.0001, respectively). Conversely, mcvBMD had no correlation with DECT- or MRI-derived MAT (r = 0.261 and r = 0.067). DECT can be used to assess MAT while simultaneously collecting mcvBMD values at each skeletal site. MAT is heterogeneous throughout the skeleton, highly variable, and should be accounted for in longitudinal mcvBMD studies. McvBMD accurately reflects the calcified tissue in cancellous bone.
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http://dx.doi.org/10.1007/s00774-016-0796-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689468PMC
July 2017

Fast Megavoltage Computed Tomography: A Rapid Imaging Method for Total Body or Marrow Irradiation in Helical Tomotherapy.

Int J Radiat Oncol Biol Phys 2016 11 6;96(3):688-95. Epub 2016 Jul 6.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota; Department of Radiation Oncology and Beckman Research Institute, City of Hope, Duarte, California. Electronic address:

Purpose: Megavoltage computed tomographic (MVCT) imaging has been widely used for the 3-dimensional (3-D) setup of patients treated with helical tomotherapy (HT). One drawback of MVCT is its very long imaging time, the result of slow couch speeds of approximately 1 mm/s, which can be difficult for the patient to tolerate. We sought to develop an MVCT imaging method allowing faster couch speeds and to assess its accuracy for image guidance for HT.

Methods And Materials: Three cadavers were scanned 4 times with couch speeds of 1, 2, 3, and 4 mm/s. The resulting MVCT images were reconstructed using an iterative reconstruction (IR) algorithm with a penalty term of total variation and with a conventional filtered back projection (FBP) algorithm. The MVCT images were registered with kilovoltage CT images, and the registration errors from the 2 reconstruction algorithms were compared. This fast MVCT imaging was tested in 3 cases of total marrow irradiation as a clinical trial.

Results: The 3-D registration errors of the MVCT images reconstructed with the IR algorithm were smaller than the errors of images reconstructed with the FBP algorithm at fast couch speeds (2, 3, 4 mm/s). The scan time and imaging dose at a speed of 4 mm/s were reduced to 30% of those from a conventional coarse mode scan. For the patient imaging, faster MVCT (3 mm/s couch speed) scanning reduced the imaging time and still generated images useful for anatomic registration.

Conclusions: Fast MVCT with the IR algorithm is clinically feasible for large 3-D target localization, which may reduce the overall time for the treatment procedure. This technique may also be useful for calculating daily dose distributions or organ motion analyses in HT treatment over a wide area. Automated integration of this imaging is at least needed to further assess its clinical benefits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081222PMC
http://dx.doi.org/10.1016/j.ijrobp.2016.06.2458DOI Listing
November 2016

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography.

Int J Radiat Oncol Biol Phys 2016 11 6;96(3):679-87. Epub 2016 Jul 6.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota; Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, California. Electronic address:

Purpose: To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition.

Methods And Materials: Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton.

Results: A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI).

Conclusions: Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081224PMC
http://dx.doi.org/10.1016/j.ijrobp.2016.06.2459DOI Listing
November 2016

A mathematical model of tumor growth and its response to single irradiation.

Theor Biol Med Model 2016 Feb 27;13. Epub 2016 Feb 27.

Department of Radiation Oncology, University of Minnesota, 420 Delaware St.SE, MMC-494, Minneapolis, MN, 55455, USA.

Background: Mathematical modeling of biological processes is widely used to enhance quantitative understanding of bio-medical phenomena. This quantitative knowledge can be applied in both clinical and experimental settings. Recently, many investigators began studying mathematical models of tumor response to radiation therapy. We developed a simple mathematical model to simulate the growth of tumor volume and its response to a single fraction of high dose irradiation. The modelling study may provide clinicians important insights on radiation therapy strategies through identification of biological factors significantly influencing the treatment effectiveness.

Methods: We made several key assumptions of the model. Tumor volume is composed of proliferating (or dividing) cancer cells and non-dividing (or dead) cells. Tumor growth rate (or tumor volume doubling time) is proportional to the ratio of the volumes of tumor vasculature and the tumor. The vascular volume grows slower than the tumor by introducing the vascular growth retardation factor, θ. Upon irradiation, the proliferating cells gradually die over a fixed time period after irradiation. Dead cells are cleared away with cell clearance time. The model was applied to simulate pre-treatment growth and post-treatment radiation response of rat rhabdomyosarcoma tumors and metastatic brain tumors of five patients who were treated with Gamma Knife stereotactic radiosurgery (GKSRS).

Results: By selecting appropriate model parameters, we showed the temporal variation of the tumors for both the rat experiment and the clinical GKSRS cases could be easily replicated by the simple model. Additionally, the application of our model to the GKSRS cases showed that the α-value, which is an indicator of radiation sensitivity in the LQ model, and the value of θ could be predictors of the post-treatment volume change.

Conclusions: The proposed model was successful in representing both the animal experimental data and the clinically observed tumor volume changes. We showed that the model can be used to find the potential biological parameters, which may be able to predict the treatment outcome. However, there is a large statistical uncertainty of the result due to the small sample size. Therefore, a future clinical study with a larger number of patients is needed to confirm the finding.
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http://dx.doi.org/10.1186/s12976-016-0032-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769590PMC
February 2016

Characterization of an orthovoltage biological irradiator used for radiobiological research.

J Radiat Res 2015 May 17;56(3):485-92. Epub 2015 Feb 17.

Department of Radiation Oncology, University of Minnesota, 420 Delaware Street, SE MMC 494, Minneapolis, MN 55455, USA

Orthovoltage irradiators are routinely used to irradiate specimens and small animals in biological research. There are several reports on the characteristics of these units for small field irradiations. However, there is limited knowledge about use of these units for large fields, which are essential for emerging large-field irregular shape irradiations, namely total marrow irradiation used as a conditioning regimen for hematological malignancies. This work describes characterization of a self-contained Orthovoltage biological irradiator for large fields using measurements and Monte Carlo simulations that could be used to compute the dose for in vivo or in vitro studies for large-field irradiation using this or a similar unit. Percentage depth dose, profiles, scatter factors, and half-value layers were measured and analyzed. A Monte Carlo model of the unit was created and used to generate depth dose and profiles, as well as scatter factors. An ion chamber array was also used for profile measurements of flatness and symmetry. The output was determined according to AAPM Task Group 61 guidelines. The depth dose measurements compare well with published data for similar beams. The Monte Carlo-generated depth dose and profiles match our measured doses to within 2%. Scatter factor measurements indicate gradual variation of these factors with field size. Dose rate measured by placing the ion chamber atop the unit's steel plate or solid water indicate enhanced readings of 5 to 28% compared with those measured in air. The stability of output over a 5-year period is within 2% of the 5-year average.
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http://dx.doi.org/10.1093/jrr/rru129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426923PMC
May 2015

Spatial and temporal fracture pattern in breast and gynecologic cancer survivors.

J Cancer 2015 1;6(1):66-9. Epub 2015 Jan 1.

2. Masonic Cancer Center, University of Minnesota, Minneapolis; ; 3. Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis;

Objective(s): 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.7150/jca.10288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278916PMC
January 2015

A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients.

Bone 2015 Apr 20;73:90-7. Epub 2014 Dec 20.

Masonic Cancer Center, University of Minnesota, MN, USA; Department of Medicine, University of Minnesota, MN, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.
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http://dx.doi.org/10.1016/j.bone.2014.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336831PMC
April 2015

Multi-institutional feasibility study of a fast patient localization method in total marrow irradiation with helical tomotherapy: a global health initiative by the international consortium of total marrow irradiation.

Int J Radiat Oncol Biol Phys 2015 Jan 30;91(1):30-8. Epub 2014 Oct 30.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: To develop, characterize, and implement a fast patient localization method for total marrow irradiation.

Methods And Materials: Topographic images were acquired using megavoltage computed tomography (MVCT) detector data by delivering static orthogonal beams while the couch traversed through the gantry. Geometric and detector response corrections were performed to generate a megavoltage topogram (MVtopo). We also generated kilovoltage topograms (kVtopo) from the projection data of 3-dimensional CT images to reproduce the same geometry as helical tomotherapy. The MVtopo imaging dose and the optimal image acquisition parameters were investigated. A multi-institutional phantom study was performed to verify the image registration uncertainty. Forty-five MVtopo images were acquired and analyzed with in-house image registration software.

Results: The smallest jaw size (front and backup jaws of 0) provided the best image contrast and longitudinal resolution. Couch velocity did not affect the image quality or geometric accuracy. The MVtopo dose was less than the MVCT dose. The image registration uncertainty from the multi-institutional study was within 2.8 mm. In patient localization, the differences in calculated couch shift between the registration with MVtopo-kVtopo and MVCT-kVCT images in lateral, cranial-caudal, and vertical directions were 2.2 ± 1.7 mm, 2.6 ± 1.4 mm, and 2.7 ± 1.1 mm, respectively. The imaging time in MVtopo acquisition at the couch speed of 3 cm/s was <1 minute, compared with ≥15 minutes in MVCT for all patients.

Conclusion: Whole-body MVtopo imaging could be an effective alternative to time-consuming MVCT for total marrow irradiation patient localization.
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http://dx.doi.org/10.1016/j.ijrobp.2014.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385424PMC
January 2015

Radiation response of mesenchymal stem cells derived from bone marrow and human pluripotent stem cells.

J Radiat Res 2015 Mar 24;56(2):269-77. Epub 2014 Nov 24.

Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 494, Minneapolis, MN 55455, USA Department of Therapeutic Radiology, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 494, Minneapolis, MN 55455, USA

Mesenchymal stem cells (MSCs) isolated from human pluripotent stem cells are comparable with bone marrow-derived MSCs in their function and immunophenotype. The purpose of this exploratory study was comparative evaluation of the radiation responses of mesenchymal stem cells derived from bone marrow- (BMMSCs) and from human embryonic stem cells (hESMSCs). BMMSCs and hESMSCs were irradiated at 0 Gy (control) to 16 Gy using a linear accelerator commonly used for cancer treatment. Cells were harvested immediately after irradiation, and at 1 and 5 days after irradiation. Cell cycle analysis, colony forming ability (CFU-F), differentiation ability, and expression of osteogenic-specific runt-related transcription factor 2 (RUNX2), adipogenic peroxisome proliferator-activated receptor gamma (PPARγ), oxidative stress-specific dismutase-1 (SOD1) and Glutathione peroxidase (GPX1) were analyzed. Irradiation arrested cell cycle progression in BMMSCs and hESMSCs. Colony formation ability of irradiated MSCs decreased in a dose-dependent manner. Irradiated hESMSCs showed higher adipogenic differentiation compared with BMMSCs, together with an increase in the adipogenic PPARγ expression. PPARγ expression was upregulated as early as 4 h after irradiation, along with the expression of SOD1. More than 70% downregulation was found in Wnt3A, Wnt4, Wnt 7A, Wnt10A and Wnt11 in BMMSCs, but not in hESMSCs. hESMSCs are highly proliferative but radiosensitive compared with BMMSCs. Increased PPARγ expression relative to RUNX2 and downregulation of Wnt ligands in irradiated MSCs suggest Wnt mediated the fate determination of irradiated MSCs.
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http://dx.doi.org/10.1093/jrr/rru098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380046PMC
March 2015

Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction.

Cell Metab 2014 Aug 3;20(2):368-375. Epub 2014 Jul 3.

Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.
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http://dx.doi.org/10.1016/j.cmet.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126847PMC
August 2014

High-throughput multiple-mouse imaging with micro-PET/CT for whole-skeleton assessment.

Phys Med 2014 Nov 3;30(7):849-53. Epub 2014 Jul 3.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, MN, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmp.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252880PMC
November 2014

A dual-radioisotope hybrid whole-body micro-positron emission tomography/computed tomography system reveals functional heterogeneity and early local and systemic changes following targeted radiation to the murine caudal skeleton.

Calcif Tissue Int 2014 May 23;94(5):544-52. Epub 2014 Feb 23.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

The purpose of this study was to develop a longitudinal non-invasive functional imaging method using a dual-radioisotope hybrid micro-positron emission tomography/computed tomography (PET/CT) scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p < 0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation, which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p < 0.0001) decreased FDG uptake but increased NaF uptake (p = 0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p < 0.01). Non-invasive longitudinal imaging with dual-radioisotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function at local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer-term studies to clarify the effects of radiation on marrow and bone.
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http://dx.doi.org/10.1007/s00223-014-9839-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987955PMC
May 2014

Fast, simple, and informative patient-specific dose verification method for intensity modulated total marrow irradiation with helical tomotherapy.

Radiat Oncol 2014 Jan 25;9:34. Epub 2014 Jan 25.

Masonic Cancer Center, University of Minnesota, 424 Harvard Street SE, Minneapolis 55455, MN, USA.

Background: Patient-specific dose verification for treatment planning in helical tomotherapy is routinely performed using a homogeneous virtual water cylindrical phantom of 30 cm diameter and 18 cm length (Cheese phantom). Because of this small length, treatment with total marrow irradiation (TMI) requires multiple deliveries of the dose verification procedures to cover a wide range of the target volumes, which significantly prolongs the dose verification process. We propose a fast, simple, and informative patient-specific dose verification method which reduce dose verification time for TMI with helical tomotherapy.

Methods: We constructed a two-step solid water slab phantom (length 110 cm, height 8 cm, and two-step width of 30 cm and 15 cm), termed the Whole Body Phantom (WB phantom). Three ionization chambers and three EDR-2 films can be inserted to cover extended field TMI treatment delivery. Three TMI treatment plans were conducted with a TomoTherapy HiArt Planning Station and verified using the WB phantom with ion chambers and films. Three regions simulating the head and neck, thorax, and pelvis were covered in a single treatment delivery. The results were compared to those with the cheese phantom supplied by Accuray, Inc. following three treatment deliveries to cover the body from head to pelvis.

Results: Use of the WB phantom provided point doses or dose distributions from head and neck to femur in a single treatment delivery of TMI. Patient-specific dose verification with the WB phantom was 62% faster than with the cheese phantom. The average pass rate in gamma analysis with the criteria of a 3-mm distance-to-agreement and 3% dose differences was 94% ± 2% for the three TMI treatment plans. The differences in pass rates between the WB and cheese phantoms at the upper thorax to abdomen regions were within 2%. The calculated dose agreed with the measured dose within 3% for all points in all five cases in both the WB and cheese phantoms.

Conclusions: Our dose verification method with the WB phantom provides simple and rapid quality assurance without limiting dose verification information in total marrow irradiation with helical tomotherapy.
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http://dx.doi.org/10.1186/1748-717X-9-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922911PMC
January 2014

Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish.

PLoS One 2013 18;8(9):e73745. Epub 2013 Sep 18.

Department of Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota Medical School, Minneapolis, Minnesota.

Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT). In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20 Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2) in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p ≤ 0.0001), and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b -/- zebrafish, (odysseus), cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI), Total body irradiation (TBI), SDF-1, Zebrafish, hematopoietic cell transplant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776794PMC
June 2014

Peripheral dose heterogeneity due to the thread effect in total marrow irradiation with helical tomotherapy.

Int J Radiat Oncol Biol Phys 2013 Nov 5;87(4):832-9. Epub 2013 Sep 5.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

Purpose: To report potential dose heterogeneity leading to underdosing at different skeletal sites in total marrow irradiation (TMI) with helical tomotherapy due to the thread effect and provide possible solutions to reduce this effect.

Methods And Materials: Nine cases were divided into 2 groups based on patient size, defined as maximum left-to-right arm distance (mLRD): small mLRD (≤47 cm) and large mLRD (>47 cm). TMI treatment planning was conducted by varying the pitch and modulation factor while a jaw size (5 cm) was kept fixed. Ripple amplitude, defined as the peak-to-trough dose relative to the average dose due to the thread effect, and the dose-volume histogram (DVH) parameters for 9 cases with various mLRD was analyzed in different skeletal regions at off-axis (eg, bones of the arm or femur), at the central axis (eg, vertebrae), and planning target volume (PTV), defined as the entire skeleton plus 1-cm margin.

Results: Average ripple amplitude for a pitch of 0.430, known as one of the magic pitches that reduce thread effect, was 9.2% at 20 cm off-axis. No significant differences in DVH parameters of PTV, vertebrae, or femur were observed between small and large mLRD groups for a pitch of ≤0.287. Conversely, in the bones of the arm, average differences in the volume receiving 95% and 107% dose (V95 and V107, respectively) between large and small mLRD groups were 4.2% (P=.016) and 16% (P=.016), respectively. Strong correlations were found between mLRD and ripple amplitude (rs=.965), mLRD and V95 (rs=-.742), and mLRD and V107 (rs=.870) of bones of the arm.

Conclusions: Thread effect significantly influences DVH parameters in the bones of the arm for large mLRD patients. By implementing a favorable pitch value and adjusting arm position, peripheral dose heterogeneity could be reduced.
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http://dx.doi.org/10.1016/j.ijrobp.2013.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805769PMC
November 2013

Impact of very long time output variation in the treatment of total marrow irradiation with helical tomotherapy.

Radiat Oncol 2013 May 20;8:123. Epub 2013 May 20.

Masonic Cancer Center, University of Minnesota, 424 Harvard Street SE, Minneapolis, MN 55455, USA.

Background: Beam-on time in Total Marrow Irradiation (TMI) delivery with helical tomotherapy is more than 30 minutes. The purpose of this study was to investigate extended time output variation in tomotherapy machine without dose servo system and its impact on the dosimetry of TMI planning.

Materials And Methods: The calibration procedures with 1800 seconds delivery were conducted. The slab and cylindrical phantoms were used for static and rotational output variation measurements, respectively. All measurements were performed in 0.1 second interval with an Exradin A1SL ionization chamber (Standard Imaging Inc., Madison, WI, USA) connected to the tomoelectrometer supplied by the manufacture. Simulated TMI treatment planning with a slab phantom was delivered and verified with ion chamber and EDR-2 films.

Results: The static output variations during 30 min averaged -2.9% ± 0.2%, -3.4% ± 0.3%, and -3.4% ± 0.3% at 10 min, 20 min, and 30 min, respectively. The rotational output variations from start averaged -2.5% ± 0.7%, -3.1% ± 0.7%, and -3.5% ± 0.8% at 10 min, 20 min, and 30 min, respectively. The maximum output variation was up to 4.5%. In a TMI planning model, in which beam-on time was over 30 min, planned dose and dose measured with ion chambers in both cranial and caudal sides agreed within 3%. Film measurements in cranial and caudal sides also showed the pass rates of 97.7% and 92.2% with the criteria of 3 mm/3% in gamma analysis.

Conclusion: These results suggest that long TMI delivery by helical tomotherapy, even without dose servo system, does not pose a risk for significant deviations from the original treatment plan regardless of the output variation. However, very long time output variation should be checked before the first treatment.
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http://dx.doi.org/10.1186/1748-717X-8-123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679448PMC
May 2013

Calcium isolation from large-volume human urine samples for 41Ca analysis by accelerator mass spectrometry.

Appl Radiat Isot 2013 Aug 17;78:57-61. Epub 2013 Apr 17.

Argonne National Laboratory, 9700 South Cass Avenue, Lemont, IL 60439, USA.

Calcium oxalate precipitation is the first step in preparation of biological samples for (41)Ca analysis by accelerator mass spectrometry. A simplified protocol for large-volume human urine samples was characterized, with statistically significant increases in ion current and decreases in interference. This large-volume assay minimizes cost and effort and maximizes time after (41)Ca administration during which human samples, collected over a lifetime, provide (41)Ca:Ca ratios that are significantly above background.
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http://dx.doi.org/10.1016/j.apradiso.2013.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089085PMC
August 2013

The influence of therapeutic radiation on the patterns of bone remodeling in ovary-intact and ovariectomized mice.

Calcif Tissue Int 2013 Apr 12;92(4):372-84. Epub 2013 Jan 12.

Department of Therapeutic Radiology, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 494, Minneapolis, MN 55455, USA.

Our purpose was to characterize changes in bone remodeling associated with localized radiation that models therapeutic cancer treatment in ovary-intact (I) and ovariectomized (OVX) mice and to evaluate the influence of radiation on the pattern of bone mineral remodeling. Young adult, female BALB/c mice, I and OVX, were used (n = 71). All mice were intravenously injected with 15 μCi (45)Ca. Thirty days post-(45)Ca administration, the hind limbs of 17 mice were exposed to a single dose of 16 Gy radiation (R). The time course of (45)Ca excretion, serum CTx and osteocalcin markers, and cancellous bone volume fraction (BV/TV) and cortical thickness (Ct.Th) of the distal femur were assayed. Cellular activity and dynamic histomorphometry were performed. Irradiation resulted in rapid increases in fecal (45)Ca excretion compared to control groups, indicating increased bone remodeling. CTx increased rapidly after irradiation, followed by an increase in osteocalcin concentration. BV/TV decreased in the I mice following irradiation. Ct.Th increased in the OVX groups following irradiation. I+R mice exhibited diminished osteoblast surface, osteoclast number, and mineral apposition. Our murine model showed the systemic effects (via (45)Ca excretion) and local effects (via bone microarchitecture and surface activity) of clinically relevant, therapeutic radiation exposure. The I and OVX murine models have similar (45)Ca excretion but different bone microarchitectural responses. The (45)Ca assay effectively indicates the onset and rate of systemic bone mineral remodeling, providing real-time assessment of changes in bone histomorphometric parameters. Monitoring bone health via a bone mineral marker may help to identify the appropriate time for clinical intervention to preserve skeletal integrity.
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http://dx.doi.org/10.1007/s00223-012-9688-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595353PMC
April 2013

Prevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate.

PLoS One 2012 5;7(10):e46915. Epub 2012 Oct 5.

Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046915PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465278PMC
April 2013

The influence of therapeutic radiation on the patterns of bone marrow in ovary-intact and ovariectomized mice.

PLoS One 2012 6;7(8):e42668. Epub 2012 Aug 6.

Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America.

Background: The functional components of bone marrow (i.e., the hematopoietic and stromal populations) and the adjacent bone have traditionally been evaluated incompletely as distinct entities rather than the integrated system. We perturbed this system in vivo using a medically relevant radiation model in the presence or absence of ovarian function to understand integrated tissue interaction.

Methodology/principal Findings: Ovary-intact and ovariectomized mice underwent either no radiation or single fractional 16 Gy radiation to the caudal skeleton (I ± R, OVX ± R). Marrow fat, hematopoietic cellularity, and cancellous bone volume fraction (BV/TV %) were assessed. Ovariectomy alone did not significantly reduce marrow cellularity in non-irradiated mice (OVX-R vs. I-R, p = 0.8445) after 30 days; however it impaired the hematopoietic recovery of marrow following radiation exposure (OVX+R vs. I+R, p = 0.0092). The combination of radiation and OVX dramatically increases marrow fat compared to either factor alone (p = 0.0062). The synergistic effect was also apparent in the reduction of hematopoietic marrow cellularity (p = 0.0661); however it was absent in BV/TV% changes (p = 0.2520). The expected inverse relationship between marrow adiposity vs. hematopoietic cellularity and bone volume was observed. Interestingly compared with OVX mice, intact mice demonstrated double the reduction in hematopoietic cellularity and a tenfold greater degree of bone loss for a given unit of expansion in marrow fat.

Conclusions/significance: Ovariectomy prior to delivery of a clinically-relevant focal radiation exposure in mice, exacerbated post-radiation adipose accumulation in the marrow space but blunted bone loss and hematopoietic suppression. In the normally coupled homeostatic relationship between the bone and marrow domains, OVX appears to alter feedback mechanisms. Confirmation of this non-linear phenomenon (presumably due to differential radiosensitivity) and demonstration of the mechanism of action is needed to provide strategies to diminish the effect of radiation on exposed tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412808PMC
January 2013

Regulatory pathways associated with bone loss and bone marrow adiposity caused by aging, chemotherapy, glucocorticoid therapy and radiotherapy.

Am J Stem Cells 2012 30;1(3):205-24. Epub 2012 Nov 30.

Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia Adelaide, SA 5001, Australia.

The bone marrow is a complex environment that houses haematopoietic and mesenchymal cell populations and regulates bone turnover throughout life. The high proliferative capacity of these cell populations however, makes them susceptible to damage and injury, altering the steady-state of the bone marrow environment. Following cancer chemotherapy, irradiation and long-term glucocorticoid use, reduced bone and increased fat formation of marrow stromal progenitor cells results in a fatty marrow cavity, reduced bone mass and increased fracture risk. These bone and marrow defects are also observed in age-related complications such as estrogen deficiency and increased oxidative stress. Although the underlying mechanisms are yet to be clarified, recent investigations have suggested a switch in lineage commitment of bone marrow mesenchymal stem cells down the adipogenic lineage at the expense of osteogenic differentiation following such stress or injury. The Wnt/β-catenin signalling pathway is however has been recognized the key mechanism regulating stromal commitment, and its involvement in the osteogenic and adipogenic lineage commitment switch under the damaging conditions has been of great interest. This article reviews the effects of various types of stress or injury on the commitment to the adipogenic and osteogenic lineages of bone marrow stromal progenitor cells, and summarizes the roles of the Wnt/β-catenin and associated signalling pathways in the lineage commitment, switch, and recovery after damage, and as a therapeutic target.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636730PMC
May 2013
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