Targeted In Vivo Delivery of NF-κB Decoy Inhibitor Augments Sensitivity of B Cell Lymphoma to Therapy.

Despite recent advances, non-Hodgkin's B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) targeting Toll-like receptor-9-expressing B cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B cell (U2932, OCI-Ly3), Burkitt (RaJi), and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3-Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B cell lymphoma.

Total marrow and total lymphoid irradiation in bone marrow transplantation for acute leukaemia.

The use of total body irradiation as part of conditioning regimens for acute leukaemia is progressively declining because of concerns of late toxic effects and the introduction of radiation-free regimens. Total marrow irradiation and total marrow and lymphoid irradiation represent more targeted forms of radiotherapy compared with total body irradiation that have the potential to decrease toxicity and escalate the dose to the bone marrow for high-risk patients. We review the technological basis and the clinical development of total marrow irradiation and total marrow and lymphoid irradiation, highlighting both the possible advantages as well as the current roadblocks for widespread implementation among transplantation units. The exact role of total marrow irradiation or total marrow and lymphoid irradiation in new conditioning regimens seems dependent on its technological implementation, aiming to make the whole procedure less time consuming, more streamlined, and easier to integrate into the clinical workflow. We also foresee a role for computer-assisted planning, as a way to improve planning and delivery and to incorporate total marrow irradiation and total marrow and lymphoid irradiation in multi-centric phase 2-3 trials.

Long-Term Outcomes of Patients with Acute Myelogenous Leukemia Treated with Myeloablative Fractionated Total Body Irradiation TBI-Based Conditioning with a Tacrolimus- and Sirolimus-Based Graft-versus-Host Disease Prophylaxis Regimen: 6-Year Follow-Up from a Single Center.

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens.

Copper 64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma.

As a growing number of patients with multiple myeloma (MM) respond to upfront therapies while eventually relapsing in a time frame that is often unpredictable, attention has increasingly focused on developing novel diagnostic criteria to also account for disease dissemination. Positron emission tomography/computed tomography (PET/CT) is often used as a noninvasive monitoring strategy to assess cancer cell dissemination, but because the uptake of the currently used radiotracer 18fluorodeoxyglucose (18F-FDG) is a function of the metabolic activity of both malignant and nonmalignant cells, the results frequently lack sufficient specificity. Radiolabeled antibodies targeting MM tissue may detect disease irrespective of cell metabolism. Hence, we conjugated the clinically significant CD38-directed human antibody daratumumab (Darzalex [Dara]) to the DOTA chelator and labeled it with the positron-emitting radionuclide copper 64 (64Cu; 64Cu-DOTA-Dara). Here, we show that 64Cu-DOTA-Dara can efficiently bind CD38 on the surface of MM cells and was mainly detected in the bones associated with tumor in a MM murine model. We also show that PET/CT based on 64Cu-DOTA-Dara displays a higher resolution and specificity to detect MM cell dissemination than does 18F-FDG PET/CT and was even more sensitive than were bioluminescence signals. We therefore have supporting evidence for using 64Cu-DOTA-Dara as a novel imaging agent for MM.

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

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.

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

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.

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

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.

Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Patients with refractory leukemia or minimal residual disease (MRD) at transplantation are at increased risk of relapse. Augmentation of irradiation, especially to sites of disease (ie, bone marrow) is one potential strategy for overcoming this risk. We studied the feasibility of radiation dose escalation in high-risk patients using total marrow irradiation (TMI) in a phase I dose-escalation trial. Four pediatric and 8 adult patients received conditioning with cyclophosphamide and fludarabine in conjunction with image-guided radiation to the bone marrow at 15 Gy and 18 Gy (in 3-Gy fractions), while maintaining the total body irradiation (TBI) dose to the vital organs (lungs, hearts, eyes, liver, and kidneys) at <13.2 Gy. The biologically effective dose of TMI delivered to the bone marrow was increased by 62% at 15 Gy and by 96% at 18 Gy compared with standard TBI. Although excessive dose-limiting toxicity, defined by graft failure or excessive specific organ toxicity, was not encountered, 3 of 6 patients experienced treatment-related mortality at 18 Gy. Thus, we halted enrollment at this dose level and treated an additional 4 patients at 15 Gy. The 1- year overall survival was 42% (95% confidence interval [CI], 15%-67%) and disease-free survival was 22% (95% CI, 4%-49%). The rate of relapse was 36% (95% CI, 10%-62%), and nonrelapse mortality was 42% (95% CI, 14%-70%). This study shows that TMI dose escalation to 15 Gy is feasible with acceptable toxicity in pediatric and adult patients with high-risk leukemia undergoing umbilical cord blood and sibling donor transplantation.

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

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.

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

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.

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.

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.

A review of low dose interleukin-2 therapy in management of chronic graft-versus-host-disease.

INTRODUCTION: Patients with chronic graft versus host disease (cGVHD) have low circulating regulatory T cells (Tregs). Interleukin-2(IL-2) is a growth factor for Tregs, and clinical trials have explored its use in cGVHD patients. AREAS COVERED: Here we will discuss the biology of IL-2, its rationale for use and results of clinical trials in cGVHD. We also describe its mechanisms of action and alteration in gene expression in T-cell subsets after treatment with low dose IL-2 and photopheresis. EXPERT OPINION: Clinical trials using Low dose IL-2 have been done at single centers in small patient series. The majority of the clinical responses seen with IL-2 in cGVHD are classified as partial responses and efficacy as a single agent is limited. Compared to currently approved oral therapies, it has to be administered subcutaneously and requires specialized processing for compounding and storage limiting its widespread use. Its use is associated with constitutional symptoms and local injection site reactions. Local reactions can be easily managed by supportive care practices like rotation of injection sites and premeditations, constitutional symptoms resolve with, dose reduction (25-50%) allowing for continued therapy. Additional studies are needed to define optimal combination strategies with approved agents. Longer acting formulations of IL-2 that require less frequent dosing may also improve patient compliance.

Exploring Automated Contouring Across Institutional Boundaries: A Deep Learning Approach with Mouse Micro-CT Datasets.

Image-guided mouse irradiation is essential to understand interventions involving radiation prior to human studies. Our objective is to employ Swin UNEt Transformers (Swin UNETR) to segment native micro-CT and contrast-enhanced micro-CT scans and benchmark the results against 3D no-new-Net (nnU-Net). Swin UNETR reformulates mouse organ segmentation as a sequence-to-sequence prediction task, using a hierarchical Swin Transformer encoder to extract features at 5 resolution levels, and connects to a Fully Convolutional Neural Network (FCNN)-based decoder via skip connections. The models were trained and evaluated on open datasets, with data separation based on individual mice. Further evaluation on an external mouse dataset acquired on a different micro-CT with lower kVp and higher imaging noise was also employed to assess model robustness and generalizability. Results indicate that Swin UNETR consistently outperforms nnU-Net and AIMOS in terms of average dice similarity coefficient (DSC) and Hausdorff distance (HD95p), except in two mice of intestine contouring. This superior performance is especially evident in the external dataset, confirming the model's robustness to variations in imaging conditions, including noise and quality, thereby positioning Swin UNETR as a highly generalizable and efficient tool for automated contouring in pre-clinical workflows.

Comparison of IL-2-antibody to IL-2-Fc with or without stereotactic radiation therapy in CEA immunocompetent mice with CEA positive tumors.

BACKGROUND: The potent immune effects of interleukin-2 (IL-2) for cancer therapy can be increased by genetic fusion of IL-2 to the Fc domain of an antibody (IL-2-Fc) or tumor targeted by genetic fusion to a whole antibody known as an immunocytokine (ICK). METHODS: An anti-CEA ICK (M5A-IL-2) was compared to an IL-2-Fc fusion protein using tumor therapy and PET imaging in CEA transgenic immunocompetent mice bearing CEA positive colon or breast tumors. Combination with stereotactic radiation therapy (SRT) was performed with either ICK or IL-2-Fc. RESULTS: ICK and IL-2-Fc had comparable antitumor effects in both tumor models, although ICK had higher tumor uptake and slower blood clearance than an IL-2-Fc. Analysis of IFNγ+ /CD8+ and FoxP3+ /CD4+ T cells revealed higher levels of IFNγ-producing CD8+ T cells in ICK treated mice versus more efficient Treg elimination in IL-2-Fc treated mice. No significant or lasting toxicity was detected for either agent. Combination therapies with SRT revealed comparable efficacy and induction of immune memory for both ICK and IL-2-Fc when mice were rechallenged post-therapy. CONCLUSIONS: IL-2-Fc had comparable antitumor efficacy to CEA-targeted M5A-IL-2 ICK, while both fusion proteins induced immune memory when combined with SRT. Differences in the therapeutic mechanisms of both agents were observed.

Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.

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

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.

Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

PURPOSE: To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Characterization of rotating gantry micro-CT configuration for the in vivo evaluation of murine trabecular bone.

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.

A framework for deformable image registration validation in radiotherapy clinical applications.

Quantitative validation of deformable image registration (DIR) algorithms is extremely difficult because of the complexity involved in constructing a deformable phantom that can duplicate various clinical scenarios. The purpose of this study is to describe a framework to test the accuracy of DIR based on computational modeling and evaluating using inverse consistency and other methods. Three clinically relevant organ deformations were created in prostate (distended rectum and rectal gas), head and neck (large neck flexion), and lung (inhale and exhale lung volumes with variable contrast enhancement) study sets. DIR was performed using both B-spline and diffeomorphic demons algorithms in the forward and inverse direction. A compositive accumulation of forward and inverse deformation vector fields was done to quantify the inverse consistency error (ICE). The anatomical correspondence of tumor and organs at risk was quantified by comparing the original RT structures with those obtained after DIR. Further, the physical characteristics of the deformation field, namely the Jacobian and harmonic energy, were computed to quantify the preservation of image topology and regularity of spatial transformation obtained in DIR. The ICE was comparable in prostate case but the B-spline algorithm had significantly better anatomical correspondence for rectum and prostate than diffeomorphic demons algorithm. The ICE was 6.5 mm for demons algorithm for head and neck case when compared to 0.7 mm for B-spline. Since the induced neck flexion was large, the average Dice similarity coefficient between both algorithms was only 0.87, 0.52, 0.81, and 0.67 for tumor, cord, parotids, and mandible, respectively. The B-spline algorithm accurately estimated deformations between images with variable contrast in our lung study, while diffeomorphic demons algorithm led to gross errors on structures affected by contrast variation. The proposed framework offers the application of known deformations on any image datasets, to evaluate the overall accuracy and limitations of a DIR algorithm used in radiation oncology. The evaluation based on anatomical correspondence, physical characteristics of deformation field, and image characteristics can facilitate DIR verification with the ultimate goal of implementing adaptive radiotherapy. The suitability of application of a particular evaluation metric in validating DIR is dependent on the clinical deformation observed.