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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 12 months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. Results Measured precision (3 mg/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. [ABSTRACT FROM AUTHOR]

Abstract: Calcium oxalate precipitation is the first step in preparation of biological samples for 41Ca 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 41Ca administration during which human samples, collected over a lifetime, provide 41Ca:Ca ratios that are significantly above background. [Copyright &y& Elsevier]

Abstract: Acute and prolonged bone complications associated with radiation and chemotherapy in cancer survivors underscore the importance of establishing a laboratory-based complementary dual-isotope tool to evaluate short- as well as long-term bone remodeling in an in vivo model. To address this need, a liquid scintillation dual-label method was investigated using different scintillation cocktails for quantitative measurement of 3H-tetracycline (3H-TC) and 45Ca as markers of bone turnover in mice. Individual samples were prepared over a wide range of known 45Ca/3H activity ratios. Results showed that 45Ca/3H activity ratios determined experimentally by the dual-label method were comparable to the known activity ratios (percentage difference ∼2%), but large variations were found in samples with 45Ca/3H activity ratios in range of 2–10 (percentage difference ∼20–30%). Urine and fecal samples from mice administered with both 3H-TC and 45Ca were analyzed with the dual-label method. Positive correlations between 3H and 45Ca in urine (R=0.93) and feces (R=0.83) indicate that 3H-TC and 45Ca can be interchangeably used to monitor longitudinal in vivo skeletal remodeling. [Copyright &y& Elsevier]

Abstract: Purpose: Several recent studies indicate high-dose-rate (HDR) breast brachytherapy as an alternative to standard external beam radiation therapy for partial breast irradiation with high dose conformality to the target. However, this article presents an exploration of the possibility of achieving higher conformal avoidance of sensitive structures through detailed and comparative 3D CT-based anatomical dose distribution of a patient in supine and prone positions. Methods and materials: A patient treated with accelerated partial breast HDR breast brachytherapy in the supine position was selected for two CT-based analyses, one in the supine and one in the prone position. The optimized plan (Nucletron HDR planning station) for each position was achieved using graphical optimization with local adjustment of isodose lines to cover the planned target volume (PTV, lumpectomy with 2 cm margin) with 100% of the prescribed dose (34 Gy in 10 fractions) while minimizing the hot spots. Cumulative dose-volume histograms (DVH) were analyzed for the PTV, lung, skin, pectoral muscle, and chest wall. Results: The PTV received 100% of prescribed dose in both the prone and supine positions. A significant (>40%) dose reduction was achieved in the lung in the prone treatment position. Similar dose reductions were also achieved for prone pectoral muscle, chest wall, and breast skin, irradiating less volume with high doses. Pectoral muscle, lumpectomy, and the breast skin showed prominent differences in shape and displacement in the prone compared with the supine position. Conclusion: CT-based treatment planning allowed calculations of volumetric dose distribution to the target and all sensitive structures with proper visualization and volumetric delineation of organs of interest. The treatment plan shows significant dose reduction may be possible in various sensitive structures if the patient is treated with HDR brachytherapy in the prone position. [Copyright &y& Elsevier]

Purpose: Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia.Methods and Materials: We developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIStissue) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).Results: Implants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIStissue with the onset of AML and ALL. Two to 10 Gy TBI increased WIStissue and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIStissue was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart).Conclusions: L-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (Ktrans), fractional extracellular extravascular space (νec), 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 Ktrans, increased νec, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Abstract: Toxic leukoencephalopathy syndromes are rare disorders of cerebral injury characterized by changes in the white matter and accompanying neurologic dysfunction. They have been reported in association with a variety of clinical etiologies, most commonly including severe hypertension, cranial irradiation, and environmental toxins. However, they have also been described in conjunction with immunosuppressive and chemotherapeutic agents. There has been one case of fatal leukoencephalopathy reported following CHOP chemotherapy for non-Hodgkin lymphoma. We report a second case of fatal necrotizing leukoencephalopathy following the administration of CHOP chemotherapy. [Copyright &y& Elsevier]