Impact of IUdR in rat 9L glioma cell survival for 25-35 keV photo-activated Auger electron therapy

Introduction: Photo-activated Auger electron therapy is a potential technique that could preferentially target cancer cells. This binary therapy uses a drug containing a high-Z element like iododeoxyuridine (IUdR), which serves as a radiosensitizer and molecular carrier of high-Z iodine into cancer cell DNA. Iodine becomes the Auger electron source when activated by photons with an appropriate energy. This work studied the survival of rat 9L glioma cells with IUdR replacing thymidine in the DNA. Irradiations at monochromatic energies above and below the iodine K-edge (33.2 keV) are part of a larger study from 25-70 keV. It was hypothesized that SER10 values for 9% and 18% IUdR-laden 9L glioma cells irradiated by 25-35 keV photons would be greatest at 35 keV due to the Auger effect. Methods: Rat 9L glioma cells survival versus dose curves with 0%, 9%, and 18% IUdR were measured using four irradiation energies (4 MV x-rays; 35, 30, and 25 keV synchrotron photons). For each of 11 conditions (Energy, %IUdR) survival curves were fit to the data (826 cell cultures) using the linear quadratic model. The ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear-energy transfer (LET), radiosensitization (RS), and Auger effect (AE) were determined. Results: At 35, 30, and 25 keV, SER10,LET values were 1.08±0.03, 1.22±0.02, and 1.37±0.02, respectively. At 4 MV SER10,RS values for 9% and 18% IUdR were 1.28±0.02 and 1.40±0.02, respectively. Assuming LET effects are independent of %IUdR and radiosensitization effects are independent of energy, SER10,AE values for 18% IUdR at 35, 30, and 25 keV were 1.35±0.05, 1.06±0.03, and 0.98±0.03, respectively; values for 9% IUdR at 35 and 25 keV were 1.01±0.04 and 0.82±0.02, respectively. Contrastingly, a different, more traditional analysis gave SER10,AE values of 1.27±0.06 and 1.25±0.06 at 35 keV for 18% and 9% IUdR, respectively. Conclusions: Results of this research proved the hypothesis correct; at 35 keV SER10,AE was significantly greater than values at 25 and 30 keV for 18% IUdR and at 25 keV for 9% IUdR. Additional data and radiobiological modeling is required to better explain these results

Verification of TG-61 dose for synchrotron-produced monochromatic x-ray beams using fluence-normalized MCNP5 calculations

Ion chamber dosimetry is being used to calibrate dose for cell irradiations designed to investigate photoactivated Auger electron therapy at the Louisiana State University CAMD synchrotron facility. This study performed a dosimetry intercomparison for synchrotron-produced monochromatic x-ray beams at 25 and 35 keV. Ion chamber depth-dose measurements in a PMMA phantom were compared with the product of MCNP5 Monte Carlo calculations of dose per fluence and measured incident fluence. Monochromatic beams of 25 and 35 keV were generated on the tomography beamline at CAMD. A cylindrical, air-equivalent ion chamber was used to measure the ionization created in a 10x10x10-cm3 PMMA phantom for depths from 0.6 to 7.7 cm. The American Association of Physicists in Medicine TG-61 protocol was applied to convert measured ionization into dose. Photon fluence was determined using a NaI detector to make scattering measurements of the beam from a thin polyethylene target at angles 30 degrees to 60 degrees. Differential Compton and Rayleigh scattering cross sections obtained from xraylib, an ANSI C library for x-ray-matter interactions, were applied to derive the incident fluence. MCNP5 simulations of the irradiation geometry provided the dose deposition per photon fluence as a function of depth in the phantom. At 25 keV the fluence-normalized MCNP5 dose overestimated the ion-chamber measured dose by an average of 7.2+/-3.0% to 2.1+/-3.0% for PMMA depths from 0.6 to 7.7 cm, respectively. At 35 keV the fluence-normalized MCNP5 dose underestimated the ion-chamber measured dose by an average of 1.0+/-3.4% to 2.5+/-3.4%, respectively. These results showed that TG-61 ion chamber dosimetry, used to calibrate dose output for cell irradiations, agreed with fluence-normalized MCNP5 calculations to within approximately 7% and 3% at 25 and 35 keV, respectively.Comment: 22 pages, 5 figure

Dose-response curve of EBT, EBT2, and EBT3 radiochromic films to synchrotron-produced monochromatic x-ray beams

Purpose: This work investigates the dose-response curves of GAFCHROMIC ® EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. Methods: Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10 × 10 × 10-cm3 polymethylmethacrylate phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Center. Results: The sensitivity (NOD per unit dose) of EBT film at 35 keV relative to that for 4-MV x-rays was 0.73 and 0.76 for doses 50 and 100 cGy, respectively. The sensitivity of EBT2 film at 25, 30, and 35 keV relative to that for 4-MV x-rays varied from 1.09-1.07, 1.23-1.17, and 1.27-1.19 for doses 50-200 cGy, respectively. For EBT3 film the relative sensitivity was within 3 of unity for all three monochromatic x-ray beams. Conclusions: EBT and EBT2 film sensitivity showed strong energy dependence over an energy range of 25 keV-4 MV, although this dependence becomes weaker for larger doses. EBT3 film shows weak energy dependence, indicating that it would be a better dosimeter for kV x-ray beams where beam hardening effects can result in large changes in the effective energy. © 2012 American Association of Physicists in Medicine

Case report of ablative magnetic resonance-guided stereotactic body radiation therapy for oligometastatic mesenteric lymph nodes from bladder cancer

Several randomized trials have demonstrated that stereotactic body radiation therapy (SBRT) can significantly improve long-term clinical outcomes for patients with oligometastatic (OM) cancer, commonly defined as 1–5 metastatic lesions. Some lesions, especially those in the abdomen and pelvis, may not be appropriate candidates for receiving ablative dose if daily on-board computed tomography (CT) is used because of limited target lesion and normal anatomy visualization. Magnetic resonance imaging (MRI) inherently provides superior soft tissue delineation as compared to CT and only recently have MR-guided linear accelerators (LINACs) become commercially available. MR-LINACs can also perform daily online adaptive replanning based on the current day’s anatomy, further positioning this novel technology as a preferred means to safely deliver ablative dose, even to targets in anatomically challenging locations. Here we present the case of a 49-year-old man with bladder cancer who underwent cystectomy and developed metachronous disease in 2 mesenteric lymph nodes for which he received MR-guided SBRT with daily online adaptive replanning to a prescription dose of 50 Gy in 5 fractions. He achieved a significant radiographic response and did not experience significant treatment-related toxicity. We discuss unique advantages of MR guidance and novel applications, especially in the context of OM disease. Keywords: Bladder cancer; magnetic resonance imaging (MRI); radiosurgery; radiotherap

Rationale, Study Design, and Cohort Characteristics for the Markers for Environmental Exposures (MEE) Study.

Environmental factors have been linked to many diseases and health conditions, but reliable assessment of environmental exposures is challenging. Developing biomarkers of environmental exposures, rather than relying on self-report, will improve our ability to assess the association of such exposures with disease. Epigenetic markers, most notably DNA methylation, have been identified for some environmental exposures, but identification of markers for additional exposures is still needed. The rationale behind the Markers for Environmental Exposures (MEE) Study was to (1) identify biomarkers, especially epigenetic markers, of environmental exposures, such as pesticides, air/food/water contaminants, and industrial chemicals that are commonly encountered in the general population; and (2) support the study of potential relationships between environmental exposures and health and health-related factors. The MEE Study is a cross-sectional study with potential for record linkage and follow-up. The well-characterized cohort of 400 postmenopausal women has generated a repository of biospecimens, including blood, urine, and saliva samples. Paired data include an environmental exposures questionnaire, a breast health questionnaire, dietary recalls, and a food frequency questionnaire. This work describes the rationale, study design, and cohort characteristics of the MEE Study. In addition to our primary research goals, we hope that the data and biorepository generated by this study will serve as a resource for future studies and collaboration

Ablative 5-fraction stereotactic magnetic resonance-guided radiation therapy (MRgRT) with on-table adaptive replanning and elective nodal irradiation for inoperable pancreas cancer

Purpose: Radiotherapy (RT) dose escalation using stereotactic body radiation therapy (SBRT) may significantly improve both local control (LC) and overall survival (OS) for patients with inoperable pancreas cancer. However, ablative dose cannot be routinely offered because of the risk of causing severe injury to adjacent normal organs. Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) represents a novel technique that may achieve safe delivery of ablative dose and improve long-term outcomes. Methods and materials: We performed a single institution retrospective analysis of 35 consecutive pancreatic cancer patients treated with SMART in mid-inspiration breath hold on an MR-LINAC. Most had locally advanced disease (80%) and received induction chemotherapy (91.4%) for a median 3.9 months prior to SBRT. All were prescribed 5 fractions delivered in consecutive days to a median total dose of 50 Gy (BED10 100 Gy10), typically with a 120-130% hotspot. Elective nodal irradiation was delivered to 20 (57.1%) patients. No patient had fiducial markers placed and all were treated with continuous intrafraction MR visualization and automatic beam triggering. Results: With median follow-up of 10.3 months from SMART, acute (2.9%) and late (2.9%) grade 3 toxicities were uncommon. One-year LC, distant metastasis-free survival, progression-free survival, cause-specific survival, and OS were 87.8%, 63.1%, 52.4%, 77.6% and 58.9%, respectively. Conclusions: To our knowledge, this is the first report of 5-fraction pancreas SMART delivered on an MR-LINAC. We observed minimal severe treatment-related toxicity and encouraging early LC. Prospective confirmation of feasibility and long-term clinical outcomes of dose intensified SMART is warranted

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ABSTRACT. Objective. To determine the effects of sodium oxybate (SXB) on sleep physiology and sleep/wakerelated symptoms in patients with fibromyalgia syndrome (F