Assessment of lung doses in patients undergoing total body irradiation for haematological malignancies with and without lung shielding.

INTRODUCTION: Total body irradiation (TBI) practices vary considerably amongst centres, and the risk of treatment related toxicities remains unclear. We report lung doses for 142 TBI patients who underwent either standing TBI with lung shield blocks or lying TBI without blocks. METHODS: Lung doses were calculated for 142 TBI patients treated between June 2016 and June 2021. Patients were planned using Eclipse (Varian Medical Systems) using AAA_15.6.06 for photon dose calculations and EMC_15.6.06 for electron chest wall boost fields. Mean and maximum lung doses were calculated. RESULTS: Thirty-seven patients (26.2%) were treated standing using lung shielding blocks with 104 (73.8%) treated lying down. Lowest relative mean lung doses were achieved using lung shielding blocks in standing TBI, reducing the mean lung doses to 75.2% of prescription (9.9 Gy), ±4.1% (range 68.6-84.1%) for a prescribed dose of 13.2 Gy in 11 fractions, including contributions from electron chest wall boost fields, compared to 12 Gy in 6 fraction lying TBI receiving 101.6% mean lung dose (12.2 Gy) ±2.4% (range 95.2-109.5%) (P ≪ 0.05). Patients treated lying down with 2 Gy single fraction received the highest relative mean lung dose on average, with 108.4% (2.2 Gy) ±2.6% of prescription (range 103.2-114.4%). CONCLUSION: Lung doses have been reported for 142 TBI patients using the lying and standing techniques described herein. Lung shielding blocks significantly reduced mean lung doses despite the addition of electron boost fields to the chest wall.

The Potential Role of Total Body PET Imaging in Assessment of Atherosclerosis.

Recent advances in molecular imaging and PET instrumentation will be of great value in assessing atherosclerosis plaques and other cardiovascular disorders. Atherosclerosis is systemic and involves critical arteries. Total body PET imaging will allow assessment of disease throughout the body as well as therapeutic monitoring. Because of the high sensitivity of total body PET, delayed imaging can be performed hours after administering tracer compounds, resulting in higher contrast at the disease site. Global assessment of the plaque burden throughout the body will substantially improve our ability to quantify plaque activity in the course of the disease.

Investigation on using high-energy proton beam for total body irradiation (TBI).

This work investigated the possibility of using proton beam for total body irradia-tion (TBI). We hypothesized the broad-slow-rising entrance dose from a monoen-ergetic proton beam can deliver a uniform dose to patient with varied thickness. Comparing to photon-based TBI, it would not require any patient-specific com-pensator or beam spoiler. The hypothesis was first tested by simulating 250 MeV, 275 MeV, and 300 MeV protons irradiating a wedge-shaped water phantom in a paired opposing arrangement using Monte Carlo (MC) method. To allow ± 7.5% dose variation, the maximum water equivalent thickness (WET) of a treatable patient separation was 29 cm for 250 MeV proton, and > 40 cm for 275 MeV and 300 MeV proton. The compared 6 MV photon can only treat patients with up to 15.5 cm water-equivalent separation. In the second step, we simulated the dose deposition from the same beams on a patient's whole-body CT scan. The maximum patient separation in WET was 23 cm. The calculated whole-body dose variations were ± 8.9%, ± 9.0%, ± 9.6%, and ± 14% for 250 MeV proton, 275 MeV proton, 300 MeV proton, and 6 MV photon. At last, we tested the current machine capability to deliver a monoenergetic proton beam with a large uniform field. Experiments were performed on a compact double scattering single-gantry proton system. With its C-shaped gantry design, the source-to-surface distance (SSD) reached 7 m. The measured dose deposition curve had 22 cm relatively flat entrance region. The full width half maximum field size was measured 105 cm. The current scatter filter had to be redesigned to produce a uniform intensity at such treatment distance. In con-clusion, this work demonstrated the possibility of using proton beam for TBI. The current commercially available proton machines would soon be ready for such task.

Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment.

An assessment of multiple biomarkers from radiation casualties undergoing limited- or full-supportive care including treatment with filgrastim is critical to develop rapid and effective diagnostic triage strategies. The efficacy of filgrastim with full-supportive care was compared with results with limited-supportive care by analyzing survival, necropsy, histopathology and serial blood samples for hematological, serum chemistry and protein profiles in a non-human primate (Macaca mulatta, male and female) model during 60-d post-monitoring period following sham- and total-body irradiation with 6.5 Gy 60Co gamma-rays at 0.6 Gy min-1 Filgrastim (10 µg kg-1) was administered beginning on Day 1 post-exposure and continued daily until neutrophil counts were ≥2,000 µL-1 for two consecutive days. Filgrastim and full-supportive care significantly decreased the pancytopenia duration and resulted in improved animal survival and recovery compared to animals with a limited-supportive care. These findings also identified and validated a multiparametric biomarker panel to support radiation diagnostic device development.

DOSE AND GAMMA-RAY SPECTRA FROM NEUTRON-INDUCED RADIOACTIVITY IN MEDICAL LINEAR ACCELERATORS FOLLOWING HIGH-ENERGY TOTAL BODY IRRADIATION.

Production of radioisotopes in medical linear accelerators (linacs) is of concern when the beam energy exceeds the threshold for the photonuclear interaction. Staff and patients may receive a radiation dose as a result of the induced radioactivity in the linac. Gamma-ray spectroscopy was used to identify the isotopes produced following the delivery of 18 MV photon beams from a Varian 21EX and an Elekta Synergy. The prominent radioisotopes produced include 187W, 63Zn, 56Mn, 24Na and 28Al in both linac models. The dose rate was measured at the beam exit window (12.6 µSv in the first 10 min) following 18 MV total body irradiation (TBI) beams. For a throughput of 24 TBI patients per year, staff members are estimated to receive an annual dose of up to 750 µSv at the patient location. This can be further reduced to 65 µSv by closing the jaws before re-entering the treatment bunker.

Organ and effective dose conversion coefficients for a sitting female hybrid computational phantom exposed to monoenergetic protons in idealized irradiation geometries.

The conversion coefficients (CCs) relate protection quantities, mean absorbed dose (DT) and effective dose (E), with physical radiation field quantities, such as fluence (Φ). The calculation of CCs through Monte Carlo simulations is useful for estimating the dose in individuals exposed to radiation. The aim of this work was the calculation of conversion coefficients for absorbed and effective doses per fluence (DT/ Φ and E/Φ) using a sitting and standing female hybrid phantom (UFH/NCI) exposure to monoenergetic protons with energy ranging from 2 MeV to 10 GeV. The radiation transport code MCNPX was used to develop exposure scenarios implementing the female UFH/NCI phantom in sitting and standing postures. Whole-body irradiations were performed using the recommended irradiation geometries by ICRP publication 116 (AP, PA, RLAT, LLAT, ROT and ISO). In most organs, the conversion coefficients DT/Φ were similar for both postures. However, relative differences were significant for organs located in the abdominal region, such as ovaries, uterus and urinary bladder, especially in the AP, RLAT and LLAT geometries. Anatomical differences caused by changing the posture of the female UFH/NCI phantom led an attenuation of incident protons with energies below 150 MeV by the thigh of the phantom in the sitting posture, for the front-to-back irradiation, and by the arms and hands of the phantom in the standing posture, for the lateral irradiation.

A Monte Carlo evaluation of beam characteristics for total body irradiation at extended treatment distances.

The aim is to study beam characteristics at large distances when focusing on the electron component. In particular, to investigate the utility of spoilers with various thicknesses as an electron source, as well as the effect of different spoiler-to-surface distances (STSD) on the beam characteristics and, consequently, on the dose in the superficial region. A MC model of a 15 MV Varian accelerator, validated earlier by experimental data at isocenter and extended distances used in large-field total body irradiation, is applied to evaluate beam characteristics at distances larger than 400 cm. Calculations are carried out using BEAMnrc/DOSXYZnrc code packages and phase space data are analyzed by the beam data processor BEAMdp. The electron component of the beam is analyzed at isocenter and extended distances, with and without spoilers as beam modifiers, assuming vacuum or air surrounding the accelerator head. Spoiler thickness of 1.6 cm is found to be optimal compared to thicknesses of 0.8 cm and 2.4 cm. The STSD variations should be taken into account when treating patients, in particular when the treatment protocols are based on a fixed distance to the patient central sagittal plane, and also, in order to maintain high dose in the superficial region.

Lifetime increased cancer risk in mice following exposure to clinical proton beam-generated neutrons.

PURPOSE: To evaluate the life span and risk of cancer following whole-body exposure of mice to neutrons generated by a passively scattered clinical spread-out Bragg peak (SOBP) proton beam. METHODS AND MATERIALS: Three hundred young adult female FVB/N mice, 152 test and 148 control, were entered into the experiment. Mice were placed in an annular cassette around a cylindrical phantom, which was positioned lateral to the mid-SOBP of a 165-MeV, clinical proton beam. The average distance from the edge of the mid-SOBP to the conscious active mice was 21.5 cm. The phantom was irradiated with once-daily fractions of 25 Gy, 4 days per week, for 6 weeks. The age at death and cause of death (ie, cancer and type vs noncancer causes) were assessed over the life span of the mice. RESULTS: Exposure of mice to a dose of 600 Gy of proton beam-generated neutrons, reduced the median life span of the mice by 4.2% (Kaplan-Meier cumulative survival, P=.053). The relative risk of death from cancer in neutron exposed versus control mice was 1.40 for cancer of all types (P=.0006) and 1.22 for solid cancers (P=.09). For a typical 60 Gy dose of clinical protons, the observed 22% increased risk of solid cancer would be expected to decrease by a factor of 10. CONCLUSIONS: Exposure of mice to neutrons generated by a proton dose that exceeds a typical course of radiation therapy by a factor of 10, resulted in a statistically significant increase in the background incidence of leukemia and a marginally significant increase in solid cancer. The results indicate that the risk of out-of-field second solid cancers from SOBP proton-generated neutrons and typical treatment schedules, is 6 to 10 times less than is suggested by current neutron risk estimates.

[Assessment of the therapeutic possibilities of systemic radiotherapy as a component of combined treatment for advanced ovarian carcinoma].

The new technology of combined treatment for patients with ovarian carcinoma of III-IV stages and its relapse is presented. The essentially new component is systemic radiotherapy in nontumoricidal doses. It is used with both traditional surgical and chemotherapeutic components. Systemic radiotherapy is carried out in a form of subtotal body irradiation in two dose-time options with total dose of 1 Gy and 9 Gy. The choice of radiation option is carried out taking into account the initial somatic resource of patients estimated by the condition of lymphopoiesis. The use of systemic radiotherapy in combined treatment of advanced ovarian carcinoma allowed to achieve the significant increase of 3-, 5-year survival in patients as compared to traditional chemo-surgical method. Indirect mechanism of nontumoricidal systemic radiotherapy is to be considered as a vital way for tumor control.

Assessment of simulated high-dose partial-body irradiation by PCC-R assay.

The estimation of the dose and the irradiated fraction of the body is important information in the primary medical response in case of a radiological accident. The PCC-R assay has been developed for high-dose estimations, but little attention has been given to its applicability for partial-body irradiations. In the present work we estimated the doses and the percentage of the irradiated fraction in simulated partial-body radiation exposures at high doses using the PCC-R assay. Peripheral whole blood of three healthy donors was exposed to doses from 0-20 Gy, with 6°Co gamma radiation. To simulate partial body irradiations, irradiated and non-irradiated blood was mixed to obtain proportions of irradiated blood from 10-90%. Lymphocyte cultures were treated with Colcemid and Calyculin-A before harvest. Conventional and triage scores were performed for each dose, proportion of irradiated blood and donor. The Papworth's u test was used to evaluate the PCC-R distribution per cell. A dose-response relationship was fitted according to the maximum likelihood method using the frequencies of PCC-R obtained from 100% irradiated blood. The dose to the partially irradiated blood was estimated using the Contaminated Poisson method. A new D0 value of 10.9 Gy was calculated and used to estimate the initial fraction of irradiated cells. The results presented here indicate that by PCC-R it is possible to distinguish between simulated partial- and whole-body irradiations by the u-test, and to accurately estimate the dose from 10-20 Gy, and the initial fraction of irradiated cells in the interval from 10-90%.

Validation of experimental whole-body SAR assessment method in a complex indoor environment.

Experimentally assessing the whole-body specific absorption rate (SAR(wb) ) in a complex indoor environment is very challenging. An experimental method based on room electromagnetics theory (accounting only the line-of-sight as specular path) is validated using numerical simulations with the finite-difference time-domain method. Furthermore, the method accounts for diffuse multipath components (DMC) in the total absorption rate by considering the reverberation time of the investigated room, which describes all the losses in a complex indoor environment. The advantage of the proposed method is that it allows discarding the computational burden because it does not use any discretizations. Results show good agreement between measurement and computation at 2.8 GHz, as long as the plane wave assumption is valid, that is, at large distances from the transmitter. Relative deviations of 0.71% and 4% have been obtained for far-field scenarios, and 77.5% for the near field-scenario. The contribution of the DMC in the total absorption rate is also quantified here, which has never been investigated before. It is found that the DMC may represent an important part of the total absorption rate; its contribution may reach up to 90% for certain scenarios in an indoor environment.

Plasma miRNA as biomarkers for assessment of total-body radiation exposure dosimetry.

The risk of radiation exposure, due to accidental or malicious release of ionizing radiation, is a major public health concern. Biomarkers that can rapidly identify severely-irradiated individuals requiring prompt medical treatment in mass-casualty incidents are urgently needed. Stable blood or plasma-based biomarkers are attractive because of the ease for sample collection. We tested the hypothesis that plasma miRNA expression profiles can accurately reflect prior radiation exposure. We demonstrated using a murine model that plasma miRNA expression signatures could distinguish mice that received total body irradiation doses of 0.5 Gy, 2 Gy, and 10 Gy (at 6 h or 24 h post radiation) with accuracy, sensitivity, and specificity of above 90%. Taken together, these data demonstrate that plasma miRNA profiles can be highly predictive of different levels of radiation exposure. Thus, plasma-based biomarkers can be used to assess radiation exposure after mass-casualty incidents, and it may provide a valuable tool in developing and implementing effective countermeasures.

Preclinical assessment of volumetric modulated arc therapy for total marrow irradiation.

PURPOSE: A preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using RapidArc, a volumetric modulated arc technique. MATERIALS AND METHODS: Computed tomography datasets of 5 patients were included. Plans with eight overlapping coaxial arcs were optimized for 6-MV photon beams. Dose prescription was 12 Gy in 2 Gy per fraction, normalized so that 100% isodose covered 85% of the planning target volume (PTV). The PTV consisted of the whole skeleton (including ribs and sternum), from the top of the skull to the medium distal third of the femurs. Planning objectives for organs at risk (OARs) were constrained to a median dose <6 to 7 Gy. OARs included brain, eyes, oral cavity, parotids, thyroid, lungs, heart, kidneys, liver, spleen, stomach, abdominal cavity, bladder, rectum, and genitals. Pretreatment quality assurance consisted of portal dosimetry comparisons, scoring the delivery to calculation agreement with the gamma agreement index. RESULTS: The median total body volume in the study was 57 liters (range, 49-81 liters), for an average diameter of 47 cm (range, 46-53 cm) and a total length ranging from 95 to 112 cm. The median PTV volume was 6.8 liters (range, 5.8-10.8 liters). The mean dose to PTV was 109% (range, 107-112%). The global mean of median dose to all OARs was 4.9 Gy (range, 4.5-5.1 Gy over the 5 patients). The individual mean of median doses per organ ranged from 2.3 Gy (oral cavity) to 7.3 Gy (bowels cavity). Preclinical quality assurance resulted in a mean gamma agreement index of 94.3 ± 5.1%. The delivery time measured from quality assurance runs was 13 minutes. CONCLUSION: Sparing of normal tissues with adequate coverage of skeletal bones was shown to be feasible with RapidArc. Pretreatment quality assurance measurements confirmed the technical agreement between expected and actually delivered dose distributions, suggesting the possibility of incorporating this technique in the treatment options for patients.

Microbeams in radiation biology: review and critical comparison.

Microbeams have undergone a renaissance since their introduction and early use in the mid-60s. Recent advances in imaging, software and beam delivery have allowed rapid technological developments in microbeams for use in a range of experimental studies. Microbeams allow the effects of single radiation tracks to be determined in a highly quantified way. They offer a unique tool for following DNA damage and repair in a highly controlled way. More importantly, they allow radiation to be targeted to specific regions within a cell to probe subcellular radiosensitivity. They are also playing an important role in our understanding of bystander responses, where cells not directly irradiated can respond to irradiated neighbours. Although these processes have been studied using a range of experimental approaches, microbeams offer a unique route by which bystander responses can be elucidated. Without exception, all of the microbeams currently active have studied bystander responses in a range of cell and tissue models. Together, these studies have considerably advanced our knowledge of the underpinning mechanisms. Much of this has come from charged particle microbeam studies, but increasingly, X-ray and electron microbeams are starting to contribute quantitative and mechanistic information on bystander effects. A recent development has been the move from studies with 2-D cell culture models to more complex 3-D systems where the possibilities of utilising the unique characteristics of microbeams in terms of their spatial and temporal delivery will make a major impact.

Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.

PURPOSE: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. METHODS AND MATERIALS: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. RESULTS: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). CONCLUSIONS: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

Design of a novel flow-and-shoot microbeam.

Presented here is a novel microbeam technology--the Flow-And-ShooT (FAST) microbeam--under development at RARAF. In this system, cells undergo controlled fluidic transport along a microfluidic channel intersecting the microbeam path. They are imaged and tracked in real-time, using a high-speed camera and dynamically targeted, using a magnetic Point and Shoot system. With the proposed FAST system, RARAF expects to reach a throughput of 100,000 cells per hour, which will allow increasing the throughput of experiments by at least one order of magnitude. The implementation of FAST will also allow the irradiation of non-adherent cells (e.g. lymphocytes), which is of great interest to many of the RARAF users. This study presents the design of a FAST microbeam and results of first tests of imaging and tracking as well as a discussion of the achievable throughput.

Improvement of radiation-mediated immunosuppression of human NSCLC tumour xenografts in a nude rat model.

Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC) xenografts in a nude rat model irradiation (2 + 2 Gy) from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Whole-body new-born and young rats' exposure assessment in a reverberating chamber operating at 2.4 GHz.

This paper presents the whole-body specific absorption rate (WBSAR) assessment of embryos and new-born rats' exposure in a reverberating chamber (RC) operating at 2.4 GHz (WiFi). The finite difference in time domain (FDTD) method often used in bio-electromagnetism is facing very slow convergence. A new simulation-measurement hybrid approach has been proposed to characterize the incident power related to the RC and the WBSAR in rats, which are linked by the mean squared electric field strength in the working volume. Peak localized SAR in the rat under exposure is not included in the content of the study. Detailed parameters of this approach are determined by simulations. Evolutions for the physical and physiological parameters of the small rats at different ages are discussed. Simulations have been made to analyse all the variability factors contributing to the global results. WBSAR information and the variability for rats at different ages are also discussed in the paper.

Experimental determination of peripheral photon dose components for different IMRT techniques and linear accelerators.

PURPOSE: To quantify the relative peripheral photon doses (PD) to healthy tissues outside the treated region for different IMRT technologies and linac head designs. MATERIAL AND METHODS: Measurements were performed on an Elekta linac for various energies (6 MV, 10 MV, 25 MV) at different depths at a distance of 29 cm off-axis (vertical measurements) and different distances from the field edge at constant depth of 10 cm (horizontal measurements). These measurements were compared with results obtained on a Siemens linac at 6 MV and 15 MV. TLD-700 detectors were used to quantify the PDs relative to the dose in the volume exposed with the primary beam. Intensity modulated (IM)-beams with identical fluence patterns were generated with a segmental multileaf (sMLC) technique and with lead-containing cerrobend compensators (MCP96). PD values of IM beams were compared with open beam values. All measurement results of the two different linacs, the different IM methods and the different energies were normalized to the same mean dose. RESULTS: PD values were distinctly higher near the surface (0.5-20 mm) than at larger depth and showed the same trend for all photon beam energies. In comparison with the open field, the photon dose component of PD for IM beams delivered with a segmental MLC technique were increased by a factor varying from 1.2 to 1.8, depending on photon energy and depth. This ratio was around 2 for compensator based IMRT. Depending on depth and distance from the field edge the PD on the Siemens machine was about 30% to 50% higher than on the Elekta machine for the same nominal photon energy. CONCLUSION: The treatment head design of a linac has a large impact on PD in IMRT as well as for open beams. PD can be minimized by proper selection of treatment delivery method and photon beam energy.