Differential tissue sparing of FLASH ultra high dose rates: an {\it in-silico} study

Purpose: To propose a theory for the differential tissue sparing of FLASH ultra high dose rates (UHDR) through inter-track reaction-diffusion mechanism. Methods: We calculate the time-evolution of particle track-structures using a system of coupled reaction-diffusion equations on a random network designed for molecular transport in porous and disordered media. The network is representative of the intra- and inter-cellular diffusion channels in tissues. Spatial cellular heterogeneities over the scale of track spacing have been constructed by incorporating random fluctuations in the connectivity among network sites. Results: We demonstrate the occurrence of phase separation among the tracks as the complexity in intra- and inter-cellular structural increases. At the weak limit of disorder, such as in water and normal tissue, neighboring tracks melt into each other and form a percolated network of nonreactive species. In contrast, at the strong limit of disorder, tracks evolve individually like isolated islands with negligible inter-track overlap. Thus, the spatio-temporal correlation among the chemical domains decreases as the inter-cellular complexity of the tissue increases (e.g. from normal tissue to fractal-type malignant tissue). Conclusions: The differential sparing of FLASH UHDR in normal and tumor tissue may be explained by differences in inter- and intra-cellular structural complexities between the tissue types. The structural complexities of cancerous cells prevent clustering and chemical interaction of tracks, whereas this interaction prevails and thus leads to sparing in normal tissue

Dual Beam-Current Transformer Design for Monitoring and Reporting of Electron Ultra-High Dose Rate (Flash) Beam Parameters

PURPOSE: To investigate the usefulness and effectiveness of a dual beam-current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real-time, and to inform on the usefulness of this design for future eFLASH beam control. METHODS: Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower-to-upper BCT signal. RESULTS: A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R CONCLUSION: The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams

Dual Beam-Current Transformer Design for Monitoring and Reporting of Electron Ultra-High Dose Rate (Flash) Beam Parameters

PURPOSE: To investigate the usefulness and effectiveness of a dual beam-current transformer (BCTs) design to monitor and record the beam dosimetry output and energy of pulsed electron FLASH (eFLASH) beams in real-time, and to inform on the usefulness of this design for future eFLASH beam control. METHODS: Two BCTs are integrated into the head of a FLASH Mobetron system, one located after the primary scattering foil and the other downstream of the secondary scattering foil. The response of the BCTs was evaluated individually to monitor beam output as a function of dose, scattering conditions, and ability to capture physical beam parameters such as pulse width (PW), pulse repetition frequency (PRF), and dose per pulse (DPP), and in combination to determine beam energy using the ratio of the lower-to-upper BCT signal. RESULTS: A linear relationship was observed between the absorbed dose measured on Gafchromic film and the BCT signals for both the upper and lower BCT (R CONCLUSION: The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams

Transcriptional response of kidney tissue after 177Lu-octreotate administration in mice

AbstractIntroductionThe kidneys are one of the main dose limiting organs in 177Lu-octreotate therapy of neuroendocrine tumors. Therefore, biomarkers for radiation damage would be of great importance in this type of therapy. The purpose of this study was to investigate the absorbed dose dependency on early transcriptional changes in the kidneys from 177Lu-octreotate exposure.MethodsFemale Balb/c nude mice were i.v. injected with 1.3, 3.6, 14, 45 or 140MBq 177Lu-octreotate. The animals were killed 24h after injection followed by excision of the kidneys. The absorbed dose to the kidneys ranged between 0.13 and 13Gy. Total RNA was extracted from separated renal tissue samples, and applied to Illumina MouseRef-8 Whole-Genome Expression Beadchips to identify regulated transcripts after irradiation. Nexus Expression 2.0 and Gene Ontology terms were used for data processing and to determine affected biological processes.ResultsDistinct transcriptional responses were observed following 177Lu-octreotate administration. A higher number of differentially expressed transcripts were observed in the kidney medulla (480) compared to cortex (281). In addition, 39 transcripts were regulated at all absorbed dose levels in the medulla, compared to 32 in the cortex. Three biological processes in the cortex and five in the medulla were also shared by all absorbed dose levels. Strong association to metabolism was found among the affected processes in both tissues. Furthermore, an association with cellular and developmental processes was prominent in kidney medulla, while transport and immune response were prominent in kidney cortex.ConclusionSpecific biological and dose-dependent responses were observed in both tissues. The number of affected transcripts and biological processes revealed distinct response differences between the absorbed doses delivered to the tissues

Development of novel ionization chambers for reference dosimetry in electron FLASH radiotherapy

The aim of this study was to optimize the design and performance of parallel plate ion chambers for use in ultra-high dose rate (UHDR) dosimetry applications, and evaluate their potential as reference class chambers for calibration purposes. Three chambers were designed and produced: the A11-VAR (0.2-1.0 mm electrode gap, 20 mm diameter collector), the A11-TPP (0.3 mm electrode gap, 20 mm diameter collector), and the A30 (0.3 mm electrode gap, 5.4 mm diameter collector).The chambers underwent full characterization using an UHDR 9 MeV electron beam with individually varied beam parameters of pulse repetition frequency (PRF, 10-120Hz), pulse width (PW, 0.5-4us), and pulse amplitude (0.01-9 Gy/pulse). The response of the ion chambers was evaluated as a function of the dose per pulse (DPP), PRF, PW, dose rate, electric field strength, and electrode gap. The chamber response was found to be dependent on DPP and PW, whose dependencies were mitigated with larger electric field strengths and smaller electrode spacing. At a constant electric field strength, we measured a larger charge collection efficiency (CCE) as a function of DPP for ion chambers with a smaller electrode gap in the A11-VAR. For ion chambers with identical electrode gap (A11-TPP and A30), higher electric field strengths were found to yield better CCE at higher DPP. A PW dependence was observed at low electric field strengths (500 V/mm) for DPP values ranging from 1-5 Gy at PWs ranging from 0.5-4 {\mu}s, but at electric field strengths of 1000 V/mm and higher, these effects become negligible. This study confirmed that the charge collection efficiency of ion chambers depends strongly on the electrode spacing and the electric field strength, and also on the DPP and the PW of the UHDR beam. The new finding of this study is that the PW dependence becomes negligible with reduced electrode spacing and increased electric field.Comment: 29 pages, 9 figure

Independent Reproduction of the FLASH Effect on the Gastrointestinal Tract: A Multi-Institutional Comparative Study

FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used

Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation

Aim To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. Methods We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. Results At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. Conclusion Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors