61 research outputs found

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

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    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

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

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    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

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

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    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

    Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice

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    Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer

    Biomarker discovery and assessment for prediction of kidney response after 177Lu-octreotate therapy

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    Patients suffering from neuroendocrine tumors are oftentimes presented with spread disease at the time of diagnosis. Therapy using somatostatin analogs is today the only potentially curative treatment option for these patients. However, the kidneys are the dose-limiting organs in this type of therapy and the biological impact from radiopharmaceutical treatment is not fully understood. Furthermore, considering the large inter-individual variations in renal absorbed dose and toxicity, biomarkers for radiation damage would be of great significance in this type of therapy. The aims of this project were to study the normal kidney tissue response in vivo in mice following 177Lu and 177Lu-octreotate administration, to identify potential biomarkers following 177Lu exposure and evaluate their dependencies of absorbed dose, dose-rate, and time after injection, and to correlate these results with functional and morphological effects. The injected activity ranged between 0.3 and 150 MBq following 177Lu/177Lu-octreotate administration and the biological effect was investigated between 15 minutes and one year after administration. Transcriptional and miRNA variations were studied using microarray analysis and protein expression was investigated using mass spectrometry. Correlations between the transcriptional and protein variations were performed with functional parameters, as determined by 99mTc-DTPA/99mTc-DMSA scintigraphy, and with the morphological effects following 177Lu-octreotate administration. The number of differentially regulated transcripts following 177Lu/177Lu-octreoate administration was dependent on absorbed dose, dose-rate, time after injection, and tissue (kidney cortex or medulla) investigated. No transcript was found to be differentially regulated at all exposure conditions. The most recurrently regulated genes were the Serpina10 gene in kidney cortex, and the Egr1, Pck1, and Hmgcs2 genes in kidney medulla. Substantial differences in response were found between 177Lu-octreotate and 177LuCl3. Concerning the miRNA and protein data, a high absorbed dose-specificity was found, with few miRNAs/proteins found recurrently regulated at most exposure conditions. The transcriptional analyses showed a strong and diverse transcriptional response and the functional analyses revealed clear negative effects on renal function, with enhanced negative effects with absorbed dose and time after administration. Several potentially useful biomarkers were detected at the transcriptional level, markers with potential applicability in early prediction of late renal injury after 177Lu/177Lu-octreotate exposure

    The Therapeutic Potential of FLASH-RT for Pancreatic Cancer

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    Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease

    Characterization of the Plastic Scintillator Detector System Exradin W2 in a High Dose Rate Flattening-Filter-Free Photon Beam

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    (1) Background: The Exradin W2 is a commercially available scintillator detector designed for reference and relative dosimetry in small fields. In this work, we investigated the performance of the W2 scintillator in a 10 MV flattening-filter-free photon beam and compared it to the performance of ion chambers designed for small field measurements. (2) Methods: We measured beam profiles and percent depth dose curves with each detector and investigated the linearity of each system based on dose per pulse (DPP) and pulse repetition frequency. (3) Results: We found excellent agreement between the W2 scintillator and the ion chambers for beam profiles and percent depth dose curves. Our results also showed that the two-voltage method of calculating the ion recombination correction factor was sufficient to correct for the ion recombination effect of ion chambers, even at the highest DPP. (4) Conclusions: These findings show that the W2 scintillator shows excellent agreement with ion chambers in high DPP conditions
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