Brain radiation impairs cognition, associated with neuronal degeneration and neuroinflammation. • Ultra-rapid FLASH produced reduced cognitive deficits vs. conventional delivery time. • Loss of hippocampal dendritic spines and neuroinflammation were less evident after FLASH. • These factors may mediate the improved therapeutic index of FLASH brain irradiation.
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.
An international, prospective, double-blind trial compared the long-term therapeutic value of glimepiride with glibenclamide in patients with Type 2 diabetes mellitus. Patients stabilised on glibenclamide were randomised to 1 mg glimepiride (524 patients) or 2.5 mg glibenclamide (520 patients). The treatment groups were comparable at baseline with respect to age (60.2 years), body mass index (26.5 kg/m2), duration of diabetes (5.0 years) and fasting blood glucose levels (163 mg/dl [9.0 mmol/l]). Doses were increased stepwise, up to 8 mg for glimepiride (once-daily) and 20 mg for glibenclamide (> 10 mg as divided dose), until metabolic control (fasting blood glucose < or = 150 mg/dl [8.3 mmol/l]), or maximum dose was achieved. After one year of treatment, patients entered a long-term follow-up study. Primary endpoints for evaluation of metabolic control, mean glycated haemoglobin and mean fasting blood glucose, were 8.4% and 174 mg/dl (9.7 mmol/l) for glimepiride and 8.3% and 168 mg/dl (9.3 mmol/l) for glibenclamide. Differences between treatment groups were not considered clinically relevant (95% confidence intervals (-0.05, 0.19%) for glycated haemoglobin and (2, 11 mg/dl) [0.1, 0.6 mmol/l] for fasting blood glucose). Statistically significant lower fasting insulin and C-peptide values were observed in glimepiride patients compared with glibenclamide (differences: insulin, -0.92 microU/ml [p = 0.04]; C-peptide, -0.14 ng/ml [p = 0.03]). Both treatment groups showed an equivalent safety profile. Adverse events were consistent with the nature of the diabetic patient population studied. Fewer hypoglycaemic reactions occurred with glimepiride than with glibenclamide (105 versus 150 episodes). The long-term follow-up (457 patients) confirmed that glimepiride (1-8 mg) once daily provides equivalent metabolic control to a higher dosage (2.5-20.0 mg) of glibenclamide. Both treatments were well tolerated.
BackgroundAstatine-211 (211At) is an alpha particle emitting halogen with almost optimal linear energy transfer for creating DNA double-strand breaks and is thus proposed for radionuclide therapy when bound to tumor-seeking agents. Unbound 211At accumulates in the thyroid gland, and the concept of basal radiation-induced biological effects in the thyroid tissue is, to a high degree, unknown and is most valuable.MethodsFemale BALB/c nude mice were intravenously injected with 0.064 to 42 kBq of 211At, resulting in absorbed doses of 0.05 to 32 Gy in the thyroid gland. Thyroids were removed 24 h after injection; total RNA was extracted from pooled thyroids and processed in triplicate using Illumina MouseRef-8 Whole-Genome Expression Beadchips.ResultsThyroids exposed to 211At revealed distinctive gene expression profiles compared to non-irradiated controls. A larger number of genes were affected at low absorbed doses (0.05 and 0.5 Gy) compared to intermediate (1.4 Gy) and higher absorbed doses (11 and 32 Gy). The proportion of dose-specific genes increased with decreased absorbed dose. Additionally, 1.4 Gy often exerted opposite regulation on gene expression compared to the other absorbed doses. Using Gene Ontology data, an immunological effect was detected at 0.05 and 11 Gy. Effects on cellular response to external stress and cell cycle regulation and proliferation were detected at 1.4 and 11 Gy.ConclusionsConclusively, the cellular response to ionizing radiation is complex and differs with absorbed dose. The response acquired at high absorbed doses cannot be extrapolated down to low absorbed doses or vice versa. We also demonstrated that the thyroid - already at absorbed doses similar to those obtained in radionuclide therapy - responds with expression of a high number of genes. Due to the increased heterogeneous irradiation at low absorbed doses, we suggest that this response partly originates from non-irradiated cells in the tissue, i.e., bystander cells.
In their seminal paper from 2014, Fauvadon et al. coined the term FLASH irradiation to describe ultra-high-dose rate irradiation with dose rates greater than 40 Gy/s, which results in delivery times of fractions of a second. The experiments presented in that paper were performed with a high-dose-per-pulse 4.5 MeV electron beam, and the results served as the basis for the modern-day field of FLASH radiation therapy (RT). In this article, we review the studies that have been published after those early experiments, demonstrating the robust effects of FLASH RT on normal tissue sparing in preclinical models. We also outline the various irradiation parameters that have been used. Although the robustness of the biological response has been established, the mechanisms behind the FLASH effect are currently under investigation in a number of laboratories. However, differences in the magnitude of the FLASH effect between experiments in different labs have been reported. Reasons for these differences even within the same animal model are currently unknown, but likely has to do with the marked differences in irradiation parameter settings used. Here, we show that these parameters are often not reported, which complicates large multistudy comparisons. For this reason, we propose a new standard for beam parameter reporting and discuss a systematic path to the clinical translation of FLASH RT.
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