Systematic analysis and modeling of the FLASH sparing effect as a function of dose and dose rate

Ultrahigh-dose-rate radiotherapy(FLASH-RT)is a revolutionary radiotherapy technology that can spare normal tissues without compromising tumor control.Although qualitative experimental results have been reported,quantitative and systematic analysis of data is necessary.Particularly,the FLASH effect response model to the dose or dose rate is still unclear.This study investigated the relationships between the FLASH effect and experimental parameters,such as dose,dose rate,and other factors by analyzing published in vivo experimental data from animal models.The data were modeled based on logistic regression analysis using the sigmoid function.The model was evaluated using prediction accuracy,receiver operating characteristic(ROC)curve,and area under the ROC curve.Results showed that the FLASH effect was closely related to the dose,mean dose rate,tissue type,and corresponding biological endpoints.The dose rate corresponding to a 50% probability of triggering cognitive protection in the brain was 45 Gy s^(-1).The dose rate corresponding to a 50% probability of triggering intestinal crypt survival and regeneration was 140 Gy s^(-1).For the skin toxicity effect,the dose corresponding to a 50% probability of triggering the FLASH effect was 24 Gy.This study helps to characterize the conditions underlying the FLASH effect and provides important information for optimizing experiments.

Treating inflammatory bowel disease by adsorptive leucocytapheresis:A desire to treat without drugs

Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.