Spatially fractionated radiotherapy (SFRT) is characterized by the coexistence of multiple hot and cold dose subregions throughout the treatment volume. In preclinical studies using single-fraction treatment, SFRT can achieve a significantly higher therapeutic index than conventional radiotherapy (RT). Published clinical studies of SFRT followed by RT have reported promising results for bulky tumors. Several clinical trials are currently underway to further explore the clinical benefits of SFRT. However, we lack the important understanding of the correlation between dosimetric parameters and treatment response that we have in RT. In this work, we reviewed and analyzed this important correlation from previous preclinical SFRT studies. We reviewed studies prior to 2022 that treated animal-bearing tumors with minibeam radiotherapy (MBRT) or microbeam radiotherapy (MRT). Eighteen studies met our selection criteria. Increased lifespan (ILS) relative to control was used as the treatment response. The preclinical SFRT dosimetric parameters analyzed were peak dose, valley dose, average dose, beam width, and beam spacing. We found that valley dose was the dosimetric parameter with the strongest correlation with ILS (p-value < 0.01). For studies using MRT, average dose and peak dose were also significantly correlated with ILS (p-value < 0.05). This first comprehensive review of preclinical SFRT studies shows that the valley dose (rather than the peak dose) correlates best with treatment outcome (ILS).

To identify key dosimetric parameters that have close associations with tumor treatment response and body weight change in SFRT treatments with a large range of spatial-fractionation scale at dose rates of several Gy/min. Six study arms using uniform tumor radiation, half-tumor radiation, 2mm beam array radiation, 0.3mm minibeam radiation, and an untreated arm were used. All treatments were delivered on a 320kV x-ray irradiator. Forty-two female Fischer 344 rats with fibrosarcoma tumor allografts were used. Dosimetric parameters studied are peak dose and width, valley dose and width, peak-to-valley-dose-ratio (PVDR), volumetric average dose, percentage volume directly irradiated, and tumor- and normal-tissue EUD. Animal survival, tumor volume change, and body weight change (indicative of treatment toxicity) are tested for association with the dosimetric parameters using linear regression and Cox Proportional Hazards models. The dosimetric parameters most closely associated with tumor response are tumor EUD (R² = 0.7923, F-stat = 15.26*; z-test = -4.07***), valley (minimum) dose (R² = 0.7636, F-stat = 12.92*; z-test = -4.338***), and percentage tumor directly irradiated (R² = 0.7153, F-stat = 10.05*; z-test = -3.837***) per the linear regression and Cox Proportional Hazards models, respectively. Tumor response is linearly proportional to valley (minimum) doses and tumor EUD. Average dose (R² = 0.2745, F-stat = 1.514 (no sig.); z-test = -2.811**) and peak dose (R² = 0.04472, F-stat = 0.6874 (not sig.); z-test = -0.786 (not sig.)) show the weakest associations to tumor response. Only the uniform radiation arm did not gain body weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetric parameters except for valley (minimum) dose (R² = 0.3814, F-stat = 13.56**), valley width (R² = 0.2853, F-stat = 8.783**), and peak width (R² = 0.2759, F-stat = 8.382**). For a single-fraction SFRT at conventional dose rates, valley, not peak, dose is closely associated with tumor treatment response and thus should be used for treatment prescription. Tumor EUD, valley (minimum) dose, and percentage tumor directly irradiated are the top three dosimetric parameters that exhibited close associations with tumor response.

Background: Exercise preconditioning (EP) is essential for preventing ischemic stroke. Recent studies have shown that EP exerts neuroprotective effects in the cerebral ischemia‐reperfusion injury model. Nonetheless, there have been few reports on the relationship between EP and the Th17/Treg balance. Moreover, it is unclear whether the JAK2/STAT3 pathway is responsible for the neuroprotective effect of EP. Therefore, we aimed to explore the impact of EP, other than the anti‐inflammatory and antiapoptotic functions, on the Th17/Treg balance via the JAK2/STAT3 pathway in a middle cerebral artery occlusion (MCAO)‐induced model.Results: Fifty rats were randomly allocated into five groups, including the sham group (n = 10), EP+sham group (n = 10), MCAO group (n = 10), EP+MCAO group (n = 10), and EP+MCAO+JAK2/STAT3 pathway agonist (coumermycin A1, CA1) group (n = 10). The results indicated that EP alleviated neurological deficits, reduced infarct volume, and ameliorated neuronal apoptosis induced by MCAO. Additionally, the MCAO‐induced Th17/Treg imbalance could be rectified by EP. The decreased levels of IL‐10 and Foxp3 and increased IL‐17 and RORα in the MCAO group were reversed by EP treatment. Regarding inflammation, EP reduced the concentrations of IL‐6 and IL‐17 and elevated those of IL‐10 and TGF‑β. The neuroprotective effects of EP were accompanied by decreased phosphorylation of JAK2 and STAT3. Furthermore, CA1 pretreatment diminished all the beneficial effects of EP partially.Conclusion: Our findings suggest that EP contributes to attenuating neuronal apoptosis, Th17/Treg imbalance, and inflammation induced by MCAO via inhibiting the JAK2/STAT3 pathway, indicating its therapeutic potential in ischemic stroke.