Clinical And Basic Research On The Sensitivity Of Hypofractionated Radiation Therapy

Objective: Part ? 1.We compare the local control rate and prognosis of patients with brain metastases undergoing stereotactic radiotherapy,and explore whether radiotherapy is suitable for patients with cystic brain metastases.2.To analyze the relevant survival factors in patients with brain metastases undergoing stereotactic radiotherapy.3.To analyze the relevant survival factors in lung cancer patients with brain metastases undergoing stereotactic radiotherapy.Part? The role of autophagy induced by radiation was still controversial.Various kinds of cell lines have different radiosensitivity.In our study,we tried to investigate the correlation between autophagy and radiosensitivity.Method: Part? A total of 426 patients with brain metastases from Tianjin Cancer Hospital were included in our study.All patients had undergone radiosurgery treatment and have complete clinical and imaging data.In our study,Cystic brain metastases were identified as that cystic content was more than 50% of the total volume of brain metastases.The Kaplan–Meier method and multivariate Cox regression analysis were used to compare survival time and evaluate risk factors for BMOS.Part? A549 and H520 cell lines were used in our assays.In our study,we tried to investigate the correlation between autophagy and radiosensitivity.Autophagy flux was regulated by transfecting with different small interfering RNAs and autophagy inhibitor and inducer in two cell lines.Clonogenic assay and Flow cytometry were used to detect radiosensitivity.Results: Part? A total of 356 patients(including 498 brain metastases)were analyzed in our study,including 67 patients(67/356,18.8%)with 75 cystic brain metastases.There is no statistical significance in BMOS between patients with cystic(17 months,3-64 months)and solid(17.5months 1-65 months)brain metastases(p=0.148).However,the volume of cystic brain metastases decreased more slowly than solid brain metastases(p<0.05).The results indicated that high RPA(recursive partitioning analysis)classification(p=0.006),large volume of brain metastases(p=0.006)and different primary lesion(especially Gastrointestinal tract tumor)(p=0.001)were associated with poor prognosis in patients with brain metastases.Part? Autophagy flux induced by radiation increased significantly at 24 h after large dose of autophagy(8Gy)and a single low dose of radiation didn't induce autophagy obviously.Clonogenic assay showed that H520 and H460 cells(lower level of basal autophagy)had higher radiosensitivity than A549 and Calu3 cells after series of various doses of radiation.For A549 cells,ATG5(Autophagy related proteins 5)gene depletion significantly increased radiosensitivity in both clonogenic assay and flow cytometry after irradiation.The difference was similar in H520 cell lines,but smaller compared to A549 cell lines.The cells with transferred ATG5 gene had higher survival rate and lower apoptosis rate compared with control group in nutrient shortage condition after radiation,whether H520 or A549 cells.Conclusions: Part? There is no difference in prognosis and local control between patients with cystic and solid brain metastases underwent radiosurgery.However,the rate and speed of tumor shrinkage were lower in cyst brain metastases after radiotherapy.Patients with larger brain metastases had shorter survival time,regardless of cystic or solid brain metastases.Part? NSCLC cell lines with higher basal autophagy are more resistant to radiation and inhibition of autophagy flux sensitize NSCLC cell lines to irradiation.However,the effect of autophagy on sensitivity of radiotherapy depend on different level of basal autophagy so that A549 cell lines(higher basal autophagy)with autophagy inhibition decreased survival rate more significantly under radiation.Induced autophagy also protect cell lines agaist radiation,similarly,the effect was much larger on H520 cell lines with lower basal autophagy.