Survival Analysis Of Simultaneous Radiotherapy And Chemotherapy With Hyperthermia In Treatment Of Glioblastoma And Study On The Mechanism Of Hyperthermia Sensitizing Radiotherapy In Glioblastoma

PART ⅠSurvival Analysis of Simultaneous Radiotherapy and Chemotherapy with Hyperthermia in Treatment of GlioblastomaBackground and Objective:Glioblastoma(GBM)is the most common primary malignant tumor in the central nervous system,with high morbidity,high mortality,high recurrence rate and low cure rate.Glioblastoma accounts for more than 60%of all brain tumors in adults and 3%of brain tumors in children.At present,the annual incidence of glioma in China is(50.8)/100000,and the 5-year mortality rate is the third among systemic tumors,second only to pancreatic cancer and lung cancer.About 90%of glioblastomas are new and have a natural history of less than 3 months as a primary tumor.At present,glioblastoma is mainly treated with postoperative radiotherapy and chemotherapy,but because of the high malignant degree of glioblastoma,high recurrence rate and mortality,the prognosis of patients is poor.Under the existing treatment conditions,the median survival time of glioblastoma patients is 14 months.On average,most patients die within 14 months after diagnosis,and less than 5%of patients survive more than 5 years.In patients over the age of 65,the 5-year survival rate dropped to about 2%.Therefore,it has always been the goal of neurosurgeons and radiotherapy doctors to find new and effective treatments to improve the prognosis and prolong the overall survival time of patients with GBM.Hyperthermia is a kind of local application of high temperature to induce irreversible cell damage in the target area.It is not only a promising method for cancer treatment,but also another tumor treatment after surgery,radiotherapy,chemotherapy and biotherapy.Clinical application is relatively safe.The advantage of hyperthermia in the treatment of cancer is based on the fact that cancer tissue is more sensitive to heat than normal tissue-perhaps due to the acidic interstitial environment of tumor tissue,poor heat dissipation capacity and high metabolic pressure-thus achieving maximum anti-tumor effect with minimal damage to surrounding healthy tissue.Hyperthermia is often combined with radiotherapy and chemotherapy to improve the efficacy of radiotherapy and chemotherapy so as to improve the prognosis and survival time of patients.It has been found that glioma cells are sensitive to hyperthermia,and hyperthermia can reduce the radiation resistance of glioma cells.Therefore,this study starts from the clinic,by comparing the short-term efficacy,recurrence rate,progression-free survival time and overall survival time of postoperative glioblastoma treated by hyperthermia simultaneous radiotherapy and chemotherapy and conventional radiotherapy and chemotherapy,in order to provide reference for clinical treatment.Methods:Clinical data:61 newly diagnosed postoperative patients with glioblastoma in our hospital from September 2016 to June 2019 were retrospectively analyzed.They were divided into control group(n=34)and observation group(n=27).The control group was treated with radiotherapy combined with temozolomide chemotherapy,while the observation group was treated with hyperthermia on the basis of the control group.The progression-free survival time,overall survival time and survival analysis were compared between the two groups.Results:The progression-free survival time and overall survival time in the observation group were higher than those in the control group(P<0.05).Survival analysis showed that the median survival time was 18 months in the observation group and 14 months in the control group.Hyperthermia combined with radiotherapy and chemotherapy could prolong the overall survival time of patients with glioblastoma(P<0.05).Conclusions:Compared with radiotherapy and chemotherapy alone,hyperthermia combined with radiotherapy and chemotherapy can prolong the overall survival time of patients with glioblastoma.PART ⅡStudy on the Mechanism of Hyperthermia Sensitized Radiotherapy in GlioblastomaBackground and Objective:At present,the most important treatment for glioblastoma is radiotherapy and chemotherapy after maximum surgical resection.However,after multidisciplinary comprehensive treatment,the survival time is still very poor.Due to the high degree of malignancy of glioblastoma,the boundary between glioblastoma and normal tissue is often unclear,and there are still micro-infiltrative foci after surgical resection,so postoperative radiotherapy is a very important and effective treatment.However,glioblastoma can produce radiotherapy resistance and reduce the curative effect after radiotherapy.Hyperthermia is one of the oldest and most effective radiosensitizers and has been shown to improve cancer control in many phase III clinical trials.When used in combination with brachytherapy,hyperthermia can significantly improve the survival rate of patients with glioblastoma.However,due to technical challenges in management,the widespread use of hyperthermia has been limited.At present,the real-time temperature measurement of hyperthermia can be realized,and the application prospect of hyperthermia in patients with glioblastoma is broad.The development of temperature measurement technology increases confidence for the development of hyperthermia technology.According to this developing treatment model,an experiment was designed to determine the efficacy of hyperthermia combined with external irradiation in the treatment of glioblastoma,and to explore the molecular mechanism of hyperthermia sensitization,in order to reveal the potential targets to improve the radiosensitivity of glioblastoma.Methods:U87MG glioblastoma cells were cultured and divided into four groups:blank control group,hyperthermia group,radiotherapy group and hyperthermia plus radiotherapy group.After that,cell proliferation was detected by cell clone formation assay,apoptosis and cell cycle were detected by flow cytometry,and signal pathways were detected by WesternBlot.Results:Through the cell clone formation experiment,the number of cell clones in the hyperthermia+radiotherapy group was lower than that in the radiotherapy group and the hyperthermia group(p<0.05),and the apoptosis rate in the hyperthermia+radiotherapy group was significantly higher than that in the radiotherapy group(p<0.05).The apoptosis rate in the hyperthermia+radiotherapy group was significantly higher than that in the radiotherapy group(p<0.05).Flow cytometry showed that the proportion of G2 phase in the hyperthermia group was higher than that in the radiotherapy group,and the proportion of G2 phase in the hyperthermia plus radiotherapy group was significantly lower than that in the radiotherapy group(p<0.05).Western Blot assay showed that phosphorylation of pAKT and its downstream related molecules was activated after radiotherapy,and hyperthermia could inhibit its activation.Conclusions:Hyperthermia combined with radiotherapy significantly improved the efficacy of radiotherapy.Hyperthermia enhanced the radiosensitivity of glioblastoma by inhibiting radiation-activated PI3K/AKT pathway.