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Objective:To evaluate the effects of proton pump inhibitors (PPIs) on the clinical outcomes for advanced solid tumor patients treated with immune checkpoint inhibitors (ICIs).Methods:A total of 204 patients with advanced solid tumors who received ICIs in the Affiliated Hospital of Yangzhou University from November 2016 to December 2020 were retrospectively analyzed. The patients were divided into PPIs group ( n=73) and Non-PPIs group ( n=131) according to whether they received PPIs within 1 month before or after the initiation of ICIs treatment. The correlations between the uses of PPIs and the clinical characteristics of patients were explored, and the clinical efficacy of the two groups was evaluated. Kaplan-Meier survival curve was applied to analyze the effects of PPIs uses on overall survival (OS) and progression-free survival (PFS) of patients. The Cox proportional hazards model was used to clarify whether PPIs was an independent indicator of patients′ prognosis. Results:During ICIs treatment of advanced solid tumors, the use of PPIs was not correlated with the patients′ gender, age, tumor type, the score of the United States Eastern Collaborative Group, types of immunotherapy drugs and treatment strategy (all P>0.05). The objective response rate of the Non-PPIs group was better than that of the PPIs group (45.0% vs. 24.7%, χ2=8.286, P=0.004). The disease control rate of the Non-PPIs group was better than that of the PPIs group (75.6% vs. 52.0%, χ2=11.755, P=0.001). In patients with advanced solid tumors, the median OS (3.4 months vs. 6.1 months) and median PFS (2.8 months vs. 4.0 months) in the PPIs group were shorter than those in the Non-PPIs group ( χ2=9.563, P=0.002; χ2=5.761, P=0.016). Univariate analysis showed that among patients with advanced solid tumors treated with ICIs, PPIs uses was significantly correlated with OS ( HR=1.85, 95% CI: 1.24-2.76, P=0.003); PPIs uses( HR=1.65, 95% CI: 1.09-2.51, P=0.019) and age ( HR=1.56, 95% CI: 1.05-2.32, P=0.029) were significantly correlated with PFS. Multivariate analysis showed that PPIs uses was an independent prognostic factor affecting OS ( HR=1.90, 95% CI: 1.27-2.85, P=0.002) and PFS ( HR=1.73, 95% CI: 1.12-2.65, P=0.013). Meanwhile, subgroup analysis discovered that in the course of ICIs treatment of lung cancer patients, the median OS (3.2 months vs. 6.2 months) and median PFS (2.2 months vs. 3.8 months) in the PPIs group ( n=64) were shorter than those in the Non-PPIs group ( n=34) ( χ2=16.187, P<0.001; χ2=5.106, P=0.020). Univariate analysis showed that PPIs uses was associated with OS ( HR=2.97, 95% CI: 1.70-5.22, P<0.001) and PFS ( HR=1.97, 95% CI: 1.09-3.55, P=0.025) in lung cancer patients treated with ICIs. Multivariate analysis showed that PPIs uses was an independent prognostic factor for OS ( HR=3.38, 95% CI: 1.87-6.11, P<0.001) and PFS ( HR=2.31, 95% CI: 1.22-4.38, P=0.010) in lung cancer patients treated with ICIs. Conclusion:The use of PPIs reduces the effect of ICIs in the treatment of advanced solid tumor, especially in lung cancer. PPIs should be used cautiously in patients with advanced solid tumors treated with ICIs.
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In the treatment of non-small cell lung cancer (NSCLC), immunotherapies represented by immune checkpoint inhibitors are developing rapidly. It is the premise of precise treatment to clarify the influencing factors of NSCLC immunotherapy. In the course of immunotherapy for advanced NSCLC, elderly patients can obtain specific effect from immunotherapy; male patients benefit more from monotherapy; when steroid hormones are used for related symptoms caused by tumors, they are poor prognostic factors for patients. The occurrence of immune-related adverse events is a favorable prognostic factor while driving gene mutations and the use of antibiotics will reduce the efficacy of immunotherapy.
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Objective To learn the effect of different combination model between irradiation and cisplatin or lobaplatin on the radiosensitization of xenographt tumor in mice.Methods Seventy C57BL/6 mice with Lewis lung carcinoma were randomly divided into fourteen groups.Then a single intravenous bolus injection of 10 mg/kg either cisplatin or lobaplatin was given.Tumor tissues were collected at the indicated times of 0.5 h, 2.0 h, 4.0 h, 24.0 h, 48.0 h, 72.0 h, and 96.0 h.The platinum levels were determined by inductively coupled plasma-mass spectrometry.Eighty tumor-bearing mice were randomly divided into 10 groups, including a blank control group, a irradiation group, two drug treatment groups and 6 combined treatment groups.The tumors were irradiated at 1 h, 24 h or 72 h after either cisplatin or lobaplatin injection.The tumor size of the groups was compared.Results The concentrations of cisplatin and lobaplatin in tumors rapidly reached 4.78 μg/g and 2.79 μg/g (t=3.82,P=0.005), respectively, then declined rapidly to 3.39 μg/g and 0.99 μg/g (t=9.10,P=0.000) at 4 h, 1.41 μg/g and 0.23 μg/g (t=3.70,P=0.006) at 96 h, respectively.The tumor growth among the three groups of irradiation at 1 h, 24 h or 72 h after cisplatin was similar, which was slower than the blank control group, the irradiation group and the cisplatin treatment group.At the 15th day, the relative volume of tumor in the three combined treatment groups were 4.73, 5.52 and 2.15(F=0.84,P=0.451), While was 16.63(F=10.50,P=0.000) in the blank control group, 10.34(F=3.12,P=0.046) in the irradiation group, and 12.80(F=8.06,P=0.001) in the cisplatin treatment group, respectively.The tumor growth among the three groups of irradiation at 1 h, 24 h or 72 h after lobaplatin was also similar, which was slower than the blank control group, the irradiation group and the lobaplatin treatment group.At the 15th day, the relative volume of tumor in the three combined treatment groups were 3.49, 4.90 and 3.86(F=0.32,P=0.727), While was 16.63(F=15.21,P=0.000) in the blank control group, 10.34(F=4.12,P=0.016) in the irradiation group, and 14.28(F=10.67,P=0.000) in the lobaplatin treatment group, respectively.The sensitizing enhancement ratio (SER) at 1 h, 24 h and 72 h after the injection were 2.13, 2.03 and 3.45 of cisplatin, and 2.53, 2.00 and 2.50 of lobaplatin, respectively.Conclusions After intravenous bolus injection, the cisplatin concentration in the tumor can be kept at least 96 hours, which results in a persistent radiosensitizing effect.Lobaplatin and cisplatin have similar anti-tumor and radiosensitizing effect.
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Objective To test the hypothesis that p53 gene therapy combined with endostatin can enhance tumor response to radiation therapy of RM-1 mouse xenograft prostate cancer and to investigate its mechanism. Methods A mouse prostate cancer model was established. Then mice with xenograft tumor were randomly divided into group A (control), B (radiation), C (radiation and rAdp53), D (radiation and rh-endostatin) and E (radiation and rAdp53 and rh-endostatin). On day 1, rAdp53 was injected intra-tumorously with 1 × 1010 vp per animal to group C and E. From day 1 to 14, rh-endostatin was given 15 mg/kg intraperitoneally daily to group D and E. On day 4 single fraction of 15 Gy was given to tumors in groups B, C, D and E. Normal saline was injected intra-tumorously or intraperitoneaUy accordingly as control. No treatment was done to group A. Tumor volume was measured daily. Samples were collected on Days 5, 10 and 15. Ki67, CD31, p53 and VEGF were detected by means of immunohistochemistry. Results (1) Radiation alone, radiation combined with intra-tumorous injection of Adp53 and/or intraperitoneal injection of rh-endostatin resulted in tumor growth arrest of RM-1 cells in vivo (P = 0.000). Radiation combined with both rAdp53 and rh-endostatin was the most effective treatment (P < 0.05). (2) All the four treatment groups had a decreased expression of mutant type P53 (P = 0.000). The expression of Ki67 in groups B and C were equal (P 0.05) and increasing (P = 0.000), respectively. Group D had a up-down-up curve (P < 0.05), but group E had a up-down one. On day 5 the expresion of VEGF in group E was the lowest (P < 0.05). An increased expression of MVD compared with the control was shown, and MVD in groups C, D and E were always higher than that in the control (P < 0.05). Conclusions The limitation of radiotherapy could be overcome by combination with beth p53 gene therapy and endostatin on the growth of mouse prostate cancer cell. Radiation, rAdp53 and endostatin have their own role but they can be interacted with each other.
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AIM: To investigate the expression of midkine in bladder transitional cell carcinoma and to analyze its relationship with the features of clinical pathology and prognosis.METHODS: The expressions of midkine protein in 50 cases of bladder transitional cell carcinoma samples were detected by SP immunohistochemical method using polyclonal antibodies against human midkine.Survival time of 40 cases was recorded.RESULTS: The protein expression of midkine was found in cytoplasm of tumor cells.The overall positive rate of midkine in 50 cases of bladder carcinoma was 90%(45/50).The positive degree of midkine showed a trend of increasing in grade and stage.There was statistically significant difference among them(P0.05).Patients with high expression of MK predicted a poor clinical outcome.CONCLUSION: Midkine is overexpressed in bladder transitional cell carcinoma than that in normal bladder.MK expression in bladder cancer is higher in less differentiated and deeper invaded cases,but it has no correlation with age,sex,treatment,tumor number and size.Patients with higher MK expression have shorter survival time than those with lower MK expression.