| Objective To analyze the effects of pre-treatment with anti-vascular endothelial growth factor(VEGF)drugs at different times on intraoperative and postoperative pars plana vitrectomy(PPV)in proliferative diabetic retinopathy(PDR)patients,and to analyze changes of VEGF and fibrosis-related factors concentrations in the vitreous humor and their correlation with vitreoretinal fibrosis,to investigate the possible molecular mechanism of the "angio-fibrosis switch",and to explore the optimal timing of preoperative intravitreal anti-VEGF injection for PDR patients.Methods The study was divided into two parts:a retrospective case-observation study and a prospective case-control study.The first part of the study enrolled 55 PDR patients who were received anti-VEGF drugs pre-treatment combined with PPV in the department of ophthalmology of the First Affiliated Hospital of Anhui University of Science and Technology from January 2019 to September 2020.According to the different timing of perioperative application of anti-VEGF drugs,they were divided into three groups:2～3 days group,5～7 days group and≥10 days group.The differences of intraoperative and postoperative clinical observation indexes of PPV among the three groups were compared.The second part of the study enrolled 31 PDR patients with stage Ⅳ～Ⅵ who were diagnosed in the department of ophthalmology and planned to receive PPV or anti-VEGF drugs pre-treatment combined with PPV from January 2019 to July 2020 as the experimental group.According to whether the anti-VEGF drugs were injected into vitreous or not and the interval between the intravitreal injection and PPV,the experimental group was further divided into four groups:no intravitreal anti-VEGF injection group,3-day group,5-day group and ≥7-day group.In addition,21 non-diabetic patients were included as the control group.Collected 0.5-1.0ml of vitreous humor from each patient included in the study,and collected it under non-perfusion conditions before routine 23 G PPV.The concentrations of VEGF,bFGF,periostin,IL-6,IL-8 and TNF-α in vitreous humor of patients in each group were detected by Luminex assay,and the differences in the concentration of each cytokine between the groups were compared.The correlation between the changes of cytokines concentrations and the progression of vitreoretinal fibrosis was analyzed by univariate ordinal logistic regression analysis combined with the clinical data.Results There were significant differences in grade of vitreous hemorrhage absorption degree,intraoperative bleeding and fibrovascular membranes among the 2～3 days group,5～7 days group and≥10 days group after intravitreal injection of anti-VEGF drugs(Z=12.913,14.245,12.285,all P<0.01).The grade of vitreous hemorrhage absorption degree and intraoperative bleeding in 5～7 days group and ≥ 10 days group were better than those in 2～3 days group,and the grade of fibrovascular membrane in 2～3 days group and 5～7 days group were both better than that in≥ 10 days group.The intraoperative coagulation rate and the incidence of iatrogenic retinal hole among the three groups were statistically significant(χ2=18.952,8.795,both P<0.05).Further pairwise comparisons between groups showed that the coagulation rate of patients in the 5～7 days group was significantly lower than that in the 2～3 days group and the≥ 10 days group(χ2=14.924,10.414,both P<0.0167),and the incidence of iatrogenic retinal hole in the≥10 days group was significantly higher than that in the 2～3 days group and 5～7 days group(both P<0.0167).The difference in average operation time among the three groups was statistically significant(F=25.079,P<0.01).The operation time of the patients in the 5～7 days group was significantly shorter than that in the 2～3 days group and the≥10 days group(both P<0.01).The differences in LogMAR BCVA among the three groups of patients at 1,3 and 6 months after PPV were statistically significant(Z=6.642,7.090,0.657,all P<0.05).The BCVA of patients at 1,3 and 6 months after operation in the 5～7 days group were all statistically better than that in the 2～3 days group(Z=12.533,12.904,13.871,all P<0.05).The BCVA of patients in 5～7 days group only at 6 months after operation was statistically better than that in≥10 days group(Z=-14.446,,P<0.05).The differences of LogMARBCVA before surgery,1 month after surgery,3 months after surgery,6 months after surgery in each of the three groups of patients were all significant differences(2～3 days group:Z=23.422,5～7 days group:Z=46.817,≥10 days group:Z=16.981,all P<0.01).There was significant difference in the incidence of postoperative vitreous hemorrhage among the three groups(χ2=6.558,P<0.05).The incidence of vitreous hemorrhage in 2～3 days group was higher than that in 5～7 days group and ≥ 10 days group.There were no significant differences in postoperative complications such as early postoperative vitreous hemorrhage,late postoperative vitreous hemorrhage,transient ocular hypertension,retinal detachment and macular edema among the three groups(all P>0.05).Statistical differences of VEGF and IL-8 concentrations between non-injection group and injection group were observed(Z=-3.491、-2.363,both P<0.05),and the concentration of VEGF decreased and the concentration of IL-8 increased in injection group.However,there were no significant differences in bFGF,periostin,IL-6 and TNF-α concentrations between the two groups(all P>0.05).The concentrations of cytokines in vitreous humor of patients in non-injection group,3-day group,5-day group,≥ 7-day group and control group were not the same,and the differences were statistically significant(F=42.105、36.653、33.396、28.517、26.554、18.326,all P<0.01).The concentrations of VEGF,bFGF,periostin,IL-6 and IL-8 in vitreous humor of PDR patients were different after intravitreal injection of anti-VEGF drugs at different times,and the differences were statistically significant(F=13.077,16.524,10.440,7.748,8.960,all P<0.05).Further pairwise comparisons showed that the concentration of VEGF in vitreous humor in 5-day group was the lowest,which was significantly lower than that in 3-day group and ≥ 7-day group(both P<0.05),and the concentrations of bFGF and periostin in vitreous humor in ≥7-day group were both the highest,which were significantly higher than that in 3-day group and 5-day group(both P<0.05).In addition,the concentrations of IL-6 and IL-8 in vitreous humor in≥7-day group were significantly higher than those in 3-day group(both P<0.05),but there was no significant difference between≥7-days group and 5-day group(P>0.05).The grade of vitreoretinal fibrosis was significant difference among 3-day group,5-day group and ≥ 7-day group(Z=8.988,P<0.05).Further pairwise comparisons showed that the grade of vitreoretinal fibrosis in ≥7-day group was significantly higher than that in 3-day group and 5-day group(both P<0.05).Spearman rank correlation analysis showed that the grade of vitreoretinal fibrosis in the injection group was positively correlated with bFGF,periostin,IL-6 and IL-8(rs=0.879,0.608,0.488,0.529,all P<0.05)concentrations,but not with VEGF and TNF-α(rs=0.182,0.112,both P>0.05).Univariate ordinal logistic regression analysis showed that high concentration of bFGF was an independent risk factor for vitreoretinal fibrosis progression in PDR patients who received intravitreal injection of anti-VEGF drugs.Conclusion The expression of multiple cytokines in vitreous humor of PDR patients will change after intravitreal anti-VEGF drugs injection before PPV.Continuous blocking of VEGF cytokine can trigger "vascular-fibrosis switch".It is suggested that PPV should be performed on the fifth day after the administration of anti-VEGF drugs in PDR patients.At this time,the clinical benefit is best.Furthermore,concentrations of VEGF in vitreous humor reach the lowest,and concentrations of bFGF and periostin have not increase significantly.While the degree of vitreoretinal fibrosis can significantly increase in patients with an interval of more than 7 days,which is mainly related to the significantly increased expression of bFGF,periostin,IL-6 and IL-8 in vitreous humor.bFGF is an independent risk factor for vitreoretinal fibrosis progression and is expected to become a new target for anti-fibrosis therapy.Figure[13]Table[17]Reference[87]... |
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