Pre-therapeutic Biomarkers for Ranibizumab Therapy among Type 2 Diabetic Patients with Diabetic Macular Edema.

SIGNIFICANCE: A differential outcome in randomized controlled trials of anti-vascular endothelial growth factor (anti-VEGF) therapy, including ranibizumab, for diabetic macular edema is a major dilemma for planning, optimizing, and managing clinical usage. The variable outcome of the therapeutics necessitates the importance of finding a predictive biomarker for anti-VEGF therapy to improve subject selection. PURPOSE: Our study correlates the baseline pro- and anti-VEGF isoforms and its three receptors (VEGFReceptor1, VEGFReceptor2, and VEGFReceptor3) for circulatory candidate protein molecules among diabetic patients with macular edema, with the clinical outcome of ranibizumab therapy. METHODS: This study included 86 individuals who were anti-VEGF naive at the time of ascertainment but have completed the standardized therapy regimen of the clinic. Plasma proteins for pro- and anti-VEGF isoforms and its three receptors were determined in replicate by an enzyme-linked immunosorbent assay. RESULTS: The study demonstrated that 56 (65.12%) individuals benefited from the therapy in terms of letter gain (Snellen chart). Baseline plasma soluble VEGF receptor 2 (sVEGFR-2) was significantly higher among responders (65.10 pg/mL; 95% confidence interval, 55.41 to 74.80 pg/mL) compared with nonresponders (46.38 pg/mL; 95% confidence interval, 38.69 to 54.07 pg/mL; PFDR = .03). Diffuse diabetic macular edema with proliferative diabetic retinopathy increases the risk of nonresponse to the therapy by 3.03-fold (PFDR = .04). CONCLUSIONS: The present study postulates that diffuse diabetic macular edema with proliferative diabetic retinopathy and baseline circulatory soluble VEGF receptor 2 may be potential candidates as therapy-stratifying markers for ranibizumab treatment among patients with diabetic macular edema.

Pro- and antiangiogenic VEGF and its receptor status for the severity of diabetic retinopathy.

PURPOSE: Alteration of pro- and antiangiogenic homeostasis of vascular endothelial growth factor (VEGF) isoforms in patients with hyperglycemia seems crucial but substantially unexplored at least quantitatively for diabetic retinopathy (DR). Therefore, in the present study we aimed to estimate the difference between the pro- (VEGF165a) and antiangiogenic (VEGF165b) VEGF isoforms and its soluble receptors for severity of DR. METHODS: The study included 123 participants (diabetic retinopathy: 81, diabetic control: 20, non-diabetic control: 22) from the Regional Institute of Ophthalmology, Kolkata. The protein levels of VEGF165a (proangiogenic), VEGF165b (antiangiogenic), VEGF receptor 1 (VEGFR1), VEGFR2, and VEGFR3 in plasma were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: An imbalance in VEGF homeostasis, a statistically significant concomitant increase (p<0.0001) in the level of VEGF165a and a decrease in the level of VEGF165b, was observed with the severity of the disease. Increased differences between VEGF165a and VEGF165b i.e. VEGF165a-b concomitantly increased statistically significantly with the severity of the disease (p<0.0001), patients with diffuse diabetic macular edema (DME) with proliferative DR (PDR) had the highest imbalance. The plasma soluble form of VEGFR2 concentration consistently increased statistically significantly with the severity of the disease (p<0.0001). CONCLUSIONS: The increased difference or imbalance between the pro- (VEGF165a) and antiangiogenic (VEGF165b) homeostasis of the VEGF isoforms, seems crucial for an adverse prognosis of DR and may be a better explanatory marker compared with either VEGF isoform.

Association of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects.

PURPOSE: New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor α, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: This case-control study comprised 493 volunteers (253 PDR cases and 240 diabetic controls). Cases and controls were ascertained such that age, sex, nutrition, and glycemic status were matched. Genotypes were determined by polymerase chain reaction-based methods. RESULTS: Interleukin 10-1082GG (P = 0.0037; odds ratio [OR] = 2.232), tumor necrosis factor α-238AA (P = 0.0001; OR = 5.791), and GA (P = 0.0015; OR = 1.909) genotypes were significantly associated with PDR occurrence. The interleukin 10-1082G allele (P = 0.0048, OR = 1.4442) and the tumor necrosis factor α-238A allele (P = 0.0001; OR = 2.2897) were significantly increased among PDR cases. CONCLUSION: From our study, it may be concluded that the genetic variation, that is, tumor necrosis factor α-238A and interleukin 10-1082G alleles are the potent risk factors for the pathogenesis of PDR.

Prospective randomized comparative study of macular thickness following phacoemulsification and manual small incision cataract surgery.

PURPOSE: To compare macular thickness following uncomplicated phacoemulsification with foldable acrylic lens and manual small incision cataract surgery (MSICS) with non-foldable polymethyl methacrylate (PMMA) lens implantation. METHODS: Prospective study was carried out with one eye each of 224 patients with senile cataract randomized into two groups, phacoemulsification and MSICS, by simple 1:1 randomization. Following surgery by either of the two methods, macular thickness was measured by optical coherence tomography (OCT) on the 1st, 7th, 42nd and 180th postoperative day. Main outcome measure was postoperative macular thickness. RESULTS: On the first postoperative day, central subfield mean thickness (CSMT) in MSICS group was 192.8 +/- 17.9 microm and that in phacoemulsification group was 192.1 +/- 27.4 microm, with no significant difference (p = 0.12). On the 7th day, CSMT in MSICS group (198.9 +/- 21.4 microm) was significantly (p = 0.04) more than that in phacoemulsification group (193.1 +/- 19.3 microm). On the 42nd day, CSMT in MSICS group was 207.8 +/- 26.3 microm and that in phacoemulsification group was 198.3 +/- 23 microm, the difference being significant (p = 0.007). Clinically macular oedema was not diagnosed in any of the patients at any visit. The increase in macular thickness was sub-clinical and did not affect final visual outcome in any patient. CONCLUSION: In spite of the greater theoretical risk of increased postoperative inflammation following MSICS, there was no evidence of cystoid macular oedema, either clinically or on OCT. However, chance of sub-clinical increase in CSMT was more following MSICS compared to phacoemulsification.