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TGF-β Serum Levels in Diabetic Retinopathy Patients and the Role of Anti-VEGF Therapy.
Bonfiglio, V, Platania, CBM, Lazzara, F, Conti, F, Pizzo, C, Reibaldi, M, Russo, A, Fallico, M, Ortisi, E, Pignatelli, F, et al
International journal of molecular sciences. 2020;(24)
Abstract
Transforming growth factor β1 (TGFβ1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGFβ1 as a diagnostic and prognostic biomarker of DR stages. Thirty-eight subjects were enrolled and, after diagnosis and evaluation of inclusion and exclusion criteria, were assigned to six groups: (1) healthy age-matched control, (2) diabetic without DR, (3) non-proliferative diabetic retinopathy (NPDR) naïve to treatment, (4) NPDR treated with intravitreal (IVT) aflibercept, (5) proliferative diabetic retinopathy (PDR) naïve to treatment and (6) PDR treated with IVT aflibercept. Serum levels of vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF) and TGFβ1 were measured by means of enzyme-linked immunosorbent assay (ELISA). Foveal macular thickness (FMT) in enrolled subjects was evaluated by means of structural-optical coherence tomography (S-OCT). VEGF-A serum levels decreased in NPDR and PDR patients treated with aflibercept, compared to naïve DR patients. PlGF serum levels were modulated only in aflibercept-treated NPDR patients. Particularly, TGFβ1 serum levels were predictive of disease progression from NPDR to PDR. A Multivariate ANOVA analysis (M-ANOVA) was also carried out to assess the effects of fixed factors on glycated hemoglobin (HbA1c) levels, TGFβ1, and diabetes duration. In conclusion, our data have strengthened the hypothesis that TGFβ1 would be a biomarker and pharmacological target of diabetic retinopathy.
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Diabetic Retinopathy and Vascular Endothelial Growth Factor Gene Insertion/Deletion Polymorphism.
Khan, SZ, Ajmal, N, Shaikh, R
Canadian journal of diabetes. 2020;(3):287-291
Abstract
Diabetic retinopathy (DR) is a microvascular complication of the retina of the eye and represents a major cause of blindness worldwide. It is a complex disorder characterized by both genetic and environmental factors. The vascular endothelial growth factor (VEGF) gene is among the main candidate genes for DR, as it is also involved in several other diseases, such as microvascular complications of diabetes mellitus and cancer. The VEGF gene is extremely polymorphic. The 18-bp fragment (insertion/deletion) polymorphism at the -2549 position of the promoter region of the VEGF gene is of great importance. In this review, we highlight the DR and VEGF gene (insertion/deletion) polymorphism. In addition, we assess this association in various DR populations and in other microvascular complications, such as diabetic nephropathy, diabetic peripheral neuropathy and cancer.
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Genetic interaction analysis of VEGF-A rs3025039 and VEGFR-2 rs2071559 identifies a genetic profile at higher risk to develop nodular goiter.
Molinaro, A, Orlandi, P, Niccolai, F, Agretti, P, De Marco, G, Ferrarini, E, Di Cosmo, C, Vitti, P, Piaggi, P, Di Desidero, T, et al
Journal of endocrinological investigation. 2020;(2):149-155
Abstract
CONTEXT Nodular goiter in patients from areas of iodine deficiency is due to the growth of follicular and endothelial cells, involving different vascular-related growth factors in its pathogenesis. OBJECTIVE The aim of our study was to examine the association of known single polymorphisms of vascular endothelial growth factor-A [VEGF-A], VEGF receptor-2 [VEGFR-2] and hypoxia-inducible factor-1α [HIF-1α] genes or their genetic interactions with the risk of nodular goiter development. PATIENTS AND METHODS 116 normal subjects, without any thyroid disease, and 108 subjects with nodular goiter [subjects with goiter and at least one thyroid nodule of > 1 cm of maximum size and in absence of signs of autoimmunity] were selected from a homogeneous population living in a mild iodine deficiency geographic area. Analyses were performed on germline DNA obtained from blood samples and VEGF-A rs3025039, VEGFR-2 rs2071559, and HIF-1αrs11549465 SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction [MDR] methodology was applied to investigate the genetic interaction between SNPs. Hardy-Weinberg equilibrium was performed. RESULTS None of the studied polymorphisms were individually associated with a higher risk to develop nodular goiter [P > 0.05]. The combination of the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms had the highest accuracy of 0.58 [P = 0.018] and the interaction of some genotypes was significantly associated with the risk of nodular goiter development. CONCLUSIONS Our results support a genetic interaction between the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms as a predictor of the risk to develop nodular goiter in subjects coming from an area with mild iodine deficiency.
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4.
Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial.
Van Cutsem, E, Paccard, C, Chiron, M, Tabernero, J
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(3):717-725
Abstract
PURPOSE Aflibercept is a targeted anti-VEGF therapy used to treat patients with metastatic colorectal cancer (mCRC) following progression on oxaliplatin-based regimens. This post hoc study evaluated the effect of prior bevacizumab treatment and growth factor levels on patient outcomes associated with aflibercept in the VELOUR phase III trial. EXPERIMENTAL DESIGN Baseline biomarker plasma concentrations were measured using a bead-based multiplex assay. Patients were grouped according to prior bevacizumab treatment, second-line treatment, and serum biomarker concentrations, and analyzed for overall survival (OS) and progression-free survival (PFS). RESULTS Plasma samples were available for 553 patients (placebo n = 265; aflibercept n = 288), of which 169 had received prior bevacizumab. Nine biomarkers implicated in angiogenesis or bevacizumab resistance correlated with prior bevacizumab therapy. VEGF-A and placental growth factor (PlGF) were the most significantly increased in patients who had received prior bevacizumab compared with those who had not received prior bevacizumab. In the placebo group, patients with high VEGF-A (>144 pg/mL) levels at baseline had worse OS and PFS compared with patients with lower levels at baseline (9.6 vs. 12.9 months). This was also seen in patients who received placebo and had high baseline PlGF (>8 pg/mL; 9.7 vs. 11.7 months). In the aflibercept group, prolonged OS and PFS were observed regardless of baseline VEGF-A or PlGF levels. CONCLUSIONS High VEGF-A and PlGF serum levels may underlie development of resistance to bevacizumab in patients with mCRC. Aflibercept retains its activity regardless of baseline VEGF-A and PlGF levels and may be an effective second-line treatment for patients with bevacizumab-induced resistance.
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5.
Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion.
Shalchi, Z, Mahroo, O, Bunce, C, Mitry, D
The Cochrane database of systematic reviews. 2020;(7):CD009510
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Abstract
BACKGROUND Branch retinal vein occlusion (BRVO) is one of the most commonly occurring retinal vascular abnormalities. The most common cause of visual loss in people with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss. Limitations to this treatment exist, however, and newer modalities may have equal or improved efficacy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has recently been used successfully to treat MO resulting from a variety of causes. OBJECTIVES To investigate the efficacy and gather evidence from randomised controlled trials (RCTs) on the potential harms of anti-vascular endothelial growth factor (VEGF) agents for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO). SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 6); MEDLINE Ovid; Embase Ovid; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. The date of the last search was 12 June 2019. SELECTION CRITERIA We included randomised controlled trials (RCTs) investigating BRVO. Eligible trials had to have at least six months' follow-up where anti-VEGF treatment was compared with another treatment, no treatment, or placebo. We excluded trials where combination treatments (anti-VEGF plus other treatments) were used; and trials that investigated the dose and duration of treatment without a comparison group (other treatment/no treatment/sham). DATA COLLECTION AND ANALYSIS Two review authors independently extracted the data using standard methodological procedures expected by Cochrane. The primary outcome was the proportion of participants with an improvement from baseline in best-corrected visual acuity of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at six months and 12 months of follow-up. The secondary outcomes were the proportion of participants who lost greater than or equal to 15 ETDRS letters (3 lines) and the mean visual acuity (VA) change at six and 12 months, as well as the change in central retinal thickness (CRT) on optical coherence tomography from baseline at six and 12 months. We also collected data on adverse events and quality of life (QoL). MAIN RESULTS We found eight RCTs of 1631 participants that met the inclusion criteria after independent and duplicate review of the search results. These studies took place in Europe, North America, Eastern Mediterranean region and East Asia. Included participants were adults aged 18 or over with VA of 20/40 or worse. Studies varied by duration of disease but permitted previously treated eyes as long as there was sufficient treatment-free interval. All anti-VEGF agents (bevacizumab, ranibizumab and aflibercept) and steroids (triamcinolone and dexamethasone) were included. Overall, we judged the studies to be at moderate or unclear risk of bias. Four of the eight studies did not mask participants or outcome assessors, or both. One trial compared anti-VEGF to sham. At six months, eyes receiving anti-VEGF were significantly more likely to have a gain of 15 or more ETDRS letters (risk ratio (RR) 1.72, 95% confidence interval (CI) 1.19 to 2.49; 283 participants; moderate-certainty evidence). Mean VA was better in the anti-VEGF group at six months compared with control (mean difference (MD) 7.50 letters, 95% CI 5.29 to 9.71; 282 participants; moderate-certainty evidence). Anti-VEGF also proved more effective at reducing CRT at six months (MD -57.50 microns, 95% CI -108.63 to -6.37; 281 participants; lower CRT is better; moderate-certainty evidence). There was only very low-certainty evidence on adverse effects. There were no reports of endophthalmitis. Mean change in QoL (measured using the National Eye Institute Visual Functioning Questionnaire VFQ-25) was better in people treated with anti-VEGF compared with people treated with sham (MD 7.6 higher score, 95% CI 4.3 to 10.9; 281 participants; moderate-certainty evidence). Three RCTs compared anti-VEGF with macular laser (total participants = 473). The proportion of eyes gaining 15 or more letters was greater in the anti-VEGF group at six months (RR 2.09, 95% CI 1.44 to 3.05; 2 studies, 201 participants; moderate-certainty evidence). Mean VA in the anti-VEGF groups was better than the laser groups at six months (MD 9.63 letters, 95% CI 7.23 to 12.03; 3 studies, 473 participants; moderate-certainty evidence). There was a greater reduction in CRT in the anti-VEGF group compared with the laser group at six months (MD -147.47 microns, 95% CI -200.19 to -94.75; 2 studies, 201 participants; moderate-certainty evidence). There was only very low-certainty evidence on adverse events. There were no reports of endophthalmitis. QoL outcomes were not reported. Four studies compared anti-VEGF with intravitreal steroid (875 participants). The proportion of eyes gaining 15 or more ETDRS letters was greater in the anti-VEGF group at six months (RR 1.67, 95% CI 1.33 to 2.10; 2 studies, 330 participants; high-certainty evidence) and 12 months (RR 1.76, 95% CI 1.36 to 2.28; 1 study, 307 participants; high-certainty evidence). Mean VA was better in the anti-VEGF group at six months (MD 8.22 letters, 95% CI 5.69 to 10.76; 2 studies, 330 participants; high-certainty evidence) and 12 months (MD 9.15 letters, 95% CI 6.32 to 11.97; 2 studies, 343 participants; high-certainty evidence). Mean CRT also showed a greater reduction in the anti-VEGF arm at 12 months compared with intravitreal steroid (MD -26.92 microns, 95% CI -65.88 to 12.04; 2 studies, 343 participants; moderate-certainty evidence). People receiving anti-VEGF showed a greater improvement in QoL at 12 months compared to those receiving steroid (MD 3.10, 95% CI 0.22 to 5.98; 1 study, 307 participants; moderate-certainty evidence). Moderate-certainty evidence suggested increased risk of cataract and raised IOP with steroids. There was only very low-certainty evidence on APTC events. No cases of endophthalmitis were observed. AUTHORS' CONCLUSIONS The available RCT evidence suggests that treatment of MO secondary to BRVO with anti-VEGF improves visual and anatomical outcomes at six and 12 months.
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Intravitreal Conbercept Injection as an Adjuvant in Vitrectomy with Silicone Oil Infusion for Severe Proliferative Diabetic Retinopathy.
Gao, S, Lin, Z, Chen, Y, Xu, J, Zhang, Q, Chen, J, Shen, X
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 2020;(5):304-310
Abstract
Purpose: To assess the clinical effects of preoperative, intraoperative, or preoperative combined with intraoperative intravitreal conbercept (IVC) injection in vitrectomy with silicone oil tamponade for severe proliferative diabetic retinopathy (PDR). Methods: Ninety-eight eyes of 98 severe PDR patients undergoing vitrectomy with silicone oil tamponade were randomly assigned to 3 groups: Group 1 (34 eyes) received IVC injections 3 to 5 days before surgery; Group 2 (35 eyes) received IVC injections at the end of surgery; and Group 3 (29 eyes) received IVC injections 3 to 5 days before and at the end of operation. Follow-up examinations were performed for 6 months. Results: The incidence and severity of intraoperative bleeding were not significantly different (P = 0.233). However, the duration of surgery was significantly shorter in Group 1 and Group 3 compared with Group 2 (P < 0.001). The incidences of early and late recurrent vitreous hemorrhage (VH) were 32.35%, 28.57%, and 13.80%, respectively. At 6-month follow-up, mean best-corrected visual acuity had significantly increased to 1.25 ± 0.45 logMAR in Group 1, 1.29 ± 0.46 logMAR in Group 2, 1.16 ± 0.44 logMAR in Group 3 (all P < 0.001). The incidence of postoperative VH, neovascular glaucoma, and retinal detachment in Group 3 was slightly lower, however, no significant differences were observed (all P > 0.05). In young patients, similar results were observed and Group 3 had better visual improvements (P = 0.037). Conclusions: Preoperative IVC injection could be a safe and effective adjunct in pars plana vitrectomy with silicone oil tamponade for severe PDR. Preoperative combined with intraoperative IVC are promising, especially in young patients.
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A randomized single-blinded, parallel-arm group feasibility trial evaluating role of pectoral nerve block on serum vascular endothelial growth factor levels in patients undergoing unilateral modified radical mastectomy.
Govil, N, Naithani, M, Ravi, B, Sharda, P, Tripathi, M, Bhardwaj, BB
Medical gas research. 2020;(4):179-184
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Abstract
Metastatic breast cancer cells carry adult and neonatal variants of NaV1.5 voltage-gated activated Na+ channels involved in cell invasion. We hypothesize that instilling lignocaine near the surgical field to anesthetize the pectoral nerves for analgesia will decrease angiogenesis by blocking voltage-gated activated Na+ channels. Twenty patients undergoing unilateral modified radical mastectomy were randomized in a single-blinded, parallel-arm group feasibility pilot study in two groups. In Group I a catheter was placed between the pectoralis major and minor muscle under direct vision before skin closure. Ten milliliters of 2% lignocaine was given as an initial bolus followed by 10 mL of 2% lignocaine every 8 hours up to 24 hours. Group II did not receive any regional block. Primary measure outcomes were pre and postoperative changes in levels of vascular endothelial growth factor. Secondary outcomes were postoperative pain scores and total rescue analgesia used. Nine patients in each group were analyzed. Baseline demographic data of all females were similar with respect to age, body mass, height and duration of anesthesia. Postoperative mean serum levels of vascular endothelial growth factor were decreased by 46.60% from baseline in Group I, while were increased by 84.27% as compared to preoperative values in Group II. Postoperative average pain scores were less in Group I. Postoperative rescue analgesia in 24 hours in Group I was lower than that in Group II. There was no postoperative adverse event related to catheter or lignocaine administration at given doses. Instilling lignocaine to block pectoral nerves provides better postoperative analgesia and decreases a marker of angiogenesis. The study protocol was approved by the Institutional Ethical Committee of the Tertiary Centre (All India Institute of Medical Sciences Rishikesh India) (No. AIIMS/IEC/19/1002) on August 9, 2019, and the larger expansion trial was prospectively registered on Clinical Trial Registry India (No. CTRI/2020/01/022784) on January 15, 2020.
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Effects of cholecalciferol supplementation on serum angiogenic biomarkers in breast cancer patients treated with tamoxifen: A controlled randomized clinical trial.
Shahvegharasl, Z, Pirouzpanah, S, Mahboob, SA, Montazeri, V, Adili, A, Asvadi, I, Sanaat, Z, Esfehani, A, Pirouzpanah, SS, Mesgari, M
Nutrition (Burbank, Los Angeles County, Calif.). 2020;:110656
Abstract
OBJECTIVE The aim of this study was to investigate the effects of cholecalciferol supplementation on serum levels of angiogenic parameters in patients with breast cancer (BC) who were treated with tamoxifen. METHODS This was a pilot-based, randomized, triple-blind, placebo-controlled clinical trial with 52 patients with BC randomly assigned to either an intervention group receiving weekly 50 000 IU cholecalciferol or a placebo group for 8 wk. At baseline and at end of study, serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-2, hypoxia-inducible factor (Hif)-1, and high-sensitivity C-reactive protein were measured by enzyme-linked immunosorbent assay. Every 4 wk, a completed 3-d, 24-h dietary record and daily sunlight exposure checklist were collected and anthropometric variables were measured. RESULTS The ultimate number of participants in each arm was 22 for analyses. For premenopausal women, cholecalciferol supplementation resulted in a significant decrease in serum levels of Ang-2 and VEGF-A after 8 wk of treatment (P < 0.05). In the absence of vascular invasion, supplementation led to a significant decrease in Ang-2 levels compared with the placebo group (P < 0.05). Supplementation caused significant increases in Hif-1 in patients diagnosed with the infiltration of tumors into vascular or lymphatic vessels (P < 0.05). CONCLUSION Cholecalciferol supplementation achieved sufficient efficacy among patients with BC taking tamoxifen and could be effective in the reduction of angiogenic biomarkers particularly dependent on the infiltration status of the tumor to vessels. Further studies with larger subgroups should be investigated.
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Current concepts of pharmacotherapy of diabetic macular edema.
Haritoglou, C, Maier, M, Neubauer, AS, Augustin, AJ
Expert opinion on pharmacotherapy. 2020;(4):467-475
Abstract
Introduction: Diabetic macular edema (DME) is a sight threatening disease and a major cause for blindness for people in working age. The pathogenesis is multifactorial and complex. The pharmacotherapy of DME addresses both the inhibition of vascular endothelial growth factor (VEGF) by the intravitreal injection of VEGF inhibitors and inflammatory processes by the intravitreal application of steroids. Several trials have been published reporting on the efficacy and safety of these treatments.Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on the role of inflammation and VEGF expression in DME. It discusses newly published clinical trials on intravitreal pharmacotherapy for DME. The literature was searched using Medline/PubMed and was selected given its relevance for the topic to be discussed.Expert opinion: Our knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Some of these insights have been successfully transferred into current treatment strategies already including VEGF suppression or anti-inflammatory treatments using steroids. The identification of additional pathophysiological aspects and their relevance as potential treatment targets will be a future challenge in the treatment of DME. A better knowledge on the complex pathophysiology will also help to establish combination strategies.
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Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis.
Yang, Q, Zhang, Y, Zhang, X, Li, X, Liu, J
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(5):264-279
Abstract
The associations between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of type 2 diabetic retinopathy (DR) - proliferative diabetic retinopathy (PDR), and nonproliferative diabetic retinopathy (NPDR) - remain unclear. A systematic search and meta-analysis using odds ratio (OR) with 95% confidence interval (CI) was performed to evaluate the association. Our study concluded 26 studies containing 10 single nucleotide polymorphisms (SNPs). In Asian populations, rs3025039 polymorphism was associated with DR risk, while in overall populations and Caucasians, the DR risk was increased by association with rs2010963. There was a significant association between rs25648 and rs833061 and DR risk in Caucasians. DR risks were found to be significantly associated between rs3025021, rs13207351, and rs2146323 in either overall populations, Caucasians or Asians. Besides, in overall and Asian populations, rs699947 and rs3025039 were associated with PDR risk. rs1570360, rs3025039, and rs833061 played a key role in PDR etiology in Caucasians. rs2010963 was associated with increased risk of PDR in overall populations. A significant association between rs699947, rs3025039, and rs833061 and NPDR risk in overall populations and Asians was found. A significant association was observed between rs2010963 and increased NPDR risk in overall and Caucasian populations. This study provides a new insight into the parthenogenesis of diabetic retinopathy. Targeting VEGF SNPs may be a potential of therapeutic approach for the treatment of DR, PDR, and NPDR.