Virtual Screening, Docking, and Designing of New VEGF Inhibitors as Anti-cancer Agents.

BACKGROUND: VEGFR-2 tyrosine kinase inhibitors are receiving a lot of attention as prospective anticancer medications in the current drug discovery process. OBJECTIVE: This work aims to explore the PubChem library for novel VEGFR-2 kinase inhibitors. 1H-Indazole-containing drug AXITINIB, or AG-013736 (FDA approved), is chosen as a rational molecule for drug design. This scaffold proved its efficiency in treating cancer and other diseases as well. METHODS: The present study used the virtual screening of the database, protein preparation, grid creation, and molecular docking analyses. RESULTS: The protein was validated on different parameters like the Ramachandran plot, the ERRAT score, and the ProSA score. The Ramachandran plot revealed that 92.1% of the amino acid residues were located in the most favorable region; this was complemented by an ERRAT score (overall quality factor) of 96.24 percent and a ProSA (Z score) of -9.24 percent. The Lipinski rule of five was used as an additional filter for screening molecules. The docking results showed values of binding affinity between -14.08 and -12.34 kcal/mol. The molecule C1 showed the highest docking value of -14.08 Kcal/mol with the maximum number of strong H-bonds by -NH of pyridine to amino acid Cys104 (4.22Å), -NH of indazole to Glu108 (4.72), and Glu70 to bridge H of -NH. These interactions are similar to Axitinib docking interactions like Glu70, Cys104, and Glu102. The docking studies revealed that pi-alkyl bonds are formed with unsubstituted pyridine, whereas important H-bonds are observed with different substitutions around -NH. Based on potential findings, we designed new molecules, and molecular docking studies were performed on the same protein along with ADMET studies. The designed molecules (M1-M4) also showed comparable docking results similar to Axitinib, along with a synthetic accessibility score of less than 4.5. CONCLUSION: The docking method employed in this work opens up new possibilities for the design and synthesis of novel compounds that can act as VEGFR-2 tyrosine kinase inhibitors and treat cancer.

Prevalence of bacillary layer detachment in diabetic macular edema and response to 3 anti-vascular endothelial growth factor treatment.

Spectral-domain optical coherence tomography is widely used in maculopathy, including diabetic macular edema (DME). Bacillary layer detachment (BALAD) is a novel optical coherence tomography finding, defined as the separation of the intraretinal layer between the inner segment myoids and ellipsoids. A total of 161 treatment-naïve eyes with centrally involved DME that underwent 3 monthly loading doses of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections were enrolled and analyzed retrospectively. BALAD was found in 6.2% of eyes with concurrent subretinal fluid (SRF). All eyes were divided into 3 groups: no either group had neither SRF or BALAD; the SRF only group had SRF but no BALAD; and the BALAD group had both SRF and BALAD. A significant increase in baseline central foveal thickness (CFT) in the BALAD group was observed (no either vs SRF only vs BALAD, baseline CFT: 387.6 ±â€…74.29 vs 440.6 ±â€…106.79 vs 642.0 ±â€…188.86; P < .01). Total resolution of BALAD was noted after anti-VEGF therapy, along with a significant decrease in CFT in all groups (CFT decrease: 82.4 ±â€…87.07 vs 187.6 ±â€…138.88 vs 252.1 ±â€…127.63; P < .01). Eyes with BALAD tended to have the worst baseline visual acuity (baseline logarithm of the minimum angle of resolution VA: 0.76 ±â€…0.353 vs 0.63 ±â€…0.303 vs 1.15 ±â€…0.300; P = .046) but showed the most improvement after treatment (logarithm of the minimum angle of resolution VA change: -0.14 ±â€…0.235 vs -0.22 ±â€…0.275 vs -0.27 ±â€…0.250; P = .079). After resolution of BALAD, all eyes in the BALAD group exhibited ellipsoid zone and/or interdigitation zone disruption corresponding to the BALAD area. BALAD is a novel optical coherence tomography finding associated with a spectrum of diseases including DME. With anti-VEGF therapy, total resolution of BALAD and a significant decrease in CFT can be obtained. However, ellipsoid zone/interdigitation zone disruption tended to develop.

Efficacy and safety of pan retinal photocoagulation combined with intravitreal anti-VEGF agents for high-risk proliferative diabetic retinopathy: A systematic review and meta-analysis.

BACKGROUND: High-risk proliferative diabetic retinopathy (HR-PDR) is the advanced stage of diabetic retinopathy progression with poor prior treatment efficacy and high rates of blindness. This meta-analysis aims to compare the efficacy and safety of pan retinal photocoagulation (PRP) combined with intravitreal anti-vascular endothelial growth factor (aVEGF) (PRP + aVEGF) versus PRP monotherapy in HR-PDR patients. METHODS: A thorough search was performed through PubMed, Web of Science, EMBASE, and the Cochran Library from inception to December 18, 2022. Outcome measures included change in central macular thickness, best-corrected visual acuity, fluorescein angiography, incidence of undergoing vitrectomy, and adverse events during the follow-up period. RESULTS: Eight studies (6 randomized controlled trials and 2 retrospective studies) with 375 eyes were included in this meta-analysis. There were no obvious differences in the changes of best-corrected visual acuity and fluorescein angiography between the PRP + aVEGF and PRP monotherapy groups. However, PRP + aVEGF group had a significant reduction in the change of central macula thickness (standard mean deviations = -1.44, 95%CI = -2.55 to -0.32, P = .01) and the rate of undergoing vitrectomy (odds ratio = 0.20, 95%CI = 0.05-0.83, P = .01). Additionally, the risks of vitreous hemorrhage and other complications were not significantly different between the 2 groups. CONCLUSION SUBSECTIONS: Our meta-analysis indicated that PRP + aVEGF might have potential benefits in the treatment of HR-PDR patients. However, given several limitations of this study, more research is needed to confirm our findings.

Acute Kidney Injury from Intravitreal Anti-vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several observational studies have reported acute kidney injury from intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for retinal diseases. However, systematic reviews and meta-analyses of randomized controlled trials on this critical topic are scant. OBJECTIVE: To evaluate acute kidney injury risk associated with intravitreal anti-VEGF drugs in patients with retinal diseases. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials on 12 July, 2023, and included randomized controlled trials reporting acute kidney injury between anti-VEGF drugs (e.g., aflibercept, bevacizumab, brolucizumab, and ranibizumab) and controls for retinal diseases (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic retinopathy/diabetic macular edema, retinal vein occlusion, and myopic choroidal neovascularization). Data were synthesized by a fixed-effects model for pooling odds ratios (ORs) using the Peto method. RESULTS: We included 13 randomized controlled trials (four and nine trials for aflibercept and ranibizumab, respectively) with a total of 4282 participants. The meta-analysis indicated intravitreal anti-VEGF drugs did not increase the acute kidney injury risk, compared with controls (odds ratio [OR]: 1.00, 95% confidence interval [CI] 0.49-2.04, I2: 0%), and no differences in the acute kidney injury risk were observed between different anti-VEGF drugs (OR: 1.10, 95% CI 0.27-4.43, I2: 0% for aflibercept; OR: 0.97, 95% CI 0.42-2.22, I2: 0% for ranibizumab) and between different retinal diseases (OR: 4.61, 95% CI 0.07-284.13, I2: not applicable for age-related macular degeneration; OR: 0.90, 95% CI 0.42-1.93, I2: 0% for diabetic retinopathy/diabetic macular edema; OR: 1.57, 95% CI 0.16-15.88, I2: 0% for retinal vein occlusion). CONCLUSIONS: Intravitreal anti-VEGF drugs were not associated with an acute kidney injury risk, regardless of which anti-VEGF drugs (aflibercept or ranibizumab) or retinal diseases (age-related macular degeneration, diabetic retinopathy/diabetic macular edema, or retinal vein occlusion) were involved. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO CRD42021267854.

Intravitreal anti-vascular endothelial growth factor monotherapy in age-related macular degeneration with submacular hemorrhage.

The purpose of this study was to evaluate the 1-year visual outcomes of patients treated with intravitreal aflibercept (IVA) or brolucizumab (IVBr) for submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD). We retrospectively studied 62 treatment-naïve eyes with SMHs exceeding one disc area (DA) secondary to AMD treated with IVA or IVBr. All patients received three monthly intravitreal injections in the loading phase followed by as-needed injections or fixed dosing. If a vitreous hemorrhage (VH) developed during the follow-up period, injections were discontinued and vitrectomy was performed. We evaluated the changes in the best-corrected visual acuity (BCVA) and factors that affected the BCVA improvement and VH development. A VH during treatment developed in five eyes (8.1%) (VH + group), and the mean BCVA worsened from 0.45 to 0.92. The BCVA improved significantly (P = 0.040) in the remaining 57 eyes (VH - group) from 0.42 to 0.36. The development of VHs was associated with significantly (P < 0.001) less VA improvement. Furthermore, large DAs and younger age at baseline were associated significantly (P = 0.010 and 0.046, respectively) with the development of VHs. Both IVA and IVBr appeared to improve functional outcomes in patients with SMH secondary to AMD when VHs did not develop. However, a VH developed in 8.1% of eyes after treatment. Although anti-vascular endothelial growth factor treatments were well-tolerated, for cases with large SMH at baseline, it should be considered that VH may occur during the monotherapy treatment process using IVA or IVBr, and that achieving good visual outcomes may be difficult in some cases.

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.

Characteristics and response of subretinal hyperreflective material to anti-vascular endothelial growth factor in myopic choroidal neovascularization.

This retrospective study evaluated the characteristics and response of subretinal hyperreflective material (SHRM) to anti-vascular endothelial growth factor (VEGF) treatment in eyes with myopic choroidal neovascularization (CNV). The visual acuity (VA) was assessed at 3, 6, and 12 months after initiating anti-VEGF treatment in 116 patients (119 eyes) with SHRM and myopic CNV. Multimodal imaging, including color fundus photography, fluorescein angiography (FA), and optical coherence tomography angiography (OCT-A), were performed. We compared type 2 neovascularization (NV) (n = 64), subretinal hyperreflective exudation (SHE) (n = 37), NV with hemorrhage (n = 15), and fibrosis (n = 3). The type 2 NV group, and NV with hemorrhage groups showed significant VA improvement after 12 months of treatment (p < 0.05 in both groups); the SHE group failed to show improvement (p = 0.366). All groups showed a significant reduction in central foveal thickness after 12 months of treatment (all p < 0.05). The SHE group had a significantly higher incidence of interrupted ellipsoid zone than the other groups (p < 0.05). Myopic CNV can present as SHRM on OCT-A. Visual prognoses vary in different SHRM types. OCT-A and FA may help predict the outcomes of different subtypes of myopic CNV. SHE is predictive of outer retinal layer atrophy in patients with various SHRM types.

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain.

Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done in vivo using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration.

Progress and Challenges of Anti-VEGF Agents and Their Sustained-Release Strategies for Retinal Angiogenesis.

Currently, the treatment for ocular neovascular diseases, including diabetic macular edema (DME) and age-related macular degeneration (AMD), mainly involves repeated intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs. Although it can preserve vision, repeated injections are an invasive treatment modality, leading to serious complications and reducing patient adherence to treatment. To reduce the frequency of administration, prolong the time of drug action, and avoid repeated intravitreal injections, the combination of sustained-release materials with anti-VEGF drug therapy has become an emphasis in ophthalmology. In this review, we highlight the current state of anti-VEGF technology, its challenges, and the sustained-release strategies under investigation or being used in clinical practice. Both continuous release and considerable therapeutic effects can be achieved by encapsulating anti-VEGF drugs in sustained-release materials to minimize the number of intravitreal injections. At present, two sustained-release materials are being tested in clinical research, and although basic research shows the strong therapeutic application prospects of extended-release drugs, its challenges mainly involve the discrepancy between the release rates in vitro and the efficiency of the drugs in vivo. Briefly, sustained release of anti-VEGF agents is an advantageous strategy for treating retinal angiogenesis.

Alpinumisoflavone ameliorates choroidal neovascularisation and fibrosis in age-related macular degeneration in in vitro and in vivo models.

Age-related macular degeneration (AMD) is a major cause of vision loss in the elderly population. Anti-vascular endothelial growth factor (VEGF) antibody therapy is applicable to neovascularisation of AMD; however, the prevention of fibrosis after anti-VEGF monotherapy is an unmet medical need. Subretinal fibrosis causes vision loss in neovascular age-related macular degeneration (nAMD) even with anti-VEGF therapy. We report the anti-fibrotic and anti-neovascularisation effects of alpinumisoflavone (AIF), an isoflavonoid derived from unripe Maclura tricuspidata fruit, in in vitro and in vivo models. For in vitro study, we treated H2O2 or THP-1 conditioned media (TCM) following activation with phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide (LPS) in a human retinal pigment epithelial cell line (ARPE-19). Choroidal neovascularisation (CNV) was induced by laser photocoagulation in mice, immediately followed by intravitreal administration of 25 µg AIF. CNV area and fibrosis were measured 7 days after laser photocoagulation. AIF showed anti-fibrosis and anti-neovascularisation effects in both the models. The laser induced CNV area was reduced upon AIF administration in nAMD mouse model. Additionally, AIF decreased the levels of the cleaved form of crystallin alpha B (CRYAB), a chaperone associated with VEGF stabilisation and fibrosis. Our results demonstrate a novel therapeutic application of AIF against neovascularisation and fibrosis in nAMD.

Laser and anti-vascular endothelial growth factor treatment for drusenoid pigment epithelial detachment in age-related macular degeneration: 24-month outcomes.

PURPOSE: After the 12-month interim safety analysis, we investigated the 24-month primary endpoint outcomes of drusenoid pigment epithelial detachment (dPED) after laser and intravitreal anti-VEGF treatment. METHODS: Twenty-one patients with treatment-naïve bilateral intermediate AMD with dPED and visual acuity ≤ 83 letters (Snellen 20/23) were enrolled. The subject eye received low-energy PASCAL® laser (532 nm) treatment, and the fellow eye was used as the control. Intravitreal injections were administered at 3-month intervals from baseline to 12 months. Treatment outcomes, safety and development of advanced AMD lesions were analyzed. RESULTS: The mean drusen area and dPED height were significantly reduced (17.3 ± 2.7% vs. 112.8 ± 3.1%, P < 0.001 and 11.8 ± 4.7% vs. 119.1 ± 4.6%, P < 0.001, respectively) and the mean BCVA improved (5.11 ± 1.35 vs. 0.83 ± 1.03 letters, P = 0.014) in the study eyes compared to those in the control eyes. Development of parafoveal iRORA (nGA) (67%, 12 of 18 eyes) and cRORA (GA) (22%, 4 of 18 eyes) was observed in the study eyes, whereas three cases of iRORA and cRORA in the control eyes (17%, 3 of 18 eyes; P = 0.010 and P = 0.791, respectively). CONCLUSIONS: Laser and anti-VEGF treatment may be a potential treatment option for intermediate AMD with dPED. However, considering the relatively high rate of secondary iRORA and cRORA development, long-term follow-up is mandatory to clarify the safety and efficacy of this treatment.

Arm-to-retina time predicts visual outcome of anti-vascular endothelial growth factor treatment for macular edema due to central retinal vein occlusion.

To explore the factors associated with best-corrected visual acuity (BCVA) after anti-vascular endothelial growth factor (anti-VEGF) treatment for macular edema secondary to central retinal vein occlusion (CRVO). We retrospectively reviewed the medical charts of 22 eyes of 22 treatment-naïve patients with CRVO diagnosed between September 2014 and December 2020. They received anti-VEGF treatment and follow-up for > 12 months. Mean patient age was 64.3 years; 13 (59.1%) were men. Eyes with baseline arm-to-retina (AR) time ≥ 16 s had better BCVA at 12 months (adjusted for baseline BCVA and age; B, - 0.658; 95% confidence interval - 1.058 to - 0.257; P = 0.003), greater mean BCVA change (P = 0.006), lower frequency of residual macular edema at 12 months (P = 0.026) and recurrent and/or unresolved macular edema during 12 months (P = 0.046), and higher frequency of reduction in central retinal thickness ≥ 150 µm at 1 and 12 months (both P = 0.046). Delayed AR time was associated with a better visual outcome and macular edema improvement in CRVO after anti-VEGF treatment regardless of initial BCVA and age. Our results may help understand the pathogenesis and predict the visual prognosis of patients before anti-VEGF therapy initiation.

Outcome of phacoemulsification without anti-vascular endothelial growth factor in patients with treatment naïve diabetic retinopathy.

INTRODUCTION: This retrospective, non-randomized, observational study was conducted at ASG Eye Hospital, Kathmandu to evaluate the outcome of phacoemulsification without anti-Vascular Endothelial Growth Factor (VEGF) in patients with treatment naïve diabetic retinopathy. MATERIALS AND METHODS: Records of all patients who underwent phacoemulsification without Bevacizumab in treatment of naïve patients with any grade of non-proliferative Diabetic Retinopathy (NPDR) were seen. Pre-operative and post-operative visual acuity along with central macular thickness (CMT) was compared. RESULTS: The study comprised 32 eyes of 20 patients with treatment naïve non-proliferative Diabetic Retinopathy who underwent phacoemulsification. Twelve were men and eight were women with an average age of 69.2 years (range 55 years to 83 years). The average preoperative central macular thickness as measured on optical coherence tomography was 254.63± 20.25 microns and 1-month postoperative central macular thickness was 254.72± 19.96 microns; the study did not find any significant difference (p-value 0.918). The average difference in the central macular thickness between the 1-month postoperative and preoperative values was 0.09 microns. CONCLUSION: Uneventful phacoemulsification in eyes with treatment naïve diabetic retinopathy does not cause an increase in central macular thickness after surgery and thus anti-Vascular Endothelial Growth Factor as an adjunct is not mandatory.

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

Design, synthesis and biological evaluation of dual HDAC and VEGFR inhibitors as multitargeted anticancer agents.

Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically evaluated based on previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed significant HDAC1, HDAC6 and VEGFR2 inhibition, which contributed to their potent antiproliferative activities against multiple cancer cell lines and significant antiangiogenic potencies in both human umbilical vein endothelial cell (HUVEC) tube formation assays and rat thoracic aorta ring assays. Further HDAC selectivity evaluations indicated that hydroxamic acids 5 and 9e possessed HDAC isoform selectivity profiles similar to that of the approved HDAC inhibitor suberoylanilide hydroxamic acid(SAHA), while hydrazide12 presented an HDAC isoform selectivity profilesimilar to that of the clinical HDAC inhibitor MS-275. The VEGFR inhibition profiles of 5, 9e and 12 were similar to that of the approved VEGFR inhibitor pazopanib. The intracellular target engagements of Compounds 5 and 12 were confirmed by western blot analysis. The metabolic stabilities of 5, 9e and 12 in mouse liver microsomes were inferior to that of pazopanib. These dual HDAC and VEGFR inhibitors provide lead compounds for further structural optimization to obtainpolypharmacological anticancer agents.

Early Predictive Factors of Visual Loss at 1 Year in Neovascular Age-Related Macular Degeneration under Anti-Vascular Endothelial Growth Factor.

PURPOSE: To evaluate early predictive factors of visual loss in patients treated with anti-vascular endothelial growth factor (VEGF) injections under an as-needed regimen for neovascular age-related macular degeneration (AMD). DESIGN: Post hoc analysis from the randomized controlled trial Groupe d'Evaluation Français Avastin versus Lucentis (GEFAL). PARTICIPANTS: A total of 393 patients with neovascular AMD. METHODS: The present analysis is based on 1-year data from patients included in the study. Patients were separately categorized according to the best-corrected visual acuity (BCVA) change at 3 months and 1 year into 3 trajectories: (1) patients with no vision loss ≥5 letters at 3 months and 1 year (absence of loss ≥5 letters); (2) patients with no vision loss ≥5 letters at 3 months but loss ≥5 letters at 1 year (secondary loss ≥5 letters); and (3) patients with vision loss ≥5 letters at 3 months and 1 year (initial loss ≥5 letters). MAIN OUTCOME MEASURES: The following factors were evaluated at baseline and 3 months: age, sex, BCVA, presence of fluid, central macular thickness, angiographic choroidal neovascularization (CNV) subtype, CNV area measured in disc area on fluorescein angiography, and number of intravitreal injections. RESULTS: An absence of loss ≥5 letters was found in 225 patients (57.3%), a secondary loss ≥5 letters after 3 months was found in 109 patients (27.7%), and an initial loss ≥5 letters was found in 59 patients (15%). Baseline characteristics were comparable among the 3 groups except for the total CNV area, which was larger in the initial and secondary loss groups (P = 0.0412). At 3 months, a significant association was found between presence of subretinal fluid (SRF) (P = 0.0318) and vision loss ≥5 letters, and an even stronger significant association between the presence of intraretinal fluid (IRF) (P = 0.0066) and vision loss ≥5 letters. CONCLUSIONS: In the present study, we found that a large CNV area at baseline was significantly associated with initial or secondary loss of visual acuity ≥5 letters despite anti-VEGF injection. The presence of fluid, both SRF and IRF, at 3 months was found in patients with poorer trajectories.

LONGITUDINAL SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF EXTRAFOVEAL POLYPS AFTER COMBINATION THERAPY.

PURPOSE: To study the efficacy of swept source optical coherence tomography angiography (SSOCTA) to longitudinally follow-up patients with extrafoveal polyps post-laser photocoagulation and anti-vascular endothelial growth factor injection. METHODS: Observational case series. Four patients diagnosed as polypoidal choroidal vasculopathy with extrafoveal polyps on multimodal imaging were followed up serially on SSOCT, en face and cross-sectional SSOCTA at a month and then 3 monthly for a year. Indocyanine green angiography was repeated at 4 months and 1 year. RESULTS: Anatomical regression of extrafoveal polyps was documented on a combination of en face and cross-sectional SSOCTA, 3 months post-laser photocoagulation and anti-vascular endothelial growth factor. Regression of polyps was maintained at the 12-month follow-up visit in all cases. Changes in branching vascular network morphology post-treatment were well-delineated on en face SSOCTA. Swept source optical coherence tomography angiography findings correlated well with the gold standard indocyanine green angiography. CONCLUSION: Swept source optical coherence tomography angiography is an effective noninvasive imaging modality to diagnose and longitudinally follow-up extrafoveal polyps postintervention. Laser photocoagulation with anti-vascular endothelial growth factor achieved regression of polyps in all cases and this was maintained over 12 months.

Impact of macular fluid features on outcomes of anti-vascular endothelial growth factor treatment for type 3 macular neovascularization.

We evaluated the impact of macular fluid features on visual and anatomical outcomes in type 3 macular neovascularization (MNV) patients treated with anti-vascular endothelial growth factor (VEGF). We retrospectively enrolled 89 eyes with type 3 MNV with at least 12 months of follow-up. All patients were treatment-naïve and received a monthly loading injection of anti-VEGF for three months, followed by further injections as required. The association of baseline macular morphology, including intraretinal fluid (IRF) and subretinal fluid (SRF), with visual and anatomical outcomes was analyzed. At baseline, IRF was present in all enrolled patients (100%), and SRF was present in 43.8% (39/89) of them. After 12 months of treatment, no significant difference was found in terms of best-corrected visual acuity (BCVA) and changes in central foveal thickness between the eyes with (39) and without (50) SRF at baseline. In addition, the proportion of improved or worsened (gain or loss of more than three lines in the BCVA) visual acuity at 12 months was not significantly different among the groups. Incidence of macular atrophy during the treatment showed no difference between the groups, regardless of the presence of SRF. In conclusion, the macular fluid morphology, specifically SRF, in type 3 MNV showed no significant correlation with visual and anatomical outcomes during anti-VEGF treatment.

Efficacy of combined anti-VEGF and photodynamic therapy for bilateral diffuse uveal melanocytic proliferation: Case series.

RATIONALE: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare retinal exudative disease with physical disorders and no established treatment standard. We describe treatment courses in 3 cases of BDUMP. PATIENTS CONCERNS: Three male patients complained active vision loss. One male patient in his 70s (patient 1) was treated with prednisolone, mesalazine, and ciclosporin for hypoplastic anemia and ulcerous colitis. One male patient in his 60s (patient 2) was on prednisolone therapy for adult Still disease. Another male patient in his 70s (patient 3) was on prednisolone therapy for polymyalgia rheumatica, giant cell arteritis, and pancreatic body tumor. DIAGNOSES: Retinal specialists diagnosed these patients with BDUMP based on characteristic fundus findings of multiple red patches and retinal exudate. INTERVENTIONS: Two patients (patients 1 and 2) with poor response to anti-vascular endothelial growth factor (VEGF) monotherapy and/or triamcinolone acetonide sub-Tenon injection were treated with combined anti-VEGF therapy and photodynamic therapy. One patient (patient 3) was treated with 3 rounds of monthly anti-VEGF monotherapy. OUTCOMES: Retinal exudates were resolved in all patients. No recurrence of retinal exudates was observed for at least 10 months, 2 years, or 4 months after the therapy in patients 1, 2, and 3, respectively. However, best-corrected visual acuity of the right eye was low (20/200) compared with that of the left eye (20/22) in patient 2 despite exudate resolution, due to permanent outer retinal damage secondary to long-term retinal exudate. LESSONS SUBSECTIONS: Combined anti-VEGF therapy and photodynamic therapy may be a feasible therapeutic option for treatment-resistant exudate in patients with BDUMP. Early diagnosis of BDUMP and prompt administration of combination therapy are crucial.