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PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non–small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation–based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib. [ABSTRACT FROM AUTHOR]

Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. Systematic review and Delphi consensus process. Twenty-five international retinal specialists participated in the Delphi consensus survey. A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to elucidate the differential immunological mechanisms and characteristics of hypertension induced by VEGF inhibitors (VEGFi) and VEGF receptor inhibitors (VEGFRi), with the goal of optimizing monitoring strategies and treatment protocols. Methods: We investigated the risk of immune-related adverse events associated with VEGFi/VEGFRi-induced hypertension by analyzing the FDA Adverse Event Reporting System (FAERS) database. Findings were corroborated with blood pressure characteristics observed in clinical patients and preclinical models exposed to various VEGF/VEGFRi. Clinical and preclinical studies were conducted to compare immunological responses and hypertension profiles between inhibitor classes. An integrative analysis across cancer types and species was performed, focusing on key signaling pathways. Results: Analysis of FAERS data, in conjunction with clinical observations, revealed that both VEGFi and VEGFRi significantly elevated the risk of immune-mediated, blood pressure-related adverse events (ROR=7.75, 95% CI: 7.76-7.95). Subsequent clinical and preclinical studies demonstrated differential immunological responses and hypertension profiles between inhibitor classes. VEGFRi exhibited a more rapid onset, greater blood pressure elevation, and higher incidence of immune-mediated adverse events compared to VEGFi (Systolic BP: ROR=0 for VEGFi vs. ROR=12.25, 95% CI: 6.54-22.96 for VEGFRi; Diastolic BP: ROR=5.09, 95% CI: 0.60-43.61 for VEGFi vs. ROR=12.90, 95% CI: 3.73-44.55 for VEGFRi). Integrative analysis across cancer types and species, focusing on key signaling pathways, revealed that VEGF/VEGFRi-induced blood pressure elevation was associated with immunomodulation of the mitogen activated protein kinase (MAPK) pathway (R=-0.379, P=0.0435), alterations in triglyceride metabolism (R=-0.664, P=0.0001), modulation of myo-inositol 1,4,5-trisphosphate-sensitive calcium release channel activity (R=0.389, P=0.0378), and dysregulation of nitric oxide eNOS activation and metabolism (R=-0.439, P=0.0179). Discussion: The temporal dynamics of these effects demonstrated greater significance than dose-dependent responses. Both VEGFi and VEGFRi significantly augmented the risk of immune-mediated, blood pressure-related adverse events, with VEGFRi inducing a more rapid and pronounced onset of blood pressure elevation and a higher incidence of immune-related, blood pressure-associated adverse events compared to VEGFi. [ABSTRACT FROM AUTHOR]

Aims: To determine the presence of sectoral changes in vessel density (VD) patterns induced by vascular endothelial growth factor inhibitors (anti-VEGF) in patients with diabetic macular edema (DME) using optical coherence tomography angiography (OCTA). Methods: Prospective, interventional study. A total of 43 patients (63 eyes) were initially enrolled in the study. We performed swept source (SS) OCT and sectorial OCTA measurement to determine parafoveal VD at baseline and after six months of anti-VEGF treatment. In the locations with statistically significant differences in VD between baseline and month 6, we performed univariate and multivariate analyses to determine which, if any, of the baseline variables were associated with the observed changes. Results: A total of 34 patients (48 eyes) were included in the final analysis. Mean VD decreased from baseline to month 6 (from 45.2 (± 3.5) to 44.6 (± 3.2) % in the SCP and from 50 (± 3.3) to 49 (± 3.9) % in the DCP). The only significant changes in VD were observed in the nasal sector of the deep capillary plexus, with a decrease of 2.9% (p = 0.001). On univariate and multivariate analyses, the only variable significantly associated with changes in VD in the nasal sector after 6 months of treatment was baseline VD in the same sector. Conclusions: Anti-VEGF therapy has a small impact on VD values over time. These variations observed after treatment seems to be related to changes over areas of vascular anomalies and displaced vessels adjacent to cystic areas, with no significant changes over ischemic areas. No correlation was observed between this trend and other clinical baseline features. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the predictive factors for persistent disease activity following anti-vascular endothelial growth factors (anti-VEGF) and their long-term effects in patients to be treated for neovascular age-related macular degeneration (nAMD) under real-world conditions. Methods: Retrospective data analysis of the PROOF study, a multi-center real-world retrospective chart review conducted across Korea in patients with nAMD included treatment-naive patients with nAMD who received first anti-VEGF (ranibizumab, bevacizumab, or aflibercept) between January 2017 and March 2019 was performed. All 600 patients (cohort 1) had a minimum follow-up of 12 months of which 453 patients (cohort 2) were followed-up for 24 months from baseline. Results: At month 12 after anti-VEGF therapy, 58.10% (95% confidence interval [CI]: 54.09, 62.12) of patients and at month 24, 66.02% of patients continued to have persistent retinal fluid. At both months 12 and 24, predictive factors for persistent disease activity were fibrovascular pigment epithelial detachments (PED) (P = 0.0494) and retinal fluid at month 3 after loading phase (P = 0.0082). The mean changes in visual acuity were + 6.2, + 10.1, and + 13.3 letters and in the central subfield thickness were − 79.1 µm, − 96.3 µm, and − 134.4 µm at 12 months from baseline, in the bevacizumab, aflibercept, and ranibizumab groups, respectively. Conclusions: The presence of retinal fluid after loading phase and fibrovascular PED were predictors of persistent disease activity after at least 1 year of anti-VEGF treatment. [ABSTRACT FROM AUTHOR]

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are multifactorial disorders that affect the macula and cause significant vision loss. Although inflammation and neoangiogenesis are hallmarks of DME and nAMD, respectively, they share some biochemical mediators. While inflammation is a trigger for the processes that lead to the development of DME, in nAMD inflammation seems to be the consequence of retinal pigment epithelium and Bruch membrane alterations. These pathophysiologic differences may be the key issue that justifies the difference in treatment strategies. Vascular endothelial growth factor inhibitors have changed the treatment of both diseases, however, many patients with DME fail to achieve the established therapeutic goals. From a clinical perspective, targeting inflammatory pathways with intravitreal corticosteroids has been proven to be effective in patients with DME. On the contrary, the clinical relevance of addressing inflammation in patients with nAMD has not been proven yet. We explore the role and implication of inflammation in the development of nAMD and DME and its therapeutical relevance. [ABSTRACT FROM AUTHOR]

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Choroidal neovascularization (CNV) underlies the crux of many angiogenic eye disorders. Although medications that target vascular endothelial growth factor (VEGF) are approved for treating CNV, their effectiveness in destroying new blood vessels is limited, and invasive intravitreal administration is required. Additionally, other drugs that destroy established neovessels, such as combretastatin A‐4, may have systemic side effects that limit their therapeutic benefits. To overcome these shortcomings, a two‐pronged anti‐vascular approach is presented for CNV treatment using a photoactivatable nanoparticle system that can release a VEGF receptor inhibitor and a vascular disrupting agent when irradiated with 690 nm light. The nanoparticles can be injected intravenously to enable anti‐angiogenic and vascular disrupting combination therapy for CNV through light irradiation to the eyes. This approach can potentiate therapeutic effects while maintaining a favorable biosafety profile for choroidal vascular diseases. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) is characterized by abnormal blood vessel growth from the choroid, leading to complications and eventual blindness. Despite anti-VEGF therapy, subretinal fibrosis remains a major concern, as VEGF/VEGF receptor-2 (VEGFR2) signaling can contribute to both angiogenesis and fibrosis. For the identification of the aqueous humor proteome, we performed liquid chromatography with tandem mass spectrometry analysis. To investigate the potential therapeutic effects of targeting the VEGF signaling pathway using apatinib, a highly selective VEGFR2 tyrosine kinase inhibitor, this study employed in vitro (THP-1 conditioned media-treated ARPE-19 cells) and in vivo (laser-induced choroidal neovascularization mouse) models of nAMD. This study revealed elevated VEGFR2 protein levels in the aqueous humor of nAMD patients, suggesting a potential target to mitigate neovascularization and fibrosis in nAMD. Apatinib effectively reduced VEGFA and αSMA levels in both in vitro and in vivo models. Moreover, apatinib showed improvement in laser-induced subretinal hyper-reflective lesions. The action mechanism was linked to the inhibition of VEGFR2 activation, leading to the suppression of both angiogenesis and fibrosis through the downregulation of STAT3 phosphorylation. Therefore, the VEGFR2 signaling pathway appears to play a central role in the development of nAMD by regulating both angiogenesis and fibrosis. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion This study aims to assess the risk of drug‐associated glaucoma and track its epidemiological characteristics using real‐world data.Adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2023 were analysed. Disproportionality analysis and the Bayesian Confidence Propagation Neural Network algorithm were used. The study classified drugs associated with glaucoma, assessed risk levels, and compared drug‐induced times across different categories.Eight hundred and five drugs were linked to glaucoma in the FAERS database. Disproportionality analysis identified 46 drugs with significant risk, mainly adrenergic medications (clobetasol propionate, fluocinolone acetonide), antihypertensives (hydrochlorothiazide), insulin (insulin human), anticholinergics (umeclidinium, darifenacin), VEGF inhibitors (brolucizumab, faricimab), and psychotropics (topiramate, ziprasidone). The top three high‐risk drugs were clobetasol propionate, umeclidinium, and fluocinolone acetonide. The shortest drug‐induced times were observed with indacaterol, salmeterol, and umeclidinium. Anticholinergic medications had the shortest drug‐induced time among all categories. Females (62.5%) and the elderly (average age 63.5 ± 16.8 years) were predominantly affected. Reports of drug‐associated glaucoma increased over the years.Preventing drug‐associated glaucoma is more effective than treatment. Identifying the risk and drug‐induced times of systemic and ophthalmic drugs can reduce occurrence risk. Clinical practitioners should be vigilant and inform patients of these risks. [ABSTRACT FROM AUTHOR]

Background: Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally. Methods: VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance. Discussion: There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test. Trial registration: ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020. [ABSTRACT FROM AUTHOR]

Background and Aims: Anti‐angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti‐angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti‐angiogenic inhibitors and identify novel anti‐angiogenic drugs with clinical applications. Results: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti‐tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti‐angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood–brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA‐Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non‐VEGF‐mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Conclusion: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non‐VEGF pathways led to anti‐angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti‐angiogenic therapy for glioblastoma with safe, low cost, and fast availability. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68+PD-L1+ PD-1+ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC. Anlotinib hydrochloride is a multi-target tyrosine kinase receptor inhibitor, previously combined with anti-PD1 as therapeutic strategy for several cancer types. Here the authors report the results of a phase II trial of nivolumab (anti-PD1) plus anlotinib hydrochloride in patients with advanced gastric adenocarcinoma and esophageal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermoresponsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation and protected retinal tissue. HydroC-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, HydroC-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients' response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Materials and Methods: We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. Results: In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and three patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6%, 12.4%, and 18.1% months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Conclusion: Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration is a progressive, blinding macular disease that has become a burden both in healthcare systems and the global economy. The vascular endothelial growth factor (VEGF) is the main agent involved in the pathogenic process of the disease. The main goal of the age-related macular degeneration treatment is to maintain and improve visual acuity by injecting intravitreal anti-VEGF agents in either a reactive or proactive manner. Subretinal and intraretinal fluids are the main biomarkers that should be considered when managing the frequency of the therapy. This review discusses both functional and morphological treatment criteria according to current recommendations as opposed to real-life situations encountered during day-to-day clinical practice and highlights situations in which the benefits of continuing therapy are arguable in terms of improving patients' quality of life. Optimizing the treatment regimen represents an important aim of current clinical ophthalmological practice, as age-related macular degeneration patients usually have a long follow-up period. [ABSTRACT FROM AUTHOR]

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials. [ABSTRACT FROM AUTHOR]

Background: Long-term results of photodynamic therapy (PDT) combined with vascular endothelial growth factor (VEGF) inhibitors for pachychoroid neovasculopathy (PNV) are not yet clear. Methods: This study is a retrospective, observational case series. We retrospectively examined untreated PNV cases (22 cases, 22 eyes, mean age of 71.0 years) who underwent PDT therapy in combination with VEGF inhibitors followed by additional treatments with pro re nata protocol. Visual acuity, number of treatments, and time to recurrence were examined. In addition, foveal choroidal thickness and choroidal vascularity index (CVI) were evaluated in 13 of 22 patients who were followed up with SpectralisOCTR from baseline. Results: Fifteen (68%) cases had polyps at baseline. LogMAR visual acuity averaged 0.24 ± 0.20 (range, − 0.079 to 0.82) at baseline and significantly improved after 1, 2, and 3 years (p = 0. 004, 0.0003, 0.002, respectively). Fourteen patients (64%) recurred, with an average time to recurrence of 1.8 ± 0.9 years. Foveal choroidal thickness decreased significantly after 1 year (average from 326 μm to 263 μm) and remained unchanged up to 3 years (255 μm). CVI also decreased after 1 year (average from 0.62 to 0.61) and remained unchanged until 3 years later (0.60). Conclusions: We examined the 3-year course of PDT in combination with the VEGF inhibitor for untreated PNV. Visual acuity was improved, foveal choroidal thickness and CVI were decreased after 3 years. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of subthreshold micropulse laser (SML) in addition to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). Methods: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were systematically searched for studies that compared anti-VEGF with SML and anti-VEGF monotherapy for DME. Outcome measures were best-corrected visual acuity (BCVA), central macular thickness (CMT), and the number of anti-VEGF injections. Results: Eight studies including 493 eyes were selected. Four studies were randomized controlled, and the other four were retrospective. Meta-analysis showed that there was no significant difference in BCVA (mean difference [MD] -0.04; 95%CI -0.09 to 0.01 logMAR; P = 0.13;). CMT was thinner in the group of anti-VEGF with SML (MD -11.08; 95%CI -21.04 to -1.12 µm; P = 0.03); however, it was due to a single study that weighed higher, and the sensitivity and subcategory analyses did not support the finding. The number of anti-VEGF injections was significantly decreased in the group of anti-VEGF with SML (MD -2.22; 95%CI -3.02 to -1.42; P < 0.0001). Conclusion: Current evidence indicates that adding SML to anti-VEGF therapy could significantly reduce the number of anti-VEGF injections compared to anti-VEGF monotherapy, while achieve similar BCVA and CMT. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. a-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such a-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects. [ABSTRACT FROM AUTHOR]

This paper assesses the preferred treatment patterns for retinopathy of prematurity (ROP) and examine trends in anti-vascular endothelial growth factor (VEGF) use for ROP. Methods: A retrospective survey consisting of 14 questions was distributed to paediatric ophthalmology interest groups internationally. Main outcome measures included treatment patterns, proportion of anti-VEGF use in different stages of ROP; and comparison of first-line treatments as well as repeat anti-VEGF treatments. Results: Fifty-four ophthalmologists from 11 different countries responded to the survey. The number of respondents per question, except one, ranged between 50–54. Per annum, there was an average number of 394 infants screened by each respondent. Anti-VEGF was the preferred treatment method for aggressive (A)-ROP (64.1%), Type 1 ROP in zone 1 (71.7%), and Type 1 ROP in posterior zone 2 (56.6%). The majority used laser as the first-line treatment of Type 1 ROP in anterior zone 2 (73.6%) and Type 1 ROP in zone 3 (79.2%). Laser was the preferred treatment modality utilised in infants requiring repeat treatment following anti-VEGF injection. The preferred anti-VEGF agent was bevacizumab administered at a dose of 0.625 mg. Conclusions: Anti-VEGF as first-line therapy has been increasing. Anti-VEGF appears to be the first-line treatment of choice for A-ROP, Type 1 ROP in zone 1 and posterior zone 2 and laser for Type 1 ROP in anterior zone 2 and zone 3. [ABSTRACT FROM AUTHOR]

Simple Summary: The FGF/FGFR-mediated pathway coordinates the activity of VEGF/VEGFR signaling in IM-resistant GISTs. Mechanistically, FGF2 triggers the activation of the FGFR pathway, turns on the activation of VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. This was observed in IM-resistant GIST T-1R cells acquired IM resistance due to "RTK switch" (KIT loss/FGFR activation) and led to the impressive synergy scores between FGFR and VEGFR inhibitors, thereby providing a rationale to re-evaluate the effectiveness of combined anti-FGFR and VEGFR therapeutic strategies for GIST-acquired IM resistance via KIT-independent mechanisms. We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms. [ABSTRACT FROM AUTHOR]

Chronic subdural hematoma (cSDH), a condition that develops over time, is characterized by inflammation, angiogenesis, and membrane development. As the population's average age increases, the incidence of cSDH is expected to grow. While surgery is the primary treatment technique, medicinal therapy options are being explored for high-risk patients. Currently, the most effective therapy combination is dexamethasone (Dex) and atorvastatin (Ato); however, it is associated with an increased risk of mortality. This study explored the effects of bevacizumab (Bev), a vascular endothelial growth factor antagonist, on cSDH. Ninety-five rats were divided into four groups (n = 18): sham, control hematoma, Dex-Ato, and Bev. Two separate autologous blood injections into the subdural space were used as the model. Weight was monitored for all rats to assess changes in their overall health. The control group was given i.p. saline, the Dex-Ato treatment was given by gavage, and the Bev treatment was given i.p. On seventh, 14th and 21st days six rats from each group were sacrificed and analyzed, while 23 rats were excluded from the experiment. The maximum immunological response to cSDH was observed on day 14. Hematoma volume decreased over time in all groups. Dex-Ato and Bev were both found effective, while Dex-Ato caused weight loss. Bev had similar effects to the Dex-Ato group and was well tolerated by rats. Given that cSDH is a disease of the elderly and vulnerable populations, Bev may be a viable alternative that can shed light on the disease's etiology for future research. [ABSTRACT FROM AUTHOR]

The purpose of the study described was to establish prediction models to initially screen the beneficiary patients with unresectable hepatocellular carcinoma (HCC) in the treatment of anti-vascular endothelial growth factor (VEGF) agents plus anti-programmed cell death-1 (PD-1) antibody. A total of 62 patients were enrolled in this study. All patients underwent ultrasound (US), color ddoppler flowing imaging (CDFI), contrast-enhanced ultrasound (CEUS) and laboratory examinations within 2 wk before the treatment. Tumor response was assessed according to mRECIST criteria. Univariate and multivariate analyses were used to select the independent predictors. US + CDFI, CEUS and FULL models were established. Three models were displayed by nomography. Receiver operating characteristic (ROC) and calibration curves were drawn to evaluate the predictive ability of models. Decision curve analysis (DCA) was used to assess the clinical utility of models. On univariate and multivariate analysis, the US boundary (p = 0.037), halo (p = 0.002) and CDFI (p = 0.024) were included in the US + CDFI model. CEUS boundary (p = 0.001) and washout time (p < 0.001) were included in the CEUS model. The number of lesions (p = 0.104), halo on US (p = 0.014), CDFI (p = 0.057) and washout time on CEUS (p = 0.015) were incorporated into the FULL model. The C indices of the US + CDFI, CEUS and FULL models were 0.918, 0.920 and 0.973. CEUS and FULL models yielded a good net benefit for almost all threshold probabilities. Nomograms based on US, CDFI, CEUS and clinical characteristics could help to non-invasively predict the response to treatment with anti-PD-1 antibodies plus anti-VEGF agents. [ABSTRACT FROM AUTHOR]

Introduction: Anti-vascular endothelial growth factor (VEGF) is generally given using pro re nata or "treat-and-extend" (T&E) regimens for neovascular age-related macular degeneration (nAMD). Randomized clinical trials have reported that T&E is superior to Pro re nata (PRN), but results from clinical trials may not always be replicated in clinical practice. Real-world data comparing T&E and PRN regimens for nAMD are limited. The objective of this work was to report 24-month outcomes of PRN versus T&E regimens for ranibizumab and aflibercept to treat nAMD in routine clinical practice. Methods: We conducted a retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project (FRB). Treatment-naïve eyes starting nAMD treatment with at least three injections using a T&E or PRN regimen were tracked by using the FRB. The primary outcome was the mean change in visual acuity (VA) measured by the number of letters read on a logarithm of the minimum angle of resolution chart at 2 years versus baseline. The secondary outcome was the number of injections at 2 years. Results: From January 1, 2015 to January 31, 2019, 3313 eyes from 2948 patients with nAMD were included: 1243 eyes from 1065 patients were classified as PRN and 2070 eyes from 1935 patients started a T&E regimen. At 24 months, patients on the T&E regimen experienced significantly greater mean (95% confidence interval) improvement in VA than those on PRN (+ 4.2 [3.1, 5.2] vs. + 1.3 [0.1, 2.6] letters; p < 0.001), with more injections (14.9 standard deviation(SD) 4.3) vs. 9.8(SD 4.3); p < 0.001). Conclusions: Eyes treated with a T&E regimen had better VA outcomes from VEGF inhibitors than eyes treated PRN. This large real-world data assessment supports previous data from randomized clinical trials that the T&E regimen delivers better outcomes than PRN. Plain Language Summary: This study focused on comparing two methods of treating neovascular age-related macular degeneration, a common eye condition. The treatments used were ranibizumab and aflibercept. We looked at the reactive "pro re nata" method, where treatment is given sporadically and only when the condition reactivates, and the proactive "treat-and-extend" method, which aims to keep the disease inactive with the fewest treatments at regular intervals. The main aim was to determine which method provides the best vision outcomes over a 24-month period and the frequency of treatment required. We found that the treat-and-extend method resulted in a greater improvement in vision than the pro re nata method, although it did require more injections. This study highlights the effectiveness of the treat-and-extend method for neovascular age-related macular degeneration, suggesting it gets better outcomes despite requiring more injections. [ABSTRACT FROM AUTHOR]

Background: Rickettsial disease has been commonly associated with retinitis, retinal vasculitis, and optic nerve involvement, but the development of retinal neovascularization has been very rarely reported. We herein describe a case of rickettsial retinitis complicated with the development of sea-fan retinal neovascularization documented with multimodal imaging, including fundus photography, SS-OCT, fluorescein angiography, and SS-OCT angiography. Case presentation: A 26-year-old female with a history of fever one week earlier presented with sudden decreased vision in the left eye. Best-corrected visual acuity (BCVA) was 20/2000 and the patient was diagnosed with rickettsial retinitis along the superotemporal retinal vascular arcade associated with serous retinal detachment and retinal hard exudates. The indirect immunofluorescence test was positive for Rickettsia conorii, and the patient was treated with oral doxycycline (200 mg/day) and oral prednisone (0.75 mg/kg/day, with gradual tapering). Four weeks after presentation, the retinal infiltrate and associated serous retinal detachment had resolved, but retinal hard exudates had increased. A large sea-fan preretinal fibrovascular neovascularization became apparent along the superotemporal retinal vascular arcade, but there was no associated retinal ischemia on fluorescein angiography. The patient received an adjunctive single intravitreal injection of 1.25 bevacizumab. Sequential follow-up examinations showed shrinking of sea-fan retinal neovascularization, a complete resolution of retinal hard exudates, and the development of a self-limited vitreous hemorrhage. On last follow-up, 30 months after intravitreal bevacizumab injection, BCVA was 20/25. Conclusion: Patients with rickettsial retinitis may develop a sea-fan retinal neovascularization, with subsequent vitreous hemorrhage, putatively through inflammatory mechanisms. Multimodal imaging including OCT, fluorescein angiography, and OCT-angiography, is highly useful for accurate diagnosis and reliable monitoring of the evolution of retinitis, retinal neovascularization, and other retinal changes. The use of a combination therapy with oral doxycycline and corticosteroids and intravitreal anti-VEGF can improve outcomes. [ABSTRACT FROM AUTHOR]

Purpose: The treatment with anti-VEGF for Retinopathy of prematurity (ROP) has already been widely applied in clinics even though there are still many concerns about this treatment. In this project we investigated the clinical outcomes of intra-vitreous conbercept (IVC) and ranibizumab (IVR) injection for treating type 1 prethreshold ROP in Zone II. Methods: The data of ROP infants receiving IVR or IVC from January 2017 to March 2020 who were followed up for at least 12 months in our hospital was studied in the present retrospective study. Regression, reactivation, complications, and ocular biological parameters were evaluated. Results: One hundred twenty-five eyes (64 infants) in IVC group and 229 eyes (117 infants) in IVR group were observed in the study. All infants showed good response to the two anti-VEGF agents. No eyes deteriorated during the observation. No significant difference was found between the two groups as to the regression within one week and one month, the reactivation rate, and the retreatment interval (p > 0.05) whereas retinal complete vascularization rate at 6 mons after the initial treatment and mean completion time of retinal vascularization after initial injection showed significant difference (p < 0.05). At 12 mons PMA the ocular parameters also presented no statistical difference between the two treated groups (p > 0.05). However, the ocular showed slight myopic tendency with the anti-VEGF treatment when compared to the control group (p < 0.05) whereas there was no statistical difference revealed between the two treated groups (p > 0.05). Conclusions: Both conbercept and ranibizumab for treating type 1 prethreshold ROP in Zone II are safe and effective. They had little effect on the development of ocular whereas there was a slight tendency of myopia after the treatment. [ABSTRACT FROM AUTHOR]

Introduction: Vascular endothelial growth factor (VEGF) is key to wet age-related macular degeneration (wAMD). Anti-VEGF drugs are the main treatment in clinics. This study assessed ocular adverse events (AE) from anti-VEGF drugs in VigiAccess, WHO's database, and compared adverse drug reaction (ADR) profiles of four drugs to aid personalized treatment choices for optimal benefit and safety. Methods: The design was a descriptive retrospective study. We observed four anti-VEGF drugs commonly used in the clinical treatment of wAMD, and their ADR reports came from WHO-VigiAccess. The collected data included the age group, gender, and regional data, as well as the data of disease systems and symptoms caused by ADR recorded in the annual ADR reports and reports received by the WHO. We observed the overall characteristics of the ADR reports of these drugs, then explored the distribution of 27 SOCs of these drugs. Subsequently, we compared the most common ocular ADRs of the drugs. Finally, we compared the commonalities and differences of ocular ADRs related to the drugs. Results: Overall, 57,779 AE associated with the four anti-VEGF drugs were reported. The results showed that the number of females experiencing ADRs (67.83%) was significantly higher than males (32.17%), the age group with the highest reported incidence was over 75 years old. More than half of the ADR reports came from the Americas (50.86%). The five most common types of AE were: eye disorders (43.56%), general disorders and administration site conditions (34.47%), injury poisoning and procedural complications (13.36%), infections and infestations (11.61%), nervous system disorders (9.99%). Compared with the other three inhibitors, brolucizumab had a significantly higher rate of ocular ADR reports. The most common ocular ADRs of these four anti-VEGF drugs were mostly related to visual impairment, vision blurred, and blindness. However, there is still a disparity of ADRs between different drugs. Conclusion: The presence of ocular AEs when using anti-VEGF drugs to treat wAMD in clinical practice should attract clinical attention. Clinicians should use these expensive drugs more rationally based on the characteristics of ADRs and develop personalized treatment plans for patients. [ABSTRACT FROM AUTHOR]

Background: Neovascular age-related macular degeneration (nAMD) is a common cause of visual impairment and blindness in the elderly with globally increasing prevalence. Vascular endothelial growth factor inhibitor (anti-VEGF) treatment has improved visual prognosis of nAMD, but continuous treatment may cause anxiety and stress, although increase in visual acuity (VA) may also have positive effects on patients' quality of life. The health care burden due to frequent treatment and monitoring is apparent, but the effect of anti-VEGF treatment on patients' quality of life is not fully understood. We evaluated the overall impact of nAMD and its treatment on newly diagnosed patients' health-related quality of life (HRQoL) in real-world setting. Methods: The present prospective cohort study included newly diagnosed nAMD patients treated with anti-VEGF injections at Oulu University Hospital during 2019–2020. Data included parameters from comprehensive ophthalmic examination and fundus imaging, age at diagnosis, sex, comorbidities, visual acuity, and frequency of anti-VEGF injections. HRQoL was assessed by 15D questionnaire at diagnosis, 6 months, and 12 months. Results: 95 nAMD patients were included. They were 78 ± 8 years old, 56 (59%) were female, and 74 (78%) had more than one comorbidity. The patients received 8 ± 3 anti-VEGF-injections. Visual acuity (VA) improved from 56 ± 18 to 61 ± 24 Early treatment diabetic retinopathy study (ETDRS) letters in 12 months. VA improved > 5 ETDRS letters in 45 (47%), remained stable in 30 (32%) and decreased > 5 letters in 17 (18%) eyes. The mean total 15D score reflecting overall HRQoL decreased from 0.850 ± 0.104 to 0.834 ± 0.103 in 12 months. Decreased HRQoL was associated with baseline best-corrected VA (BCVA) ≥ 70 ETDRS letters (p = 0.023) and more than one comorbidity (p = 0.034). HRQoL regarding visual function increased from 0.765 ± 0.194 to 0.789 ± 0.184 during the 12-month follow-up. Conclusions: In real world setting, HRQoL regarding visual function improved in anti-VEGF-treated nAMD patients during the first 12 months after the diagnosis and treatment initiation. Good baseline VA or several comorbidities were associated with decreased overall HRQoL during the follow-up. Despite the effectiveness of anti-VEGF treatment on visual function, several other aspects affecting elderly patients' everyday life should be considered when nAMD treatment is implemented. [ABSTRACT FROM AUTHOR]

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65–92%). Median progression free and overall survival were 14.0 (95% CI, 11.3–36.4) and 23.2 months (95% CI, 16.6–36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2–8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted. Preclinical studies indicate that simultaneous HER2 and VEGF blockade may be beneficial in gastroesophageal adenocarcinoma (GEA). Here, the authors report the efficacy and biomarker analysis of a phase II clinical trial investigating the combination of bevacizumab (anti-VEGF) and standard-of-care CAPOX (capecitabine, oxaliplatin) and trastuzumab in previously untreated advanced HER2 + GEA. [ABSTRACT FROM AUTHOR]

Purpose: To determine the recurrence rate of neovascular age-related macular degeneration (nAMD) during a 5-year period after the suspension of anti-vascular endothelial growth factor (anti-VEGF) treatments. Methods: Thirty-four eyes of 34 nAMD patients who met the inclusion criteria and were treated by anti-VEGF drugs were studied. All met the treatment suspension criteria and were followed for 5 years after the suspension of the anti-VEGF treatment. Patients with a recurrence within one year were placed in Group A, and patients with a recurrence between 1 and 5 years were placed in Group B. The rate and time of a recurrence were analyzed using the Kaplan–Meier method. We also examined whether there were differences in the baseline factors of age, sex, subtype, treatment period, and treatment interval between Groups A and B. Results: Twenty-five of 34 eyes (73.5%) had a recurrence within 5 years of stopping the anti-VEGF treatments. Thirteen (52.0%) of the 25 eyes had a recurrence within 1 year, 4 (16.0%) eyes between 1 and 2 years, 4 (16.0%) eyes between 2 and 3 years, 2 (8%) between 3 and 4 years, and 2 eyes (8%) between 4 and 5 years. The baseline factors were not significantly different between Groups A and B. Conclusions: The results showed that the recurrence rate was highest within one year after the suspension of the anti-VEGF treatments, with a number of recurrences one year after the suspension. Clinicians should remember that nAMD may recur several years after the suspension of anti-VEGF treatments. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 430,000 new cases of renal cell carcinoma (RCC) occurred worldwide in 2022, and about one-third of RCC cases are diagnosed at an advanced stage of disease (aRCC). When patients with aRCC fail first-line treatment, they commonly receive one of the recommended second-line treatments, i.e., axitinib, cabozantinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib. Axitinib is a second-generation tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor tyrosine kinases 1, 2, and 3. It has been available since 2011 for the treatment of aRCC after the failure of prior therapy with sunitinib or cytokines. The aim of our research was to understand how axitinib compares with other treatment options considering data from clinical trials and observational studies that reflect real-world clinical practice. Therefore, we conducted a systematic literature review to summarise evidence on commonly used and recommended treatments in aRCC after the failure of prior therapy with sunitinib or cytokines. Background: We conducted a systematic literature review (SLR) to identify clinical evidence on treatments in advanced renal cell carcinoma (aRCC) after the failure of prior therapy with cytokines, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Herein, we summarise the evidence for axitinib in aRCC after the failure of prior therapy with cytokines or sunitinib. Methods: This SLR was registered with PROSPERO (CRD42023492931) and followed the 2020 PRISMA statement and the Cochrane guidelines. Comprehensive searches were conducted in MEDLINE and Embase as well as for conference proceedings. Study eligibility was defined according to population, intervention, comparator, outcome, and study design. Results: Of 1252 titles/abstracts screened, 266 peer-reviewed publications were reviewed, of which 182 were included. In addition, 28 conference abstracts were eligible. Data on axitinib were reported in 55 publications, of which 16 provided efficacy and/or safety outcomes on axitinib after therapy with sunitinib or cytokines. In these patients, median progression-free and overall survival ranged between 5.5 and 8.7 months and 11.0 and 69.5 months, respectively. Conclusions: Axitinib is commonly used in clinical practice and has a well-characterised safety and efficacy profile in the treatment of patients with aRCC after the failure of prior therapy with sunitinib or cytokines. [ABSTRACT FROM AUTHOR]

The direct antitumor effect of bevacizumab (BEV) has long been debated. Evidence of the direct antitumor activities of drugs are mainly obtained from in vitro experiments, which are greatly affected by experimental conditions. In this study, we evaluated the effect of BEV-containing medium renewal on the results of in vitro cytotoxicity experiments in A549 and U251 cancer cells. We observed starkly different results between the experiments with and without BEV-containing medium renewal. Specifically, BEV inhibited the tumor cell growth in the timely replacement with a BEV-containing medium but promoted tumor cell growth without medium renewal. Meanwhile, compared with the control, a significant basic fibroblast growth factor (bFGF) accumulation in the supernatant was observed in the group without medium renewal but none in that with replaced medium. Furthermore, bFGF neutralization partially reversed the pro-proliferative effect of BEV in the medium non-renewed group, while exogenous bFGF attenuated the tumor cell growth inhibition of BEV in the medium-renewed group. Our data explain the controversy over the direct antitumor effect of BEV in different studies from the perspective of the compensatory autocrine cytokines in tumor cells. [ABSTRACT FROM AUTHOR]

Introduction: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. Methods: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. Results: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Conclusions: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. Recently, AMD prevalence in Korea has increased from 6.6% to 13.9% over the past decade, which may be a threat to the public health of Korean society. This study describes the current status, including risk factors, treatment, and economic burden of AMD in Korea. Current Concepts: Major AMD risk factors have been consistently reported, including age, hypertension, smoking, and ultraviolet radiation. The primary AMD treatment is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF). Anti-VEGF was developed and improved in terms of efficacy and safety. However, AMD treatment's economic burden is significant. Therefore, several treatment strategies have been introduced, such as monthly, as-needed, and treat-and-extend injection strategies. Discussion and Conclusion: With the rapid increase in AMD prevalence in Korea, the economic burden of AMD management will be a significant challenge for the Korean healthcare system. Therefore, cost-effectiveness and resource allocation for AMD treatment needs to be investigated. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic macular edema (DME) is a vision threatening accumulation of fluid within the macula. Current treatments involve the use of intravitreal anti-vascular endothelial growth factor (anti-VEGF), steroids, and laser to preserve vision. Areas covered: This review covers phase III therapeutics including KSI-301, which targets VEGF-A, UBX1325 which promotes apoptosis of senescent vascular endothelial cells and topical dexamethasone drops. Phase I and phase II therapeutics are also discussed including APX3330, a reduction-oxidation factor (Ref-1) inhibitor, ASP8232 – a vascular adhesion protein-1 (VAP-1) inhibitor, OTT-166, an anti-integrin agent, EYE103, a Wnt agonist and AXT107 and AG-73305, which have both anti-integrin and anti-VEGF functions. Tyrosine kinase inhibitors such as EYP-1901 and AXPALI, and YD312, gene therapies such as 4D–150 and RGX-314. Expert opinion: Current treatments for DME are limited greatly by the need for frequent dosing, treatment adherence, and invasive administration. Newer technologies that promote alternative routes of administration or increased longevity hold promise for the management of DME. [ABSTRACT FROM AUTHOR]

Background: Retinopathy of prematurity (ROP) is a significant cause of blindness in infants. Appropriate therapeutic intervention is essential because retinal detachment due to the progression of ROP is critical to visual function. The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents has been increasingly applied to inhibit the development and progression of ROP. In this study, we compared the efficacy of single intravitreal bevacizumab (IVB) and ranibizumab (IVR) injections for the treatment of ROP. Methods: A total of 39 eyes in 21 patients with severe ROP and IVB (15 eyes of 8 patients) and IVR (24 eyes of 13 patients) were retrospectively reviewed. Patient background, the severity of ROP, and the percentage of cases in which ROP regressed without additional treatment were compared between the two groups. Results: Patient background and ROP severity were not significantly different between the two groups. Recurrence was observed in one eye of one patient in the IVB group, and thirteen eyes in seven patients in the IVR group required additional laser photocoagulation, which was significantly different in the two groups (p < 0.01, Fisher's exact test). In the IVR group, two eyes of two patients underwent vitreous surgery. Conclusion: Compared with IVR, IVB is likely to control the severity of ROP with a single treatment. [ABSTRACT FROM AUTHOR]

Cardio-oncology is a critical field due to the escalating significance of cardiovascular toxicity as a side effect of anticancer treatments. Cancer therapy-related cardiac dysfunction (CTRCD) is a prevalent condition associated with cardiovascular toxicity, necessitating effective strategies for prediction, monitoring, management, and tracking. This comprehensive review examines the definition and risk stratification of CTRCD, explores monitoring approaches during anticancer therapy, and highlights specific cardiovascular toxicities linked to various cancer treatments. These include anthracyclines, HER2-targeted agents, vascular endothelial growth factor inhibitors, immune checkpoint inhibitors, chimeric antigen receptor T-cell therapies, and tumor-infiltrating lymphocytes therapies. Incorporating the Korean data, this review offers insights into the regional nuances in managing CTRCD. Using systematic follow-up incorporating cardiovascular imaging and biomarkers, a better understanding and management of CTRCD can be achieved, optimizing the cardiovascular health of both cancer patients and survivors. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the clinical efficacy of dexamethasone (DEX) implant, for the treatment of macular edema (ME) caused by retinal vein occlusion (RVO) and diabetic retinopathy (DR) through a systematic review and meta-analysis. Methods: The PubMed, Embase and Cochrane Library databases were comprehensively searched from inception to November 21, 2022, for studies evaluating the clinical efficacy of DEX implant for patients with retinal vein occlusion macular edema (RVO-ME) or diabetic macular edema (DME). Randomized controlled trials (RCTs) published in English were considered eligible. The Cochrane Collaboration tool was applied to assess the risk of bias in each study. Effect estimates with 95% confidence intervals (CIs) were pooled using the random effects model. We also conducted subgroup analyses to explore the sources of heterogeneity and the stability of the results. Results: This meta-analysis included 8 RCTs (RVO-ME [n = 2] and DME [n = 6]) assessing a total of 336 eyes. Compared with anti-VEGF therapy, DEX implant treatment achieved superior outcomes in terms of best corrected visual acuity (BCVA) (mean difference [MD] = -3.68 ([95% CI, -6.11 to -1.25], P = 0.003), and no heterogeneity was observed (P = 0.43, I2 = 0%). DEX implant treatment also significantly reduced central macular thickness (CMT) compared with anti-VEGF treatment (MD = -31.32 [95% CI, -57.92 to -4.72], P = 0.02), and there was a high level of heterogeneity between trials (P = 0.04, I2 = 54%). In terms of severe adverse events, DEX implant treatment had a higher risk of elevated intraocular pressure than anti-VEGF therapy (RR = 6.98; 95% CI: 2.16 to 22.50; P = 0.001), and there was no significant difference in cataract progression between the two groups (RR = 1.83; 95% CI: 0.63 to 5.27, P = 0.31). Conclusions: Compared with anti-VEGF therapy, DEX implant treatment is more effective in improving BCVA and reducing ME. Additionally, DEX implant treatment has a higher risk of elevated intraocular pressure. Due to the small number of studies and the short follow-up period, the results should be interpreted with caution. The long-term effects of the two treatments need to be further determined. Trial registration: Prospero Registration NumberCRD42021243185. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the dropout rate of anti‐vascular endothelial growth factor (VEGF) treatment for macular edema (ME) secondary to branch retinal vein occlusion (BRVO) and identify the characteristics of dropout cases. Methods. We studied 235 eyes of 235 treatment‐naïve BRVO‐ME patients receiving intravitreal injection of ranibizumab. Additional intravitreal anti‐VEGF drug was given when ME relapsed or persisted, and photocoagulation was performed as needed. Adherence until treatment completion was defined as disappearance of ME within 2 years after the first injection without recurrence for more than 6 months or mild ME remaining but no visual deterioration for more than 6 months without additional anti‐VEGF drug. In patients with ME recurrence, those who were followed for more than 2 years were considered adherence, and those followed for less than 2 years were considered dropout. The clinical course and background of the two groups were compared. Results. 179 patients (76.2%) adhered to treatment and 56 patients (23.8%) dropped out. Mean follow‐up periods in adherence and dropout groups were 23.4 and 7.1 months, respectively. There were no significant differences between the two groups in demographic and baseline factors of age, gender ratio, distance from home to hospital, visual acuity, and foveal thickness (FT). At the last follow‐up, visual acuity was significantly poorer in the dropout group than in the adherence group (0.23 vs. 0.11 logMAR, p = 0.003), and FT was significantly greater in the dropout group than in the adherence group (316 vs. 273 µm, p = 0.002). Reasons for dropout included patient declining further treatment in 12.5%, progression of dementia in 8.9%, others, and unknown in 64.3%. Conclusion. The clinical outcome of patients who dropped out of anti‐VEGF therapy for BRVO‐ME was worse compared to patients who adhered to therapy, and the reasons for discontinuation varied. [ABSTRACT FROM AUTHOR]

Recently, the discovery of small molecules as inhibitors for vascular endothelial growth factor receptor 2 (VEGFR2) is of timely interest, especially in the area of ocular neovascular diseases. Meanwhile, PyPLIF HIPPOS, in combination with machine-learning techniques, has been reported to increase the prediction quality of structure-based virtual screening (SBVS) protocols. The original version of PyPLIF has served in the development of an SBVS protocol that successfully identified novel chalcone derivatives and short peptides as potent inhibitors for acetylcholinesterase. In this short communication, construction and retrospective validation of an SBVS protocol employing PyPLIF HIPPOS targeting VEGFR2 are presented to make it publicly available. The retrospective validation employed 409 active compounds and 24,950 decoys from the enhanced version of the directory of useful decoys. All compounds were docked independently three times using AutoDock Vina followed by the identification of the protein-ligand interaction fingerprints (PLIF) employing PyPLIF HIPPOS. The derived ensemble PLIF descriptors were then used in the decision tree construction using a machinelearning technique called recursive partitioning and regression trees. The best decision was then incorporated in the SBVS protocol. The F-measure and enrichment factor values of the SBVS protocol were 0.387 and 76.879, respectively. Accordingly, the SBVS protocol could be used for further prospective screening campaigns. [ABSTRACT FROM AUTHOR]

Angiogenesis, a crucial process in tumor growth, is widely recognized as a key factor in cancer progression. The vascular endothelial growth factor (VEGF) signaling pathway is important for its pivotal role in promoting angiogenesis. The primary objective of this study was to identify a powerful classifier for distinguishing compounds as active or inactive inhibitors of VEGF receptors. To build the machine learning model, compounds were sourced from the BindingDB database. A variety of common feature selection techniques, including both filter‐based and wrapper‐based methods, were applied to reduce dimensionality, subsequently, overfitting problem. Robust and accurate tree‐based classifiers were employed in the classification procedure. Application of the extra‐tree classifier using the MultiSURF* feature selection method provided a model with superior accuracy (83.7%) compared with other feature selection techniques. High‐throughput molecular docking followed by an accurate docking and comprehensive analysis of the results was performed to provide the best possible inhibitors of these receptors. Comprehensive analysis of the docking results revealed successful prediction of molecules with VEGFR1 and VEGFR2 inhibitory activity. These results emphasized that the performance of the extra‐tree model, coupled with MultiSURF* feature selection, surpassed other methods in identifying chemical compounds targeting specific VEGF receptors. Extracting Input data of machine learning step.Applying a variety of common feature selection techniques.Employing Tree‐based classifiers in the classification procedure.Extracting over 900,000 drug‐like compounds.Finding more probable small molecules, as potential inhibitors for VEGFRs via the proposed ML algorithm.Exploiting the interactions of the proposed compounds with VEGFRs.The results revealed that the applied ligand‐based and structure‐based screening strategy was highly efficient in predicting molecules with VEGFR1, VEGFR2, and VEGFR3 inhibitory activity. [ABSTRACT FROM AUTHOR]

Purpose: To assess the impact of switching to, or adding, an intravitreal dexamethasone implant (Dex; Ozurdex®) in anti-vascular endothelial growth factor (VEGF) therapy on disease stability and treatment intervals in eyes with neovascular age-related macular degeneration (nAMD) and persistent disease activity and high treatment demand. Methods: This retrospective noncomparative multicenter longitudinal case series included pseudophakic eyes with nAMD and persistent retinal fluid despite regular anti-VEGF therapy (ranibizumab or aflibercept) that received at least 1 intravitreal Dex implant. Visual acuity, central retinal thickness (CRT), and intraocular pressure were recorded before, and after, the addition of Dex to anti-VEGF therapy. Results: Sixteen eyes of 16 patients met the inclusion criteria of persistent fluid despite anti-VEGF therapy, under treatment intervals of ≤7 weeks in 14 instances. Patients were 80.9 ± 7.4 years old and had received 25.5 ± 17.4 anti-VEGF injections before Dex over a period of 36.4 ± 21.9 months before switching. The treatment interval increased from 5.5 ± 3.2 weeks between the last anti-VEGF and first Dex injection to 11.7 ± 7.3 weeks thereafter (P = 0.022). CRT remained stable (385.3 ± 152.1, 383.9 ± 129.7, and 458.3 ± 155.2 μm before switching as well as 12 and 24 months after switching; P = 0.78 and P = 0.36, respectively). An insignificant mean short-term early increase in visual acuity was not sustained over time. Conclusions: The addition of Dex resulted in a relevant and sustained increase in treatment intervals, whereas CRT and visual acuity remained stable in these difficult-to-treat eyes. It may be discussed whether inflammation or other steroid-responsive factors play a significant role in cases of nAMD with nonsatisfactory responses to anti-VEGF. [ABSTRACT FROM AUTHOR]

In recent years, the progress made in the field of optical coherence tomography has helped to understand the changes in eye layers in patients with exudative age-related macular degeneration (nAMD). Early diagnosis of nAMD, a leading cause of irreversible vision impairment, is helpful. Therefore, we performed a meta-analysis on OCT measurement alterations before and after anti-VEGF therapy in patients with nAMD and controls. We systematically searched Scopus, PubMed, Cochrane, and Web of Science to find articles that measured choroidal and retinal layer changes after anti-VEGF therapy in nAMD Patients. We chose either a fixed-effects or random-effects model based on the assessed heterogeneity level to perform a meta-analysis. In addition, we conducted meta-regression, subgroup analyses, publication bias, and quality assessment for included studies. Thirteen studies were included in the meta-analysis, with 733 total participants. Foveal thickness and subfoveal choroidal thickness (CT) decreased significantly in the first 3 years after injections, except for subfoveal CT in the third year after injection. It also showed that CT at 1500 µm temporal and nasal to the fovea did not significantly change. Our results showed anti-VEGF treatment for nAMD patients was associated with a significant reduction in foveal thickness and subfoveal CT in the first 2 years after treatment. Our analysis did not reveal any correlation between changes in foveal thickness and subfoveal CT with best-corrected visual acuity or other factors. [ABSTRACT FROM AUTHOR]

Laser photocoagulation (LPC) and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections constitute the current standard treatment for retinopathy of prematurity (ROP). This network meta-analysis focus on whether a ranking of interventions may be established for different dose levels of intravitreal injection of anti-VEGF agents (aflibercept, bevacizumab, conbercept, ranibizumab) as primary treatments for ROP versus laser in terms of retreatment rate as primary outcome, and time to retreatment and refractive error as secondary endpoints, since best anti-VEGF dosage remains under debate. Sixty-eight studies (15 randomized control trials and 53 nonrandomized studies) of 12,356 eyes of 6445 infants were retrieved from databases (2005 Jan. – 2023 June). Studies were evaluated for model fit, risk of bias and confidence of evidence in Network Meta-Analysis (CINeMA). Bayesian NMA showed that anti-VEGF drugs were not inferior to laser in terms of retreatment rate. For intravitreal bevacizumab (IVB), doses half of the conventional infant dose showed a low risk of retreatment rate (risk ratio (RR) of 1.43; 95% credible interval (CrI): 0.508, 4.03). On probability ranking as surface under the cumulative ranking curve (SUCRA) plot, half dose of bevacizumab had a better position than conventional and augmented (1.2–2 times the regular dose) doses. A similar probability trend was observed for half vs. conventional doses of aflibercept and ranibizumab. Conventional infant dose of conbercept showed the lowest risk for retreatment (RR 0.846; 95% CrI: 0.245, 2.91). For secondary endpoints, lower doses of anti-VEGF agents were associated with shorter times to retreatment. The largest changes were noted for the augmented doses of bevacizumab and ranibizumab (0.3 mg) with means of 14.1 weeks (95% CrI: 6.65, 21.6) and 12.8 weeks (95% CrI: 3.19, 20.9), respectively. Finally, NMA demonstrated better refractive profile for anti-VEGF than laser therapy, especially for the conventional infant doses of bevacizumab and ranibizumab which exhibited a significantly better refractive profile than LPC, with mean differences of 1.67 (spherical equivalent - diopters) (95% CrI: 0.705, 2.67) and 2.19 (95% CrI: 0.782, 3.59), respectively. In the SUCRA plots, LPC had a markedly different position with a higher probability for myopia. Further clinical trials comparing different intravitreal doses of anti-VEGF agents are needed, but our findings suggest that low doses of these drugs retain efficacy and may reduce ocular and systemic undesired events. • ROP is a serious neovascular disorder caused by proliferation of abnormal fibrovascular tissue in premature infants. • Laser therapy is considered the standard treatment for ROP but the use of anti-VEGF agents has increasingly being recognized. • Anti-VEGF therapy has demonstrated some advantages but impact on organogenesis remains of concern. • Reduced doses of anti-VEGF seem to maintain efficacy while avoiding toxicity. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is an ideal therapeutic option for selected patients with hepatocellular carcinoma (HCC). The selection criteria of HCC for LT have evolved in recent decades. Downstaging therapy is a promising strategy for patients with tumor burden beyond transplant criteria to increase the chance of receiving LT and improve posttransplant survival. Downstaging therapy is also a selection tool that refines the conventional selection criteria based on tumor morphology. Recently, the success of systemic treatment, including immune checkpoint inhibitors, antiangiogenic tyrosine kinase inhibitors, and VEGF inhibitors, in advanced HCC has prompted the discussion regarding the role of systemic therapies for HCC downstaging before transplantation. In this review, we aimed to summarize the current advances in selection criteria and therapeutic options of downstaging therapy for HCC before LT. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the wellknown anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and in vitro models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different in vitro models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 μM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 μM, respectively), was able to significantly reduce (p < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose vs. axitinib 1 μM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly (p < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose vs. axitinib 1 μM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 μM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action. [ABSTRACT FROM AUTHOR]