Search Results (202)

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Retinal ischemia is implicated in ocular diseases involving aberrant neovessel proliferation that characterizes proliferative retinopathies. Their therapy still remains confined to the intravitreal administration of anti-vascular endothelial growth factor (VEGF) medication, which is limited by side effects and progressive reduction in efficacy. Mimicking neovascular diseases in rodents, although of great help for translating fundamental mechanistic findings and assessing therapeutic potential in humans, is limited by the rodent’s short life span, which prevents retinal vessel proliferation over time. However, the oxygen-induced retinopathy (OIR) model, which mimics retinopathy of prematurity, seems to meet some criteria that are common to proliferative retinopathies. The present review provides insight into preclinical models and their suitability to mimic proliferative retinopathies. Further considerations will be applied to emerging approaches and advanced methodologies for the management of proliferative retinopathies, leading to the identification of new therapeutic targets, including our contribution in the field. Major emphasis is given to the possibility of using systemic therapies either alone or in combination with intravitreal anti-VEGF administration to maximize clinical benefits by combining drugs with different modes of action. This review is concluded by an in-depth discussion on future advancements and a critical view of preclinical finding translatability. Despite the major effort of preclinical and clinical research to develop novel therapies, the blockade of VEGF activity still remains the only treatment for proliferative retinopathies for more than twenty years since its first therapeutic application. Full article

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Objectives: This study aimed to assess the initial anatomical and functional outcomes of switching to aflibercept 8 mg in patients with neovascular age-related macular degeneration (nAMD) previously treated with anti-vascular endothelial growth factor (VEGF) therapy. Methods: Patients with nAMD previously treated with anti-VEGF drugs were switched to aflibercept 8 mg. Patients with any exudative changes (subretinal fluid [SRF], intraretinal fluid [IRF] or serous pigment epithelial detachment [sPED]) at the time of the first aflibercept 8 mg injection and whose dosing interval before and after switching did not differ by more than ±7 days were included. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), and the presence of SRF, IRF, and sPED were evaluated before and after switching to aflibercept 8 mg. Results: A total of 102 eyes from 98 patients were included in the analysis. The drugs used prior to switching were faricimab in five eyes, brolucizumab in six eyes, and aflibercept 2 mg in 91 eyes, with a mean interval of 63.7 ± 20.0 days from the last pre-switch injection and 64.9 ± 20.1 days to the first post-switch visit. The CFT was significantly reduced from 272 ± 85 µm to 246 ± 79 µm (p < 0.0001). The BCVA remained unchanged at 0.27 ± 0.35 logMAR. During switching, SRF, IRF, and sPED were observed in 70, 24, and 38 eyes, respectively. At the post-switch visit, complete resolution of exudative changes was observed in 44% of eyes with SRF, 55% with IRF, and 29% with sPED. No ocular or systemic adverse effects were observed. Conclusions: As an initial response to switching to aflibercept 8 mg in a real-world setting, SRF and IRF completely resolved in approximately half of the patients, and sPED resolved in about 30% of cases. Full article

Background/Objectives: To evaluate the potential of Optical Coherence Tomography (OCT) and OCT angiography parameters in predicting treatment requirements and visual outcomes after one year in therapy-naïve eyes with neovascular age-related macular degeneration (nAMD). Methods: A retrospective study of 96 therapy-naïve eyes newly diagnosed with nAMD was carried out. All eyes received baseline OCT and OCTA. Follow-up OCT after initial upload was then carried out, involving three intravitreal injections (IVIs) with anti-Vascular Endothelial Growth Factor (anti-VEGF) at four-week intervals. OCT parameters, including intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelium detachment (PED), and central retinal thickness (CRT), were assessed qualitatively and quantitatively. Macular Neovascularization (MNV) morphology at baseline was described in terms of area, total vessel length, flow density, and fractal dimension. OCT and OCTA parameters were correlated with best corrected visual acuity (BCVA) and number of administered IVIs after 1 year of treatment. Results: Eyes with persistent subretinal fluid (SRF) or both intraretinal fluid (IRF) and SRF after upload showed a significantly higher need for IVIs (p < 0.01). Also, pigment epithelium detachment (PED) presence at baseline (p < 0.05), PED height at baseline (p < 0.01), PED presence after upload (p < 0.01), and PED height after upload (p < 0.01) were each correlated with a greater number of IVIs. Decrease in PED height during upload was accompanied by a lower number of IVIs (p < 0.01). All the aforementioned parameters had no influence on BCVA after 1 year (p > 0.05). Baseline central retinal thickness (CRT) was linked to worse BCVA at 12 months (p < 0.05), but not the number of IVIs. Follow-up CRT correlated with worse BCVA (p < 0.01) and more IVIs (p < 0.01), while CRT decrease was associated with better BCVA (p < 0.05) and fewer IVIs (p < 0.01) at 1 year. In OCTA, area and total vessel length of MNVs were correlated with BCVA after 1 year (p < 0.01) but had no influence on number of IVIs (p > 0.05). Flow density had no influence on either outcome parameter (p > 0.05). Fractal dimension was associated with BCVA (p < 0.01) and number of IVIs (p < 0.05) after 1 year. Conclusions: MNV area, vessel length, and fractal dimension in OCTA, along with fluid distribution in OCT at baseline and after follow-up, may serve as indicators of treatment needs and visual outcomes after one year. Further studies with longer observation periods and the use of deep learning models are needed to improve analyses and to verify the applicability of these findings to clinical practice. Full article

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. Methods: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy vs. NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia–Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS 28.0 version and R software 4.5 version to compare fibrosis rates and survival outcomes. Results: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1), and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p < 0.001. Overall survival was similar between both cohorts (p = 0.96), with a median follow-up of 41.6 months. Conclusions: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC. Full article

Background/Objectives: Uncontrolled or long-standing diabetes can lead to proliferative diabetic retinopathy (PDR), a condition that significantly impairs vision. A subset of patients does not respond adequately to conventional therapies, such as intravitreal injections of anti-vascular endothelial growth factor (VEGF) or laser treatment. This study aims to identify potential biomarkers for alternative treatment pathways in the vitreous and blood of patients with severe PDR. Methods: Vitreous samples were collected from PDR patients (n = 3) undergoing vitrectomy for vitreous hemorrhage and from control patients (n = 9) undergoing ocular surgery for epiretinal membrane or macular holes. Blood samples were collected from a separate group of PDR patients (n = 13) and non-diabetic control patients without retinopathy (n = 13). Medical histories were obtained. Two-stage real-time quantitative polymerase chain reaction (qPCR) was used to evaluate mRNA expression levels of genes potentially implicated in PDR, including HIF2A, PAI-1, TIE1, TIE2, ANGPT2, and VEGFA. Molecular and statistical analyses were performed to compare PDR and control vitreous and blood samples. Results: The PDR vitrectomy group included two females and one male, aged 71–77 years (mean 74 years). All participants had undergone pan-retinal photocoagulation and two had received anti-VEGF injections before vitrectomy. These participants had elevated HbA1c levels. Targeted vitreous gene analysis revealed varying levels of increased expression of all genes examined as compared to the control group. A trend for increased median expression was demonstrated for all examined genes: HIF2A by 1.44-fold (PDR = 2.50, control = 1.74, p = 0.21), PAI-1 by 1.56-fold (PDR = 3.00, control = 1.93, p = 0.37), TIE1 by 1.36-fold (PDR = 2.33, control = 1.72, p = 0.66), TIE2 by 2.06-fold (PDR = 2.81, control = 1.36, p = 0.51), ANGPT2 by 2.93-fold (PDR = 6.32, control = 2.16, p = 0.1), and VEGFA by 3.53-fold (PDR = 3.51, control = 0.99, p = 0.08). PDR blood sample analysis as compared to controls showed a trend for increased expression of VEGFA by 1.2-fold (PDR = 0.88, control = 0.74, p = 0.57), whereas the other examined genes showed a trend of reduced expression; HIF2A decreased by 0.50-fold (PDR = 0.38, control = 0.75, p = 0.07), PAI by 0.51-fold (PDR = 0.35, control = 0.69, p = 0.09), TIE-1 by 0.79-fold (PDR = 0.79, control = 1.00, p = 0.54), TIE-2 by 0.70-fold (PDR = 0.58, control = 0.82, p = 0.34), and ANGPT2 by 0.45-fold (PDR = 0.51, control = 1.15, p = 0.11). Conclusions: Vitreous sample analysis revealed a trend of increased mRNA expression of ANGPT2 and VEGFA in patients with PDR. Blood sample analysis did not show a significant increase of VEGFA mRNA expression but a decreased trend of HIF2A, PAI-1, and ANGPT2 mRNA expression. These trends warrant validation in a larger cohort to explore alternative pathways for targeted treatment. Full article

Background: Diabetic macular edema (DME) is the leading cause of vision impairment in diabetic patients, with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections being the first-line therapy. However, one-third of patients exhibit persistent DME despite treatment, suggesting additional pathogenic factors. This study aimed to evaluate the predictive value of complete blood count (CBC)-based inflammation indexes and optical coherence tomography (OCT) parameters in determining early anti-VEGF treatment effectiveness in DME. Methods: One hundred and four naïve patients with DME, treated with 0.05 mL of intravitreal aflibercept were retrospectively analyzed. Blood parameters analyzed included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Baseline OCT biomarkers included subretinal fluid (SRF), intraretinal cysts (IRC), hyperreflective retinal spots (HRS), and disorganization of retinal inner layers (DRIL). Treatment response was defined as a minimum 10% reduction in central macular thickness (CMT) at one month post-injection. Results: NLR, MLR, PLR, and SII were significantly higher in non-responders (p < 0.001), but their predictive value was fair, with an area under the ROC curve ranging between 0.704 (MLR) and 0.788 (SII). A multivariate model including SII, initial CMT, and the presence of IRC showed an excellent prediction value for early anatomical response (AUC ROC of 0.911). At the same time, lower PLR, DRIL, SRF, and the absence of HRF were correlated with early gain in BCVA. Conclusions: CBC-derived inflammation indices and OCT biomarkers have prognostic value in predicting early response to anti-VEGF therapy in DME in terms of functional and anatomical outcomes. These findings could help identify poor responders and guide personalized treatment strategies. Full article

Background/Objectives: Anti-vascular therapy presents a potential strategy for activating anti-tumor immunity. Disrupted vascular debris provides effective antigens that activate dendritic cells, leading to subsequent immune responses. However, the resulting tumor hypoxia following vascular disruption may contribute to immune suppression, thereby hindering effective immune activation. Ultrasound-stimulated microbubble cavitation can locally disrupt tumor vessels through mechanical effects to achieve physical anti-vascular therapy. Therefore, this study designed oxygen-loaded nanobubbles (ONBs) to combine anti-vascular effects with local oxygen release under ultrasound stimulation. The feasibility of enhancing anti-tumor immune activation by alleviating tumor hypoxia was evaluated. Methods: A murine pancreatic subcutaneous solid tumor model was used to evaluate the efficacy of anti-vascular therapy-associated immunotherapy. Results: After ONB treatment, tumor perfusion was reduced to 52 ± 5%, which resulted in a subsequent 57 ± 11% necrosis and a 29 ± 4% reduction in hypoxia, demonstrating the anti-vascular effect and reoxygenation, respectively. However, subsequent immune responses exhibited no significant activation in intratumoral cytokine expression or splenic immune cell composition. Primary tumors exhibited a 15.7 ± 5.0% increase in necrosis following ONB treatment, but distant tumor growth was not significantly inhibited. Conclusions: These results highlighted a crucial issue regarding the complex correlations between vessel disruption, antigen production, oxygen delivery, hypoxia, and immunity when combining anti-vascular therapy with immunotherapy. Full article

Background/Objectives: Submacular hemorrhage (SMH) associated with neovascular age-related macular degeneration (nAMD) can lead to significant vision loss, and the optimal management strategy remains uncertain. This study aimed to evaluate the efficacy and safety of pneumatic displacement (PD) without tissue plasminogen activator (t-PA) for SMH secondary to nAMD. Methods: A retrospective analysis was conducted on 22 eyes with SMH secondary to nAMD treated with PD without t-PA. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of intravitreal injections, and postoperative complications were assessed at baseline and follow-up. Multiple logistic regression analyses were used to identify factors associated with visual outcomes. Results: In the 22 eyes that completed the 6-month follow-up, BCVA (logMAR) was 0.88 ± 0.46 at baseline and 0.76 ± 0.63 at 6 months (p = 0.24). In the 15 eyes with 12-month follow-up, BCVA improved significantly from 0.92 ± 0.47 at baseline to 0.56 ± 0.51 at 12 months (p = 0.01). CRT significantly decreased at 3 months (p < 0.01). During this period, patients received an average of 8.13 ± 2.90 intravitreal anti-vascular endothelial growth factor (VEGF) injections. A shorter duration from symptom onset to treatment was associated with better visual outcomes (p = 0.02). Postoperative vitreous hemorrhage occurred in 31.8% of cases. Conclusions: PD without t-PA, in combination with anti-VEGF therapy, improved visual outcomes over 12 months. Early intervention and continuous anti-VEGF administration appear to be key factors in optimizing treatment outcomes. Further studies are needed to establish standardized treatment protocols for SMH associated with nAMD. Full article

Retina, a light-sensitive layer of tissue of the eye, requires high levels of oxygen for its physiology. Retinal ischemia occurs due to inadequate supply of blood to the retina and choroid. Retinal ischemia is implicated in the development or progression of many ocular diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). To date, anti-vascular endothelial growth factor (VEGF) treatment has been widely used to manage neovascular diseases associated with retinal ischemia. Nonetheless, a substantial number of patients with DR or AMD still suffer from incomplete response and adverse effects related to its therapy with limitations. Therefore, research scientists have been developing and finding novel treatments to protect against or prevent vision loss in those diseases. In this review article, we summarize the recent novel therapeutic approaches for the treatment of ischemic retinopathy (e.g., cell therapy, advanced molecular targeting, or drug delivery). This summary enables further research to obtain more solid evidence of novel effective drug development in retinal ischemic diseases. Full article

Background: Anti-Vascular Endothelial Growth Factor (VEGF) therapy is an effective therapy for improving and stabilizing the vision of patients with neovascular age-related macular degeneration (nAMD). However, the treatment requirements, particularly the number of intraocular injections, can vary significantly among patients. This study aimed to analyze the vascular characteristics of macular neovascularizations (MNVs) to identify potential biomarkers that could predict the required injection frequency throughout the disease course. Methods: In all patients, the initial diagnosis of nAMD was confirmed using optic coherence tomography (OCT), fluorescein angiography, and OCT angiography (OCTA). MNVs detected using OCTA were subjected to quantitative vascular analysis of their area, total vascular length (sumL), fractal dimension (FD), and flow density. These results were then correlated with the number of intravitreal anti-VEGF treatments administered during the first 3 years of treatment. Additionally, the relationship between the parameters and visual acuity progression was analyzed. Results: A total of 68 treatment-naïve eyes were included in the study, comprising 31 eyes with type 1 MNV, 19 eyes with type 2 MNV, and 18 eyes with type 3 MNV. The average MNV area at baseline was 1.11 mm² ± 1.18 mm², the mean total vascular length was 12.95 mm ± 14.24 mm, the mean fractal dimension was 1.26 ± 0.14, and the mean flow density was 41.19 ± 5.87. On average, patients in our cohort received 19.8 ± 8.5 intravitreal injections (IVIs). A significant correlation was found between the number of administered IVIs in the first 3 treatment years and the MNV area (p < 0.005), sumL (p < 0.005), and FD (p < 0.05), while no correlation was found with flow density. Additionally, there was no significant association between MNV type and treatment requirements, nor between MNV vascular architecture and visual acuity progression. Conclusions: The results suggest that the specific vascular structure of untreated MNV may serve as a predictor of long-term treatment demand. With the emergence of new drug classes and advancements in imaging techniques, these parameters could offer valuable insights for forecasting treatment requirements. Full article

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. Its pathogenesis involves multiple factors, including aging, environmental influences, genetic predisposition, oxidative stress, metabolic dysfunction, and immune dysregulation. Currently, AMD treatment focuses primarily on wet AMD, managed through repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) therapies. While anti-VEGF agents represent a major breakthrough in wet AMD care, repeated injections may lead to incomplete responses or resistance in some patients, and carry a risk of progressive fibrosis. Artemisinin (ART) and its derivatives, originally developed as antimalarial drugs, exhibit a broad spectrum of pleiotropic activities beyond their established use, including anti-inflammatory, anti-angiogenic, antioxidant, anti-fibrotic, mitochondrial regulatory, lipid metabolic, and immunosuppressive effects. These properties position ART as a promising therapeutic candidate for AMD. A growing interest in ART-based therapies for AMD has emerged in recent years, with numerous studies demonstrating their potential benefits. However, no comprehensive review has systematically summarized the specific roles of ART and its derivatives in AMD pathogenesis and treatment. This paper aims to fill the knowledge gap by synthesizing the therapeutic efficacy and molecular mechanisms of ART and its derivatives in AMD, thereby providing a foundation for future investigations. Full article

Background/Objectives: Macular edema (ME), due to retinal vein occlusion (RVO), is a major cause of vision impairment. Many patients experience suboptimal responses to anti-vascular endothelial growth factor (anti-VEGF) monotherapy, necessitating alternative treatment approaches. Faricimab, a bispecific antibody targeting VEGF-A and angiopoietin-2 (Ang-2), introduces a novel dual-mechanism therapy. This study evaluates the short-term real-world efficacy of switching to Faricimab in patients with treatment-resistant ME secondary to RVO. Methods: This retrospective study included patients from LMU University Hospital who were switched to Faricimab due to an inadequate response or adverse events related to prior intravitreal therapy (Ranibizumab, Aflibercept, or Ozurdex^TM). All patients completed a structured loading phase of four monthly injections. Key outcome measures included changes in best-corrected visual acuity (BCVA, logMAR), central subfield thickness (CST, µm), and intraretinal fluid (IRF) presence on optical coherence tomography (OCT). Changes were assessed from baseline (mo0) to three months (mo3). Results: The study included 19 eyes from 19 patients (mean age 63.0 ± 14.2 years). BCVA improved from 0.20 logMAR at baseline to 0.00 logMAR at mo3 (p < 0.01). CST decreased from 325 µm to 280 µm (p < 0.01). The proportion of eyes with IRF reduced from 100% to 32% (p < 0.01). Significant reductions in retinal volume within the 1 mm and 6 mm (both p < 0.01) circles of the ETDRS grid were observed. Conclusions: Switching to Faricimab in patients resulted in significant short-term improvements in BCVA, CST, and IRF resolution. Given the small sample size and retrospective design, these findings should be interpreted as exploratory and hypothesis-generating. Further studies are needed to evaluate long-term efficacy and optimal treatment regimens. Full article

Advanced gastric adenocarcinoma (GAC) carries a poor prognosis. Targeted therapy in GAC has traditionally been limited to anti-human epidermal growth factor receptor-2 and anti-vascular endothelial growth factor agents. Recent years have brought immune checkpoint therapy to the GAC treatment landscape. However, continued discovery of targeted therapy in GAC is needed. Claudins, transmembrane proteins located in tight junctions of epithelial and endothelial cells, help regulate cellular polarity. Claudin dysregulation has been linked to cancers and other diseases. Claudin 18.2 specifically has become a new novel and exciting biomarker for GAC. Many agents are in the investigative pipeline, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric T-cell therapy. Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab’s place in therapy along with other agents being explored. Full article