Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Hierarchical-unlocking virus-esque NanoCRISPR precisely disrupts autocrine and paracrine pathway of VEGF for tumor inhibition and antiangiogenesis.

Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine pathway. Strategies targeting VEGF holds tremendous potential for tumor therapy, however, agents targeting VEGF are limited by intolerable side effects, together with incomplete and temporary blocking of VEGF, resulting in unsatisfactory and unsustained therapeutic outcomes. Herein, hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. After intravenous administration, HUNGER exhibits prolonged blood circulation and hyaluronic acid-CD44 mediated tumor-targeting capability. Subsequently, when matrix metalloproteinase-2 is overexpressed in the tumor microenvironment, the PEG layer will be removed. The cell-penetrating peptide R8 endows HUNGER deep tumor penetration and specific cellular uptake. Upon cellular internalization, HUNGER undergoes hyaluronidase-triggered deshielding in lysosome, lysosomal escape is realized swiftly, and then the loaded CRISPR/Cas9 plasmid (>8 kb) is transported to nucleus efficiently. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Overall, this work opens a brand-new avenue for anti-VEGF therapy and presents a feasible strategy for in vivo delivery of CRISPR/Cas9 system.

Age-Related Macular Degeneration: A Review.

Importance: Age-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040. Observations: Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment. Conclusions and Relevance: The prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.

Texture-Based Radiomic SD-OCT Features Associated With Response to Anti-VEGF Therapy in a Phase III Neovascular AMD Clinical Trial.

Purpose: The goal of this study was to evaluate the role of texture-based baseline radiomic features (Fr) and dynamic radiomics alterations (delta, FΔr) within multiple targeted compartments on optical coherence tomography (OCT) scans to predict response to anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD). Methods: HAWK is a phase 3 clinical trial data set of active nAMD patients (N = 1082) comparing brolucizumab and aflibercept. This analysis included patients receiving 6 mg brolucizumab or 2 mg aflibercept and categorized as complete responders (n = 280) and incomplete responders (n = 239) based on whether or not the eyes achieved/maintained fluid resolution on OCT. A total of 481 Fr were extracted from each of the fluid, subretinal hyperreflective material (SHRM), retinal tissue, and sub-retinal pigment epithelium (RPE) compartments. Most discriminating eight baseline features, selected by the minimum redundancy, maximum relevance feature selection, were evaluated using a quadratic discriminant analysis (QDA) classifier on the training set (Str, n = 363) to differentiate between the two patient groups. Classifier performance was subsequently validated on independent test set (St, n = 156). Results: In total, 519 participants were included in this analysis from the HAWK phase 3 study. There were 280 complete responders and 219 incomplete responders. Compartmental analysis of radiomics featured identified the sub-RPE and SHRM compartments as the most distinguishing between the two response groups. The QDA classifier yielded areas under the curve of 0.78, 0.79, and 0.84, respectively, using Fr, FΔr, and combined Fr, FΔr, and Fc on St. Conclusions: Utilizing compartmental static and dynamic radiomics features, unique differences were identified between eyes that respond differently to anti-VEGF therapy in a large phase 3 trial that may provide important predictive value. Translational Relevance: Imaging biomarkers, such as radiomics features identified in this analysis, for predicting treatment response are needed to enhanced precision medicine in the management of nAMD.

Applications of nanomaterials in anti-VEGF treatment for ophthalmic diseases.

Angiogenesis has been determined to be essential in the occurrence and metastasis of diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), choroidal neovascularization (CNV), retinopathy of prematurity (ROP), tumor, etc. However, the clinical use of anti-vascular endothelial growth factors (VEGF) drugs is currently limited due to its high cost, potential side effects, and need for repeated injections. In recent years, nanotechnology has shown promising results in inhibiting neovascularization and reducing reactive oxygen species (ROS) or inflammatory factors. Some nanomaterials can also act as vehicles for drug delivery, such as lipid nanoparticles and PLGA. The process of angiogenesis and its molecular mechanism are discussed in this article. At the same time, this study aims to systematically review the research progress of nanotechnology and offer more treatment options for neovascularization-related diseases in clinical ophthalmology.

Comparative efficacy and safety of Faricimab and other anti-VEGF therapy for age-related macular degeneration and diabetic macular edema: A systematic review and meta-analysis of randomized clinical trials.

INTRODUCTION: A systematic review and meta-analysis were conducted to evaluate the efficacy and the overall safety of Faricimab compared with other anti-vascular endothelial growth factors (VEGF) therapy for neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). MATERIALS AND METHODS: A systematic literature search of a comprehensive electronic database was performed to identify randomized clinical trials published from January 2013 to January 2023 for Faricimab in AMD and DME. Weighted mean differences and risk ratios were used to integrate the different studies. RESULTS: A total of 4 randomized controlled trials (RCTs) with 1678 AMD patients and 3 RCTs with 20 DME patients were included in the meta-analysis.In patients with AMD, a significant difference was found in the number of injections between Faricimab and other anti-VEGF therapy (MD = -2.42, 95% CI [-3.93 to -0.90], P = .002).No significant difference was found for the change in best corrected visual acuity (BVCA), central subfoveal thickness (CST), and gaining 15 or more letters. Similarly, no significant difference was found for adverse events.In patients with DME, a significant difference was observed for CST (MD = -22.41, 95% CI [-29.95 to -14.86], P < .00001) and the number of injections(MD = -0.93, 95% CI [-1.33 to -0.54], P < .00001). No significant difference was found for BVCA and gaining 15 or more letters, and no significant difference was found for adverse events. CONCLUSIONS: Comprehensive evidence confirms that Faricimab achieves non-inferior or even better CST improvement than other anti-VEGF therapies with extended dosing intervals, but more long-term follow-up studies are needed to support our conclusions.

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

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

Comparison of micropulse subthreshold laser plus anti-VEGF versus anti-VEGF alone in diabetic macular edema: Systematic review.

Intravitreal injection of anti- Vascular Endothelial Growth Factor (VEGF)is commonly used to treat patients with diabetic macular edema (DME). However, the injection alone requires high cost and compliance. Combining micropulse subthreshold laser (MPSL) and anti-VEGF is a new approach to treating DME. This study intended to answer the question of whether MPSL plus anti-VEGF is effective compared to anti-VEGF alone. The following terms were used in PubMed, clinicaltrial.gov, and Google Scholar: anti-VEGF, DME, MPSL, and diabetic retinopathy. All studies of DME comparing the intervention of MPSL plus anti-VEGF and VEGF alone between the years 2017-2021 were included. Studies with no comparison between the intervention and control group, abstract-only papers, case reports, case series, and systematic review studies were excluded. Five Randomized Controlled Trial (RCTs) and three retrospective studies were analyzed. Four studies found that best-corrected visual acuity (BCVA) improved in both therapies. Central macular thickness in six studies was also improved. The improvement differences between both therapies were insignificant and the number of anti-VEGF injections was significantly lower in combination therapy. These studies show equal outcomes of both therapies. The reduced number of anti-VEGF injections of the combination therapy could improve the management of DME in terms of cost-effectiveness. Further analysis should be conducted to pool the data from the studies and evaluate the overall outcome.

The Safety of Anti-VEGF Treatment, in the Context of the Retinal Nerve Fibre Layer, in Patients with Wet Age-Related Macular Degeneration: A Review.

Anti-vascular endothelial growth factor (VEGF) drugs are widely used in modern ophthalmology, especially in treating macular disorders like age-related macular degeneration or diabetic macular edema. Protocols for such treatments include repeated administration of intravitreal injections, with the volume of drug injected into the vitreous chamber seemingly high enough to cause an increase in intraocular pressure. Hence, questions might arise if such therapeutic approaches are safe for ocular tissue. Moreover, anti-VEGF compounds may theoretically harm the retinal nerve fibers due to the inhibition of VEGF and its neuroprotective effects. Thus, this manuscript aims to review the literature regarding studies evaluating the retinal nerve fiber layer (RNFL) in eyes receiving anti-VEGF treatment due to age-related macular degeneration. The RNFL was chosen as a subject of this review, as it is the innermost retinal layer exposed to the direct action of intravitreally administered drugs. The results of the available studies remain inconclusive. Most researchers seem to confirm the safety of the anti-VEGF treatment in wet age-related macular degeneration, at least regarding the retinal nerve fiber layer. However, some authors noticed that the influence of anti-VEGFs on RNFL could become apparent after more than thirty injections. Nonetheless, the authors of all studies agree that further, long-term observations are needed to help clinicians understand the effect of anti-VEGF treatment on the dynamics of changes in the thickness of retinal nerve fibers in patients with the wet form of age-related macular degeneration.

A contrast-enhanced ultrasound-based nomogram for the prediction of therapeutic efficiency of anti-PD-1 plus anti-VEGF agents in advanced hepatocellular carcinoma patients.

Background: There is no study focusing on noninvasive predictors for the efficacy of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) treatment in advanced hepatocellular carcinoma (HCC). Method: A total of 33 patients with advanced HCC were prospectively enrolled and received sintilimab plus IBI305 treatment from November 2018 to October 2019. Baseline characteristics including clinical data, laboratory data, and tumor features based on pretreatment CT/MR were collected. Meanwhile, pretreatment contrast-enhanced ultrasound (CEUS) for target tumor was performed and quantitative parameters were derived from time-intensity curves (TICs). A nomogram was developed based on the variables identified by the univariable and multivariable logistic regression analysis. The discrimination, calibration, and clinical utility of the nomogram were evaluated. Results: Tumor embolus and grad ratio were significant variables related to the efficacy of sintilimab plus IBI305 strategy. The nomogram based on these two variables achieved an excellent predictive performance with an area under curve (AUC) of 0.909 (95% CI, 0.813-1). A bootstrapping for 500 repetitions was performed to validate this model and the AUC of the bootstrap model was 0.91 (95% CI, 0.8-0.98). The calibration curve and decision curve analysis (DCA) showed that the nomogram had a good consistency and clinical utility. Conclusions: This study has established and validated a nomogram by incorporating the quantitative parameters of pretreatment CEUS and baseline clinical characteristics to predict the anti-PD-1 plus anti-VEGF treatment efficacy in advanced HCC patients.

Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.

BACKGROUND: Genetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis. METHODS: Clonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy. RESULTS: Two clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation. CONCLUSION: A glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy.

[The population affected by neovascular age-related macular degeneration and treated with anti-Vegf through Italian administrative healthcare data.] / La popolazione con degenerazione maculare neovascolare correlata all'età trattata con anti-Vegf attraverso i dati amministrativi sanitari.

INTRODUCTION: The neo-vascular age-related macular degeneration (nAmd) is a frequent cause of vision loss, although the intravitreal (Ivt) injections of anti-Vegf (vascular endothelial growth factor) have improved functional outcomes. This study has assessed the healthcare and economic burden on the Italian national health service (Inhs) for patients with nAmd and new users of anti-Vegf. METHODS: From the database of Fondazione Ricerca e Salute (ReS), people aged ≥55 and with an in-hospital diagnosis of nAmd and/or an injection of anti-Vegf (aflibercept, ranibizumab, pegaptanib; index date) in 2018 are selected. Those with other conditions treated with anti-Vegf and with an Ivt injection before 2018 are excluded. New users of anti-Vegf are analyzed by sex, age, comorbidities, Ivt administrations, switch of anti-Vegf, local outpatient specialist services (with some focuses) and direct healthcare costs charged to the Inhs Results. In 2018, of 8125 inhabitants aged ≥55 with nAmd (4.6x1000 inhab.; mean age 76±9; F: 50%), 1513 (19%) are new users of Ivt anti-Vegf (mean age 74±9), whose incidence (0.9x1000) increased with age until 84 years old. A proportion of 60.7% had ≥2 comorbidities (mainly hypertension, dyslipidemia and diabetes). Within the 2nd follow-up year, only 598 patients are still treated (60% were lost). On average, 4.8 Ivt injections in the first and 3.1 in the second year are registered. On average, the total cost charged to the Inhs per new user of anti-Vegf was € 6726 (Ivt anti-Vegf accounted for the 76%) and € 3282 (hospitalizations for causes different from nAmd accounted for the 47%), during the first and the second year, respectively. CONCLUSIONS: This analysis suggests that in Italy people with nAmd and new users of anti-Vegf are elderly, affected by many comorbidities, treated with Ivt anti-VEGF less than what is required and authorized to achieve a benefit, undergo very few follow-up outpatient specialist visits and tests and, within the 2nd year, their hospitalizations for causes different from nAmd mainly weighs on the total expenditure charged to the Inhs.

Efficacy of as-needed intravitreal injection compared to 3-monthly loading of anti-vascular endothelial growth factor agents for branch retinal vein occlusion.

We investigated the efficacy of intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents in branch retinal vein occlusion (BRVO). Databases, including PubMed, EMBASE, and the Cochrane Library, were searched on November 11, 2022. Studies comparing the pro-re-nata (PRN) regimen after the first treatment (PRN group) to three consecutive monthly injection regimens followed by the PRN regimen (3 + PRN group) were investigated. The primary outcomes were the change in best-corrected visual acuity (BCVA) and the change in central retinal thickness (CRT), with the secondary outcome being the injection frequency. Among 195 reports on anti-VEGF treatment, six comparative studies were included in this meta-analysis. The two groups had no statistically significant differences in terms of BCVA or CRT. However, the total number of injections during follow-up was significantly lower in the PRN group than in the 3 + PRN group (95% CI - 2.09 to - 0.83). The as-needed injection regimen is as effective as 3-monthly loading in terms of anatomical and functional improvement for BRVO, along with a lower treatment burden for patients and physicians.

Distance and near vision changes after intravitreal anti-vascular endothelial growth factor injection in eyes with center-involving diabetic macular edema.

Purpose: To elucidate distance and near vision changes after intravitreal injections in center-involving diabetic macular edema (CIDME) in phakic and pseudophakic groups. Methods: A retrospective study was done on 148 eyes (72 phakic and 76 pseudophakic) with center-involving DME. All eyes were treated with intravitreal anti-vascular endothelial growth factor (VEGF) injection. All patients underwent distance best-corrected visual acuity (BCVA) testing, near BCVA testing, dilated fundus examination, and optical coherence tomography (OCT) at baseline and follow-up visits. Eyes that could not improve after the first injection were given 2nd, 3rd, and more injections in the subsequent visits. Results: On follow-up, post injections in the phakic group (n = 72), there were 65 eyes (90.3%) with stable/improved near vision and 59 eyes (81.9%) with stable/improved distance vision, whereas in the pseudophakic group (n = 76), 63 eyes (82.9%) and 60 eyes (78.9%), respectively. Both in phakic and pseudophakic eyes, 7.7%-13% of the cohort showed only near vision improvement. Conclusion: In DME, besides the changes in distance vision, there are also changes in near vision. These changes should be taken into account while determining the response to anti-VEGF in DME treatment.

Correlación entre la sensibilidad al contraste y las características morfológicas obtenidas por OCT en pacientes con degeneración macular relacionada con la edad avanzada tratados con dosis de carga de inhibidores del factor de crecimiento endotelial vascular / Correlation between contrast sensitivity and morphological features obtained by OCT in patients with age-related macular degeneration treated with a loading dose of vascular endothelial growth factor inhibitors

Objetivo Determinar la correlación entre la sensibilidad al contraste y las características morfológicas obtenidas por tomografía de coherencia óptica en pacientes con degeneración macular relacionada con la edad avanzada tratados con dosis de carga de inhibidores del factor de crecimiento endotelial vascular (anti-VEGF). Diseño Se trata de un estudio ambispectivo (prospectivo+retrospectivo) observacional y analítico. Participantes Todos los pacientes de 55 años o más con degeneración macular relacionada con la edad que acudieron al departamento de Retina del servicio de Oftalmología y cumplieron con los criterios de inclusión entre marzo-mayo de 2022. Métodos Se recolectaron los datos por medio de la revisión de expedientes. Se analizaron los estudios de tomografía de coherencia óptica previa a la aplicación de inyecciones intravítreas de los pacientes que se encontraban en el mes posterior a la última dosis. Se incluyeron un total de 33 sujetos y un total de 30 continuaron seguimiento. Se realizaron pruebas de normalidad (Shapiro y Bartlett) entre los grupos de estudio, dando como resultado grupos no normales no homocedásticos. Los sujetos fueron sometidos a una nueva evaluación oftalmológica y nueva toma de mediciones retinianas. Resultados Se realizó un análisis de regresión lineal comparando los valores logarítmicos de la agudeza visual y la sensibilidad al contraste, obteniendo una relación significativa entre ambos valores posterior a la aplicación del tratamiento (p<0,0001). Asimismo, se demostró una correlación entre la disminución de los valores de la sensibilidad al contraste y todas las características evaluadas en el tomografía de coherencia óptica. Conclusiones Las estrategias de antiangiogénesis pueden conducir a mejores resultados en la función visual global, impactando positivamente en la sensibilidad al contraste (AU)

Objective To determine the correlation between contrast sensitivity and morphological characteristics obtained by optical coherence tomography in patients with age-related macular degeneration treated with a loading dose of vascular endothelial growth factor inhibitors (anti-VEGF). Design This is an ambispective (prospective+retrospective) observational, cross-sectional, and analytical study. Participants All patients over 55 years of age with age-related macular degeneration who attended the Retina service of the Ophthalmology department and met the inclusion criteria between March-May 2022. Methods Data collection was carried out by reviewing the records of patients.Optical coherence tomography studies prior to the application of intravitreal injections of patients who were currently in the first month after the last dose of anti-VEGF were analyzed. A total of 33 subjects were included, of which 30 continued follow-ups. Normality tests (Shapiro and Bartlett) were performed where a nonparametric data distribution was demonstrated. The subjects underwent a new ophthalmological evaluation and new retinal measurements of the affected eye. Results A linear regression analysis was performed comparing the logarithmic values of both visual acuity and contrast sensitivity, obtaining a significant relationship between both values after the application of treatment (P<.0001). Likewise, correlation was demonstrated between the decrease in contrast sensitivity values and all the characteristics evaluated in the patients’ optical coherence tomography. Conclusions Antiangiogenesis strategies can lead to better results in global visual function, positively impacting contrast sensitivity (AU)

Non-adherence and non-persistence to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy: a systematic review and meta-analysis.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections play a key role in treating a range of macular diseases. The effectiveness of these therapies is dependent on patients' adherence (the extent to which a patient takes their medicines as per agreed recommendations from the healthcare provider) and persistence (continuation of the treatment for the prescribed duration) to their prescribed treatment regimens. The aim of this systematic review was to demonstrate the need for further investigation into the prevalence of, and factors contributing to, patient-led non-adherence and non-persistence, thus facilitating improved clinical outcomes. METHODS: Systematic searches were conducted in Google Scholar, Web of Science, PubMed, MEDLINE, and the Cochrane Library. Studies in English conducted before February 2023 that reported the level of, and/or barriers to, non-adherence or non-persistence to intravitreal anti-VEGF ocular disease therapy were included. Duplicate papers, literature reviews, expert opinion articles, case studies, and case series were excluded following screening by two independent authors. RESULTS: Data from a total of 409,215 patients across 52 studies were analysed. Treatment regimens included pro re nata, monthly and treat-and-extend protocols; study durations ranged from 4 months to 8 years. Of the 52 studies, 22 included a breakdown of reasons for patient non-adherence/non-persistence. Patient-led non-adherence varied between 17.5 and 35.0% depending on the definition used. Overall pooled prevalence of patient-led treatment non-persistence was 30.0% (P = 0.000). Reasons for non-adherence/non-persistence included dissatisfaction with treatment results (29.9%), financial burden (19%), older age/comorbidities (15.5%), difficulty booking appointments (8.5%), travel distance/social isolation (7.9%), lack of time (5.8%), satisfaction with the perceived improvement in their condition (4.4%), fear of injection (4.0%), loss of motivation (4.0%), apathy towards eyesight (2.5%), dissatisfaction with facilities 2.3%, and discomfort/pain (0.3%). Three studies found non-adherence rates between 51.6 and 68.8% during the COVID-19 pandemic, in part due to fear of exposure to COVID-19 and difficulties travelling during lockdown. DISCUSSION: Results suggest high levels of patient-led non-adherence/non-persistence to anti-VEGF therapy, mostly due to dissatisfaction with treatment results, a combination of comorbidities, loss of motivation and the burden of travel. This study provides key information on prevalence and factors contributing to non-adherence/non-persistence in anti-VEGF treatment for macular diseases, aiding identification of at-risk individuals to improve real-world visual outcomes. Improvements in the literature can be achieved by establishing uniform definitions and standard timescales for what constitutes non-adherence/non-persistence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020216205.

Development of a Silk Fibroin-Small Intestinal Submucosa Small-Diameter Vascular Graft with Sequential VEGF and TGF-ß1 Inhibitor Delivery for In Situ Tissue Engineering.

Proper endothelialization and limited collagen deposition on the luminal surface after graft implantation plays a crucial role to prevent the occurrence of stenosis. To achieve these conditions, a biodegradable graft with adequate mechanical properties and the ability to sequentially deliver therapeutic agents isfabricated. In this study, a dual-release system is constructed through coaxial electrospinning by incorporating recombinant human vascular endothelial growth factor (VEGF) and transforming growth factor ß1 (TGF-ß1) inhibitor into silk fibroin (SF) nanofibers to form a bioactive membrane. The functionalized SF membrane as the inner layer of the graft is characterized by the release profile, cell proliferation and protein expression. It presents excellent biocompatibility and biodegradation, facilitating cell attachment, proliferation, and infiltration. The core-shell structure enables rapid VEGF release within 10 days and sustained plasmid delivery for 21 days. A 2.0-mm-diameter vascular graft is fabricated by integrating the SF membrane with decellularized porcine small intestinal submucosa (SIS), aiming to facilitate the integration process under a stable extracellular matrix structure. The bioengineered graft is functionalized with the sequential administration of VEGF and TGF-ß1, and with the reinforced and compatible mechanical properties, thereby offers an orchestrated solution for stenosis with potential for in situ vascular tissue engineering applications.

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis.

BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

Phase I study of the VEGF/Ang-2 inhibitor BI 836880 alone or combined with the anti-programmed cell death protein-1 antibody ezabenlimab in Japanese patients with advanced solid tumors.

PURPOSE: This two-part, open-label, non-randomized dose-escalation study aimed to define the maximum tolerated dose (MTD) of BI 836880 (humanized bispecific nanobody® targeting vascular endothelial growth factor and angiopoietin-2) as monotherapy and in combination with ezabenlimab (programmed death protein-1 inhibitor) in Japanese patients with advanced and/or metastatic solid tumors. METHODS: In part 1, patients received an intravenous infusion of BI 836880 at 360 or 720 mg every 3 weeks (Q3W). In part 2, patients received BI 836880 at doses of 120, 360, or 720 mg in combination with ezabenlimab 240 mg Q3W. The primary endpoints were the MTD and the recommended phase II dose (RP2D) of BI 836880 as monotherapy and in combination with ezabenlimab, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Twenty-one patients were treated; nine in part 1 and 12 in part 2. No DLTs were reported in either part and the MTD was not reached. The RP2Ds were BI 836880 720 mg Q3W as monotherapy and BI 836880 720 mg plus ezabenlimab 240 mg Q3W. The most common adverse events were hypertension and proteinuria (33.3%) with BI 836880 monotherapy and diarrhea (41.7%) with the combination. Four patients (44.4%) in part 1 had stable disease as best overall tumor response. In part 2, two patients (16.7%) had confirmed partial responses and five had stable disease (41.7%). CONCLUSION: MTD was not reached. BI 836880 alone and in combination with ezabenlimab had a manageable safety profile with preliminary clinical activity in Japanese patients with advanced solid tumors. TRIAL REGISTRATION AND DATE: NCT03972150, registered on June 3, 2019.