Vascular Endothelial Growth Factor Agents Research Articles

Clinical outcome of bevacizumab or ramucirumab combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as the first line therapy in susceptible EGFR-mutated advanced non-small-cell lung.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, including 34 (72%) and 13 (28%) patients receiving bevacizumab and ramucirumab, respectively. The response rate was similar in both groups (p = 0.38). Patients receiving bevacizumab had similar progression free survival (PFS) as those receiving ramucirumab (median PFS: 21.9 vs. 24.2 months, p = 0.4871); similar finding was noted in overall survival (OS) (median OS: 33.5 months vs. not reached, p = 0.4618). Patients receiving ramucirumab experienced a significantly high-grade hypertension compared to those receiving bevacizumab (p = 0.0351). Multivariable Cox regression analysis found independent risk factors for worse PFS included poorer ECOG performance status, multiple (≥3) metastatic sites, brain metastasis, and pleural metastasis/effusion, while the type of anti-VEGF agent was not a risk factor. Pericardial metastasis/effusion was the only one independent risk factor for worse OS. In summary, ramucirumab may have similar effectiveness as bevacizumab in combination with an EGFR-TKI as first line therapy for advanced lung adenocarcinoma harboring susceptible EGFR mutation. Further large-scale registry-based cohort studies may be needed to validate our findings.

Heparan Sulfate Modulation Affects Breast Cancer Cell Adhesion and Transmigration across In Vitro Blood-Brain Barrier.

The disruption of endothelial heparan sulfate (HS) is an early event in tumor cell metastasis across vascular barriers, and the reinforcement of endothelial HS reduces tumor cell adhesion to endothelium. Our recent study showed that while vascular endothelial growth factor (VEGF) greatly reduces HS at an in vitro blood-brain barrier (BBB) formed by human cerebral microvascular endothelial cells (hCMECs), it significantly enhances HS on a breast cancer cell, MDA-MB-231 (MB231). Here, we tested that this differential effect of VEGF on the HS favors MB231 adhesion and transmigration. We also tested if agents that enhance endothelial HS may affect the HS of MB231 and reduce its adhesion and transmigration. To test these hypotheses, we generated an in vitro BBB by culturing hCMECs on either a glass-bottom dish or a Transwell filter. We first quantified the HS of the BBB and MB231 after treatment with VEGF and endothelial HS-enhancing agents and then quantified the adhesion and transmigration of MB231 across the BBB after pretreatment with these agents. Our results demonstrated that the reduced/enhanced BBB HS and enhanced/reduced MB231 HS increase/decrease MB231 adhesion to and transmigration across the BBB. Our findings suggest a therapeutic intervention by targeting the HS-mediated breast cancer brain metastasis.

VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation.

The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

The Efficacy, Safety, and Efficiency of the Off-Label Use of Bevacizumab in Patients Diagnosed With Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis

Background Age-related macular degeneration (AMD) is recognized as the leading cause of vision loss in older people. Considering the phenomenon of aging societies worldwide, the prevalence of AMD is expected to increase gradually in the future. AMD can be divided into early, intermediate, and late stages, with the early and intermediate stages being mainly asymptomatic, and the late stage being classified as geographic atrophy, neovascular AMD, or both. Current pharmacological treatments for neovascular AMD include anti–vascular endothelial growth factor agents, such as ranibizumab, pegaptanib, and aflibercept. Additionally, it has been reported that the off-label use of intravitreally administered bevacizumab is effective. It is also lower cost than other agents, which makes it an interesting pharmacological approach. Objective This review aims to evaluate the efficacy, safety, and efficiency of bevacizumab for the treatment of neovascular AMD. Methods This review will only consider randomized controlled clinical trials that compare the use of bevacizumab with another pharmacological agent or a placebo in patients aged 50 years and older who are diagnosed with vascular AMD. It will exclude studies that include participants diagnosed with polypoidal choroidal vasculopathy or retinal angiomatous proliferation. To identify and select relevant articles, we will develop a highly sensitive search strategy and apply it in MEDLINE via the PubMed platform. Upon selection of the studies and analysis of the titles, abstracts, and full texts, the results will be presented according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis and extraction of the data will be performed by 2 independent reviewers. Risk of bias will be evaluated with the Critical Appraisal Skills Programme (CASP) checklist. Finally, the same reviewers will also perform a quality assessment of the included studies with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Results The search strategy, after the application of the inclusion and exclusion criteria, identified 15 randomized clinical trials, which are currently being analyzed. This project has no funding and it has been developed by a multidisciplinary research team of pharmacologists and orthoptists. The study was initiated in May 2021 and it is expected to conclude by the end of 2023. Conclusions This review will provide a synthesis of current information and underlying evidence about the off-label use of bevacizumab in neovascular AMD. It will provide a clearer vision of a possible new pharmacological approach, as well as the most suitable treatment designs, for the treatment of neovascular AMD. Trial Registration PROSPERO CRD42021244931; https://tinyurl.com/p6m5ycpk International Registered Report Identifier (IRRID) DERR1-10.2196/38658

Systemic Adverse Events Among Patients With Diabetes Treated With Intravitreal Anti–Vascular Endothelial Growth Factor Injections

Anti-vascular endothelial growth factor (VEGF) agents are currently the mainstay of treatment for diabetic retinopathy (DR). Although effective, data on their systemic safety remains inconclusive, particularly in high-risk patient groups. To explore the systemic safety of intravitreal anti-VEGF agents among patients with diabetes. This was a retrospective, longitudinal population-based analysis of the Corporate Data Warehouse, a large-scale database of patients within the US Veteran Health Affairs. All patients 18 years and older with type 2 diabetes who were seen at any Veterans Affairs health care facility in the US between January 1, 2011, and December 31, 2012, were identified. Data were then extracted on incident systemic adverse events among this patient cohort from January 1, 2013, to December 31, 2017. All individuals with diabetes who did and did not receive anti-VEGF injections were included. Patients with a history of prior systemic adverse events and those who received an intravitreal injection between January 1, 2011, and December 31, 2012, were excluded. Data were analyzed from October 2019 to March 2023. Anti-VEGF injection. Proportion of patients with any incident systemic adverse event, acute myocardial infarction, cardiovascular disease, or kidney disease at 1-, 3-, and 5-year follow-up. A total of 1 731 782 patients (mean [SD] age, 63.8 [12.3] years; 1 656 589 [95.7%] male) with type 2 diabetes were included. DR was present in 476 013 (27.5%), and 14 022 (0.8%) received anti-VEGF injections. Of the total number of patients with type 2 diabetes, 321 940 (18.6%) developed systemic adverse events between 2013 and 2017. The 5-year cumulative incidence of any systemic adverse event was 37.0% (5187/14 022) in the injection group vs 18.4% (316 753/1 717 760) in the noninjection group (P < .001). Anti-VEGF injections were independently associated with a higher likelihood of developing any systemic adverse event (odds ratio, 1.8; 95% CI, 1.7-1.9) when controlling for age, race, sex, ethnicity, tobacco use, severity of DR, Deyo-Charlson Comorbidity Index score, mean hemoglobin A1c, total number of injections, and statin use. In this study, intravitreal anti-VEGF injections were independently associated with a higher likelihood of systemic adverse events among patients with diabetes.

Clinical Features Associated with Acute Elevated Intraocular Pressure After Intravitreal Anti-VEGF Injections.

To study the effects of intravitreal injection (IVI) of anti-VEGF (vascular endothelial growth factor) agents on intraocular pressure (IOP) and find associations with acute pressure spikes. This was a three-month, prospective study of patients receiving outpatient IVI of anti-VEGF agents for diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO) at the Acuity Eye Group Medical Centers. IOP was measured pre- and post-injection at 10-minute intervals up to 50 minutes after injection with a handheld tonometer. Patients with an IOP greater than 35 mmHg at 30 minutes received an anterior chamber paracentesis (ACP), while patients below 35 mmHg were monitored without intervention. A total of 617 patients (51% female, 49% male) received IVI for DR (n = 199), AMD (n = 355), and RVO (n = 63). ACP was performed in 17 patients. Average pre-injection IOP was 16 ± 4 compared to 24 ± 7 mmHg for the non-ACP vs ACP group, respectively (mean ± standard deviation), p < 0.0001. IOP returned to baseline in 98% of patients at 50 minutes. A diagnosis of glaucoma and glaucoma suspect was more prevalent in the ACP group compared to the non-ACP group, 82.3% vs 14.2% and 17.6% vs 9.0%, respectively, p < 0.0001 and p > 0.05. Patients with a pre-injection IOP >25 mmHg and a history of glaucoma had a 58.3% rate of ACP. A 31-gauge needle had a higher mean increase in IOP from baseline compared to 30-gauge needle, p < 0.0001. IOP spikes are most significant in the first 10 minutes after IVI but typically resolve within the first hour. However, utilizing a smaller 31-gauge IVI in patients with a glaucoma history and pre-injection IOP >25 mmHg may be associated with significant IOP spikes lasting longer than 30 minutes.

Risk analysis for patients with arterial thromboembolic events after intravitreal ranibizumab or aflibercept injections

Intravitreal anti–vascular endothelial growth factor (anti-VEGF) agents have been increasingly applied in the treatment of retinal neovascular diseases. Concerns have arisen that these intravitreal agents may be associated with a potential risk of arterial thromboembolic (ATE) events. We conducted a retrospective, nationwide population‐based cohort study to analyze the risks for ATE events in patients receiving intravitreal ranibizumab (IVR) or intravitreal aflibercept (IVA). Data (2011–2018) were obtained from Taiwan’s National Health Insurance Research Database. Cox proportional-hazards model was used to identify the risk factors for ATEs. Of the total 3,469 patients, 1393 and 2076 patients received IVR and IVA, respectively. In our result, 38 ATEs occurred within 6 months after IVR or IVA. The risk of ATEs was lower in patients receiving IVR than in those receiving IVA (adjusted hazard ratio [aHR], 0.27; 95% confidence interval [CI], 0.11–0.66). Patients with coronary artery disease (CAD) exhibited a higher risk of ATEs than did those without CAD (aHR, 3.47; 95% CI, 1.41–8.53). The risk of ATEs was higher in patients with an event of acute myocardial infarction (AMI) or ischemic stroke (IS) within 6 months prior to index IVI than in those without recent AMI/IS events (aHR, 23.8; 95% CI, 7.35–77.2 and IS: aHR, 290.2; 95% CI, 103.1–816.4). In conclusion, compared with IVA, IVR was associated with a lower risk of ATEs. When strategies for anti-VEGF agents are devised, risk factors, such as CAD and a history of AMI or IS within 6 months should be considered. Further large-scale studies are warranted to elucidate the safety of anti-VEGF injections.

Fiji-Assisted Automatic Quantitative Volumetric Analysis of Choroidal Neovascularization in a Laser-Induced Choroidal Neovascularization Mouse Model.

The laser-induced choroidal neovascularization (CNV) mouse model is the most frequently used animal model of CNV. To test new therapeutic agents that suppress CNV, CNV measurement in an accurate, precise, and efficient manner is important. We present the utility of Fiji-assisted automatic volumetric quantification of CNV in comparison with two-dimensional CNV analyses. Laser-induced CNV was induced in C57BL/6J mice according to the established protocol. After CNV induction, mice were treated with intravitreal injection of either phosphate-buffered saline solution (PBS) or Aflibercept, an anti- vascular endothelial growth factor agent. One week after intravitreal injection treatment, retina pigment epithelium/choroid flat mounts were stained with rhodamine-conjugated Griffonia simplicifolia lectin B4. Z-stacks of the entire CNV lesion obtained using laser confocal microscopy were converted to binary stacks using Fiji for volumetric analysis. Data from volumetric analysis and multiple area analyses from z-stack projection, the maximum, blindly selected, and mean area were compared using Fiji. Fiji-assisted automatic quantitative volumetric analysis of CNV was useful in detecting experimental outliers in laser-induced CNV genesis and provided accurate and precise measurements of total areas of CNV with a lower coefficient of variance (63%) than in multiple area analyses, including the z-stack projection, maximum, blindly selected, and mean areas (67%, 67%, 76%, and 69%, respectively). A lower coefficient of variance in volumetric analysis than in multiple area analyses resulted in increased statistical significance when comparing CNV lesions in PBS, and Aflibercept-treated groups; P = 0.004 in volumetric analysis versus P value range between 0.03 and 0.05 in multiple area analyses. Fiji-assisted automatic quantitative volumetric analysis can be useful for accurate, precise, and efficient measurements of total areas of CNV. Volumetric measurement for CNV lesions can be advantageous in verifying the efficacy of therapeutic agents in the laser-induced CNV mouse model.

Trends and Characteristics of Industry Payments for Ophthalmology Research From 2014 to 2020

Characterizing industry-ophthalmology collaborations in research can highlight current areas of focus, improve transparency, and identify potential sources for conflicts of interest. To assess the trends and characteristics in research payments reported from industry to ophthalmologists from 2014 to 2020. This cross-sectional study used data from the Centers of Medicare & Medicaid Services' Open Payments database (OPD), which contains public records of payments between industry and physicians, to identify all ophthalmologists who received industry payments for research purposes between 2014 and 2020. Industry funding was compared with public research funding by the National Eye Institute. The value and distribution of payments, sponsoring manufacturers, and research products were assessed. Changes in aggregate and per individual-level funding were characterized using formal trend analysis. From 2014 to 2020, 2102 ophthalmologists were reported to have received $825 417 233 in industry research payments. Industry funding increased 203% from $62 924 525 in 2014 to $190 714 508 in 2020 (P = .01). Comparatively, total National Eye Institute research funding during the same period was $5 003 407 764 and increased 6.6% from $701 313 262 in 2014 to $747 929 556 in 2020 (P = .04). The share of all medical research funding from industry directed specifically toward ophthalmology research increased from 1.2% in 2014 to 3.2% in 2020 (P = .04). The distribution of industry payments was skewed, with the top 15 of 108 manufacturers accounting for 93.9% of funding. The top 10% of ophthalmologists (210) were reported to have received 65.7% of all research dollars ($542 299 121). The highest funded research products were anti-vascular endothelial growth factor agents, glaucoma treatments, and intraocular lenses. Although unequal in distribution, industry-funded research in ophthalmology is extensive and increasing in scope. Industry funding for research is less than that of public funding; however, industry funding increased faster between 2014 and 2020. Results of this study highlight the increasing importance of industry funding in ophthalmology research, but it may also present ethical challenges for clinicians collaborating with industry.

Association Between Open Payments–Reported Industry Transfers of Value and Prostaglandin Analog Prescribing in the US

Reported transfers of value (TOV) from pharmaceutical companies have been associated with greater use of branded anti-vascular endothelial growth factor agents by ophthalmologists, but payment under the Medicare Part B buy-and-bill model includes a financial incentive to choose costlier agents, potentially confounding analyses of pharmaceutical TOV and prescribing patterns. How these reported TOV are associated with prescribing patterns for prescription eye drops, not subject to the incentives created by Part B payments, should be considered. To assess the association between prostaglandin analog (PGA) eye drop prescribing and reported nonresearch TOV by makers of branded PGAs to US vision care professionals. This retrospective cohort analysis used a 20% nationally representative sample of 2018 Medicare Part D claims and industry TOV reported to the Open Payments program. Optometrists and ophthalmologists who had more than 10 claims for PGA drops in the 20% sample were analyzed. Analysis took place from June 2021 to February 2022. Multivariable logistic regression assessing the association between membership in strata of reported TOV and branded PGA prescribing rate, controlling for prescriber demographic factors, local area practices, total PGA prescribing volume, and plan formularies involved. A total of 20 612 ophthalmologists and 5426 optometrists (7449 [29%] female and 18 589 [71%] male) prescribed PGA eye drops. Of these, 9685 (37%) were reported to have received TOV from manufacturers of branded PGAs in 2018, totaling $5 060 346. The median (IQR) reported TOV was $65 ($24-$147). Multivariable logistic regression showed that the predicted probability of primarily prescribing branded PGAs among prescribers who reported receiving no TOV was 12.9% (95% CI, 12.4%-13.4%). This figure increased to 19.6% (95% CI, 18.8%-20.4%) among prescribers receiving TOV, a 50% increase. There was a dose-response association, such that the top 10% of TOV recipients had a 29.2% probability (95% CI, 26.4%-31.9%) of preferential branded use. While the median reported TOV to a PGA prescriber was relatively low in this study, there was a positive association between amount of reported nonresearch TOV received from PGA makers and the frequency of branded PGA use. This shows that small reported TOV were associated with differences in prescribing. High rates of branded PGA prescribing may pose a cost burden to patients that affects adherence. Clinicians and policy makers should be aware of these associations.

CHARACTERIZING COVID-19-RELATED RETINAL VASCULAR OCCLUSIONS: A Case Series and Review of the Literature.

To describe clinical and ophthalmologic features and outcomes of patients with coronavirus disease-19 with retinal vascular occlusions. Retrospective multicenter case series and PubMed review of cases reported from March 2020 to September 2021. Outcome measures are as follows: type of occlusion, treatments, best-corrected visual acuity, and central macular thickness on optical coherence tomography. Thirty-nine patients were identified. Fifteen patients with a median age of 39 (30-67) years were included in the multicenter study. Vascular occlusions included central retinal vein occlusion (12 eyes), branch retinal vein occlusion (4 eyes), and central retinal artery occlusion (2 eyes). Three cases were bilateral. Baseline best-corrected visual acuity was 20/45 (no light perception-20/20). Baseline central macular thickness was 348.64 (±83) μm. Nine eyes received anti-vascular endothelial growth factor agents, dexamethasone intravitreal implant, or both. Final best-corrected visual acuity was 20/25 (no light perception-20/20), and central macular thickness was 273.7 ± 68 μm (follow-up of 19.6 ± 6 weeks). Among the 24 cases from the literature review, retinal vein occlusion was the predominant lesion. Clinical characteristics and outcomes were similar to those found in our series. Coronavirus disease-19-associated retinal vascular occlusions tend to occur in individuals younger than 60 years. Retinal vein occlusion is the most frequent occlusive event, and outcomes are favorable in most cases.

The Quantification and Impact of Persistent Retinal Fluid Compartments on Best-Corrected Visual Acuity of Patients With Retinal Vein Occlusion

To evaluate the impact of persistent intraretinal fluid (IRF) and subretinal fluid (SRF) on best visual acuity (BVA) of patients with retinal vein occlusions (RVOs). This retrospective cohort study observed 92 treatment-naïve patients with RVO during 12 months of treatment with anti-vascular endothelial growth factor agents. Deep learning was used to quantify IRF and SRF volumes, and linear mixed effects regression modeled the impact on BVA. Average IRF volume declined -923.1 ± 2,382.5 nL from baseline to 12 months (P < .001). Average SRF volume declined -35.4 ± 223.4 nL from baseline to 12 months (P = .139). linear mixed effects regression modeling disclosed IRF≥ 1,616 nL at all time points predicted a -10.38 letter loss at 12 months (95% CI, -14.58 to -5.9 letters; P < .001). A similar relationship was not found for SRF. Persistent IRF may be an important prognostic biomarker for BVA outcomes in real-world patients with RVO. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:139-147.].

Aflibercept for Retinopathy of Prematurity: A Systematic Review and Meta-Analysis

To determine the effectiveness of aflibercept in retinopathy of prematurity (ROP). We performed a systematic review and meta-analysis of proportions from the literature in PubMed and Cochrane Library using search terms related to the use of aflibercept in ROP. Studies in non-preterm infants or that did not use aflibercept as the initial treatment were excluded. Risk of bias was assessed by the ROBINS-I (Risk Of Bias in Non-randomized Studies of Interventions) tool. We identified six case series. Collectively, 218 eyes were treated with aflibercept for ROP. We found an average 97% (95% confidence interval [CI], 93% to 99%) regression rate with aflibercept and an average 16% (95% CI, 5% to 41%) recurrence rate. With the exception of one outlier study, these numbers are similar to previous reports using anti-vascular endothelial growth factor (VEGF) agents in ROP. Aflibercept holds promise for use in ROP and has been demonstrated to be efficacious in six case series. Randomized, controlled clinical trials appear warranted to compare aflibercept with other anti-VEGF agents. [Ophthalmic Surg Lasers Imaging. 2021;52:673-681.].

Modern diagnostic and therapeutic approaches in familial maculopathy with reference to North Carolina macular dystrophy.

We present a familial hereditary macular dystrophy, resembling North Carolina Macular Dystrophy. In members of a family, we describe the development of diagnostic-therapeutic approaches and their impact on the prognosis of those whose vision was affected. The macular dystrophy of varying degrees of severity was diagnosed in 3 consecutive generations in different family members, both men and women. Modern therapeutic tools were used for the diagnostics. In one patient of the youngest generation, the development of secondary choroidal neovascularization (CNV) was identified and treated with an anti-VEGF (vascular endothelial growth factor) agent. DNA was isolated from venous blood and genome sequencing was performed in a proband. We analysed the data of 13 members of one family of three consecutive generations. Six of them had macular dystrophy. The first were two of three siblings, a woman (73 years old) and a man (67). The offspring of the afflicted man, a female (36) and a male (80), had maculopathy. The first daughter of the woman (12) revealed findings of maculopathy but with normal electrical activity of the retina. The second girl (18), developed secondary CNV which responded well to intravitreal anti-VEGF treatment. Genetic analysis excluded mutations previously reported to be pathogenic for NCMD. If there is a maculopathy of unclear etiology in younger patients or in patients with unclear development or appearance, it is advisable to focus carefully on the family history and trace the occurrence of impaired vision in other family members.

Ophthalmology and COVID-19: The Impact of the Pandemic on Patient Care and Outcomes: An IRIS® Registry Study

In response to the coronavirus disease 2019 (COVID-19) pandemic, a direct e-mail to American Academy of Ophthalmology membership urged “that all ophthalmologists cease providing any treatment other than urgent or emergent care immediately.”1 In the United States, the Academy’s Intelligent Research in Sight (IRIS®) Registry represents one of the largest and most advanced registry databases: more than 70% of United States ophthalmologists contribute to the IRIS Registry database.2 We used the IRIS Registry to study the treatment of common ophthalmic conditions before and after the Academy’s letter, specifically for those receiving intravitreal injections of anti–vascular endothelial growth factor (VEGF) agents to stabilize and improve vision.

Intraocular Pressure Elevation Following Intravitreal Anti-VEGF Injections: Short- and Long-term Considerations.

Published studies agree that transient intraocular pressure (IOP) spikes are common after intravitreal injections of anti–vascular endothelial growth factor agents. Currently, there is no standard of care guiding if and when to prevent these IOP spikes. Furthermore, there are challenges in determining the impact of postinjection IOP elevation on the health of the retinal ganglion cells, particularly given the often-existing comorbidities of retinal and glaucoma pathology. This review highlights the current literature regarding both acute and chronic postinjection IOP elevations and discusses management of postinjection IOP elevation, especially in patients at high risk for glaucomatous damage.

Efficacy and safety of intravitreal aflibercept in ranibizumab-refractory patients with neovascular age-related macular degeneration

BackgroundAnti–vascular endothelial growth factor (anti-VEGF) agents have become the standard of care in neovascular age-related macular degeneration (nAMD). Despite generally excellent response rates to anti-VEGF therapy, some patients do not respond or may respond suboptimally. In the case of refractory or rapidly recurring fluid in nAMD, clinicians may switch to another anti-VEGF agent. TITAN was an observational study that assessed the effectiveness and safety of intravitreal aflibercept (IVT-AFL) in patients with nAMD refractory to ranibizumab who switched to IVT-AFL after less than 12 months of ranibizumab treatment in routine clinical practice in France.MethodsTITAN was an observational, retrospective and prospective 12-month study conducted at 28 centres in France. Patients with nAMD refractory to ranibizumab were enrolled. Patients who were switched from ranibizumab to IVT-AFL were followed for 12 months. Data were obtained from medical records for retrospectively included patients, and at routine follow-up visits for those included prospectively. The main outcome measure was percentage of patients who achieved treatment success (gain of ≥1 Early Treatment Diabetic Retinopathy Study letters in best-corrected visual acuity [BCVA] and/or any reduction in central retinal thickness [CRT]) from baseline to 12 months after switching. A sample size of 225 patients was determined based on a 2-sided 95% confidence interval with a width equal to 0.12 when the sample proportion was 0.70.ResultsWe analysed safety data (N = 217) and clinical outcomes from patients in the per-protocol population (n = 125). The mean (standard deviation) number of IVT-AFL injections was 7.5 (2.6). Treatment success was achieved in 68.8% of patients. Mean BCVA change from baseline to Month 12 was + 1.5 letters (P = 0.105) and the mean CRT change was − 45.0 μm (P < 0.001). In a subgroup analysis, in patients who received three initial monthly IVT-AFL injections, mean BCVA gain was 3.3 letters at Month 12 (P = 0.015). Excluding lack of efficacy and inappropriate scheduling of drug administration, the most common adverse event was eye pain (2.3%).ConclusionsSwitching ranibizumab-refractory patients with nAMD to IVT-AFL may improve visual outcomes in some patients, particularly those who receive three initial monthly injections.Trial registrationClinicalTrials.gov, NCT02321241. First posted: December 22, 2014; Last update posted: July 2, 2018

Current and emerging therapies for first line treatment of metastatic clear cell renal cell carcinoma.

The therapeutic landscape for advanced clear cell renal cell carcinoma (ccRCC) is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and immunotherapies. In this review, we discuss historical, current, and emerging first line treatment options for patients with advanced ccRCC. These include data with single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs): sunitinib, pazopanib and cabozantinib as well as the recently reported results for the combination of lenvatinib and everolimus (mTOR inhibitor). We also discuss results of the nivolumab anti-programmed cell death (PD-1)/ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4) combination as well as emerging front-line data with nivolumab and pembrolizumab (anti-PD-1) monotherapy. Finally, we review data supporting recent approvals of TKI and anti-PD-1 or anti-PD-Ligand 1 (PD-L1) combinations (e.g., axitinib/pembrolizumab, axitinib/avelumab and cabozantinib/nivolumab) and initial outcomes of lenvatinib (multi-kinase inhibitor) and pembrolizumab. With many individual and combination treatment options and the lack of head-to-head comparisons, treatment selection will depend on the goals of therapy (endpoints) and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints.

Pterygium: an update on pathophysiology, clinical features, and management.

Pterygium is a relatively common ocular surface disease. The clinical aspects and the treatment options have been studied since many years ago, but many uncertainties still exist. The core pathologic pathway and the role of heredity in the development of pterygium are still attractive fields for the researchers. The role of pterygium in corneal irregularities, in addition to the refractive properties of pterygium removal, has been increasingly recognized through numerous studies. The association between pterygium and ocular surface neoplasia is challenging the traditional beliefs regarding the safe profile of the disease. The need for a comprehensive clinical classification system has encouraged homogenization of trials and prediction of the recurrence rate of the pterygium following surgical removal. Evolving surgical methods have been associated with some complications, whose diagnosis and management are necessary for ophthalmic surgeons. According to the review, the main risk factor of pterygium progression remains to be the ultraviolet exposure. A major part of the clinical evaluation should consist of differentiating between typical and atypical pterygia, where the latter may be associated with the risk of ocular surface neoplasia. The effect of pterygium on astigmatism and the aberrations of the cornea may evoke the need for an early removal with a purpose of reducing secondary refractive error. Among the surgical methods, conjunctival or conjunctival-limbal autografting seems to be the first choice for ophthalmic surgeons because the recurrence rate following the procedure has been reported to be lower, compared with other procedures. The use of adjuvant options is supported in the literature, where intraoperative and postoperative mitomycin C has been the adjuvant treatment of choice. The efficacy and safety of anti–vascular endothelial growth factor agents and cyclosporine have been postulated; however, their exact role in the treatment of the pterygium requires further studies.

Effectiveness of Combining Bevacizumab With First-Line Chemotherapy Regimens for Metastatic Colorectal Cancer in Real-World Practice

BackgroundAnti–vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting. Patients and MethodsWe retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy. ResultsIn an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018). ConclusionThe addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions.