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Purpose: Clinical trials have demonstrated higher complete response rates in the immuno-oncologye based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies. Materials and Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncologye based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1. Results: A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncologye based and tyrosine kinase inhibitor therapies, respectively (P [ .005). An adjusted odds ratio for complete response achieved by immuno-oncologye based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17; P [ .009). Among patients who experienced complete response, the immuno-oncologye based cohort had a higher proportion of noneclear cell histology (15.9% and 4.7%; P [ .016), sarcomatoid dedifferentiation (29.8% and 13.5%; P [ .014), and multiple sites of metastases (80.4% and 50.0%; P < .001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncologye based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72; P [ .016) and 0.28 (95% CI 0.21-0.38; P < .001). Conclusions: The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncologye based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival. [ABSTRACT FROM AUTHOR]

Aflibercept and brolucizumab, two anti-VEGF agents used as intravitreal injections in ophthalmology, differ significantly in molecular weight (aflibercept-115 kDa and brolucizumab-26 kDa). Using aqueous humor samples collected after drug administration, we measured and performed a comparative analysis of pharmacokinetics and half-lives of these drugs in the human eye. Since the quantification of monoclonal antibodies (mAbs) using antigen-antibody reactions, such as ELISA, is influenced by endogenous ligands or anti-drug antibodies, we employed nano-surface and molecular-orientation limited proteolysis (nSMOL), combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), for accurate measurements. Aqueous humor samples were collected from 59 eyes of 59 patients treated with aflibercept and 52 eyes of 52 patients treated with brolucizumab. Samples were obtained with a median post-injection period of 30 (range, 2-49) days for aflibercept and 28 (range, 4-60) days for brolucizumab. A population pharmacokinetic (PPK) analysis revealed that the half-life of aflibercept in human aqueous humor was significantly shorter than that of brolucizumab, 2.88 days versus 9.00 days, respectively ( p = 1.16 × 10 -7 ). Using the same mass spectrometry conditions, we calculated the half-lives of the two drugs. These results may be useful for optimizing the efficacy of these drugs in clinical practice.

Our current prospective cross-sectional study aimed to investigate the effect of anti-vascular endothelial growth factor (VEGF) drugs used in the treatment of retinopathy of prematurity on retinal maturation and persistent avascular retina (PAR). Retinal imaging was performed with Optos confocal laser ophthalmoscopy for 100 patients aged 4 to 8 years who were screened and treated for retinopathy of prematurity (ROP) during the neonatal period. The ROP examination findings (stage and zone) and treatment history (age in weeks at time of treatment and anti-VEGF drug used) from the neonatal period were reviewed. Retinal vascularization was assessed in fundus images using the green filter on the Optos device and the presence of PAR was evaluated by two investigators. Relationships between the rate of PAR, age in weeks at time of treatment, and type of anti-VEGF drug used were analyzed statistically. The study included 196 eyes of 100 patients. Sixty-four eyes were analyzed in Group 1 (no ROP), 23 eyes in Group 2 (ROP, no treatment), and 108 eyes in Group 3 (treated group; anti-VEGF treatment of ROP with ranibizumab, bevacizumab, or aflibercept). The number of eyes with PAR in these groups was 2 (3.7%), 4 (17.4%), and 45 (41.7%), respectively. PAR was detected in 30 of 44 eyes treated with aflibercept. The rate of PAR was higher after aflibercept treatment (68.2%) with statistical significance (p = 0.000). This study showed that the prevalence of PAR differs between anti-VEGF drugs. Patients treated with aflibercept have a higher risk of late complications and should be followed closely., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Anti-VEGF therapy is the standard treatment for exudative neovascular age-related macular degeneration (nAMD) caused by the development of macular neovascularisation (MNV) with associated fluid exudation. The therapeutic strategies (T&E or PRN) assumed a scarring transformation of the MNV and exit strategies and were formulated accordingly. The present study investigates this hypothesis as a real-life long-term analysis., Patients: 150 eyes of 97 patients were continuously followed up over a mean period of 5.1 years (1 - 14 years) after initiation of anti-VEGF therapy between 2009 - 2017 until 2022. Treatment was based on the PRN regimen analogous to the IVAN study with ranibizumab, aflibercept or bevacizumab. The length and intensity of therapy were evaluated., Results: Of these 150 eyes, 119 (79.3%) required ongoing anti-VEGF therapy, while in 18 eyes (12.0%) therapy could be discontinued due to stabilisation of the situation. In 13 eyes (8.7%), therapy was discontinued due to deterioration in visual acuity to < 0.05. With ongoing therapy, therapy was often protracted, with an indication for therapy at the last documented doctor's visit, while stabilisation was often achieved within the first 2 years of treatment. The treatment intensity increased to 7.7 - 8.0 injections/year, especially after 2013, with the introduction of OCT-based treatment criteria. Most eyes (74.8%) with ongoing therapy required 6 - 9 injections/year even in the last three years of treatment., Conclusion: The fact that in the present study there is a long-term and intensive need for therapy in the majority of patients (approx. 80%) with exudative nAMD, supports the assessment that nAMD should be regarded as a chronic disease. Therefore, a proactive treatment strategy with consistent therapy at any sign of lesion activity might be recommended. Particularly in view of the risk of irreversible loss of vision, long term adherence of patients is also crucial for the best possible long term therapeutic outcome., Competing Interests: Pauleikhoff, D: Roche, Novartis, Bayer, Heidelberg Engineering, ApellisLommatzsch, A: Roche, Novartis, Bayer, Heidelberg Engineering, ApellisDie übrigen Autoren haben keinen Interessenkonflikt zu erklären./Pauleikhoff, D: Roche, Novartis, Bayer, Heidelberg Engineering, ApellisLommatzsch, A: Roche, Novartis, Bayer, Heidelberg Engineering, ApellisThe other authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: This study aimed to investigate the effects of subconjunctival injection of aflibercept, a soluble protein decoy for VEGFR-1 and VEGFR-2, on corneal angiogenesis and VEGFR-expressing CD11b + cells in a mouse model of suture-induced corneal neovascularization., Methods: Corneal neovascularization was induced in BALB/c mice by placing three sutures on the cornea. Immediately after surgery, either 200 µg aflibercept (5 µL) or an equal volume of phosphate-buffered saline (PBS) was administered into the subconjunctival space. Seven days after later, corneal new vessels were quantified through clinical examination and measurement of the CD31-stained area in corneal flat mounts. The levels of pro-angiogenic and inflammatory markers in the cornea were evaluated using RT-qPCR. The percentages of VEGFR-2 + CD11b + cells and VEGFR-3 + CD11b + cells were analyzed in the cornea, blood, and draining cervical lymph nodes (DLNs) using flow cytometry., Results: Subconjunctival injection of aflibercept significantly reduced the growth of corneal new vessels compared to subconjunctival PBS injection. The mRNA levels of Cd31, vascular growth factors (Vegfc and Angpt1), and pro-angiogenic/inflammatory markers (Tek/Tie2, Mrc1, Mrc2, and Il6) in the cornea were downregulated by subconjunctival aflibercept. Also, the percentage of VEGFR-3 + CD11b + cells in the cornea, blood, and DLNs was decreased by aflibercept, whereas that of VEGFR-2 + CD11b + cells was unaffected., Conclusion: Subconjunctival aflibercept administration inhibits inflammatory angiogenesis in the cornea and reduces the numbers of cornea-infiltrating and circulating VEGFR-3 + CD11b + cells., Competing Interests: Declarations. Ethical approval: The experimental protocol was approved from the Institutional Animal Care and Use Committee of Seoul National University Hospital Biomedical Research Institute (Seoul, Korea) and followed the guidelines stated by ARVO for ophthalmic and vision research. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Background: The combination chemotherapy i.v. 5-fluorouracil (5-FU), irinotecan, and aflibercept (FOLFIRI-A) is a standard second-line treatment of metastatic colorectal cancer (mCRC). The aim was to assess maintenance treatment in second-line setting in older patients (aged ≥70 years) with mCRC., Patients and Methods: We evaluated FOLFIRI-A given for six cycles followed by maintenance with 5-FU/leucovorin (LV)-A (arm A) or FOLFIRI-A (arm B) until progression in older adults with mCRC in the AFEMA randomized, open-label, non-inferiority phase II trial (EudraCT2016-004076-21/NCT03279289). Patients aged ≥70 years who previously failed oxaliplatin-fluoropyrimidine were randomly allocated (1 : 1) to either arm A (experimental) or arm B (control). After enrolling 35 patients, the FOLFIRI dose was reduced to level 1 in both arms due to toxicity. The primary endpoint was median progression-free survival (PFS); and secondary endpoints were median overall survival, objective response rate, and safety. Non-inferiority required the upper confidence interval (CI) limit to not exceed a hazard ratio (HR) of 1.5 (one-sided α = 0.075, 80% power)., Results: A total of 170 patients were randomly allocated to arm A or arm B (n = 85 each). The median follow-up was 12.2 versus 10.9 months in arm A versus arm B. Most patients died (83.5% versus 88.2% in arm A versus arm B), mainly from disease progression. PFS non-inferiority was met (HR = 0.78, 95% CI 0.566-1.076, P = 0.131) with a median PFS of 6.1 versus 5.5 months in arm A versus arm B. Median overall survival was similar in arms A and B (12.2 and 11.5 months, respectively) (HR = 0.89, 95% CI 0.640-1.227, P = 0.467). During the maintenance phase, severe asthenia (4.5% versus 21.6%, P = 0.038), serious adverse events (SAEs) (17.8% versus 37.8%, P = 0.049), and treatment-related SAEs (6.7% versus 10.8%, P = 0.695) were reduced in arm A versus arm B., Conclusion: In older adults, induction with six cycles of FOLFIRI-A plus maintenance with 5-FU/LV-A was non-inferior to FOLFIRI-A until progression. Severe asthenia, SAEs, and treatment-related SAEs were reduced with 5-FU/LV-A maintenance., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The majority of metastatic renal cell carcinoma (mRCC) patients receive one or more VEGFR TKI agents, alone or in combination with an immune-oncology (IO) agent or an mTOR inhibitor. To date, the cost of adverse events (AEs) common to VEGFR TKIs has not been quantified. This study estimated the potential impact of differences in VEGFR TKI AE profiles on treatment cost efficiency in the relapsed/refractory (R/R) setting., Methods: Patients with documented mRCC who were treated with VEGFR TKI therapies between Jan 2015 and Mar 2021 were identified using EMR. ICD-10 diagnosis codes were used to identify the first occurrence of each class effect AE. Patients were matched to 3rd party insurance claims, and costs associated to TKI AEs within 90 days of index event were captured. Average per patient AE cost data was calculated and applied to published incidence data to estimate regimen-specific AE total cost burden within a hypothetical commercial plan for mRCC patients undergoing treatment in the R/R setting., Results: The highest total cost for AE management was attributed to lenvatinib and everolimus use at $13,303, followed closely by sunitinib at $13,092. Tivozanib treatment was associated with the lowest total cost of AE management at $7,523, driven by the relatively lower incidence of certain high-cost AEs., Conclusions: The estimated costs of managing VEGFR TKI class-effect AEs were lowest with tivozanib, and highest with lenvatinib and everolimus, indicating potentially differential healthcare resource burden by TKI regimen. The use of tivozanib in the 3 L + mRCC setting suggests potential costs offsets when compared to other TKI regimens., (© 2024. The Author(s).)

This study aimed to evaluate the incidence of clinically significant intraocular inflammation (csIOI) after treatment with intravitreal injection (IVI) of brolucizumab and identify csIOI risk factors. We categorized 60,966 South Korean patients from a nationwide population-based cohort into 4 groups: groups 1 (Ranibizumab), 2 (Aflibercept), 3 (Brolucizumab), and 4 (switched to brolucizumab). We used the Kaplan-Meier method to estimate the cumulative incidence of csIOI in each group and calculated the hazard ratios (HRs) and 95% confidence intervals (CIs). We constructed a multivariate model using forward selection methods to identify risk factors for csIOI. The cumulative incidence of csIOI within 180 days of the index date in groups 1, 2, 3, and 4 was 0.36% (67/18,537), 0.49% (186/37,951), 3.47% (38/1,095), and 3.69% (125/3,383), respectively. Multivariate analysis revealed a significant increase in csIOI risk in groups 3 (HR 11.08, 95% CI 7.42-16.53, P < 0.001) and 4 (HR 10.40, 95% CI 7.67-14.09, P < 0.001). History of retinal vascular occlusion (HR 1.56, 95% CI 1.01-2.40, P = 0.043) significantly increased csIOI risk after brolucizumab IVI treatment; female sex (HR 0.78, 95% CI 0.64-0.96, p = 0.020) and diabetes (HR 0.72, 95% CI 0.58-0.90, p = 0.004) decreased the risk. csIOI incidence was higher after brolucizumab IVI treatment than after ranibizumab and aflibercept IVI treatment. Retinal vein occlusion history, female sex, and diabetes are associated with csIOI after brolucizumab IVI treatment., (© 2024. The Author(s).)

Purpose: To characterize trends in use of and expenditure for the intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept, ranibizumab, and bevacizumab among the population enrolled in Original Medicare from 2014 to 2019., Methods: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to extract Medicare Part B fee-for-service outpatient injection claims data submitted by ophthalmologists. Multivariable linear regression models were used to evaluate the association between reimbursement, ophthalmologist availability, and agent administration rate., Results: Between 2014 and 2019, 17,588,995 intravitreal injection claims were filed by 4218 US ophthalmologists. Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019. Increased state-level ophthalmologist availability and incremental increases in average reimbursement amounts were found to be significantly associated with a 6.8-fold variation in 2019 overall anti-VEGF injection rates across states., Conclusions: Medicare injection rates and costs for anti-VEGF injections have both increased between 2014 and 2019, largely driven by increased aflibercept use. There is a significant association between ophthalmologist availability and anti-VEGF injection rate on the state level, suggesting access to care may contribute to the observed state-level disparities in intravitreal injection rates. Further characterization of factors contributing to the state-level variation in injection rates of individual anti-VEGF agents may help inform interventions promoting equitable access to and use of these drugs.

Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl (breakpoint cluster region-Abelson proto-oncogene) KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs., Competing Interests: I.Z. Jaffe is a consultant at Boeringer Ingelheim. The other authors report no conflicts.

Background: Neoadjuvant chemotherapy is an option for patients with locally advanced rectal cancer at low risk for local recurrence. This randomized phase II trial investigated whether the addition of aflibercept to modified FOLFOX6 (mFOLFOX6) could improve the rates of centrally confirmed pathological complete remissions (pCR) and (disease-free) survival in magnetic resonance imaging (MRI)-staged cT3 rectal cancer., Patients and Methods: Patients with rectal cancer fulfilling the following criteria were included: lower border of tumor >5 cm and <16 cm from anal verge; circumferential resection margin >2 mm and T3-tumor with a maximum infiltration of 10 mm, as determined by MRI. Patients were randomized 1 : 2 to six cycles mFOLFOX6 ± aflibercept. Surgery was scheduled 4 weeks after chemotherapy. Primary endpoint was the rate of centrally confirmed pCR. The study was designed to detect an improvement of pCR from 10% to 27% (power 80%, type I error 20%)., Results: A total of 119 randomized patients started treatment (39 patients mFOLFOX6, arm A, and 80 mFOLFOX + aflibercept, arm B). The incidence of all grade adverse events was similar in both arms, however, adverse events grade ≥3 were more than twice as high in the experimental arm due to hypertension. Surgical complications were comparable. Aflibercept did not improve the pCR rate (arm A 26% versus arm B 19%, P = 0.47) and more patients in arm B had node positivity. With a median follow-up of 40.1 months, the 4-year disease-free survival was 83% in arm A and 85% in arm B (P = 0.82). Only two patients in arm A and one patient in arm B developed local recurrence., Conclusions: In patients with locally advanced rectal cancer and MRI-defined low risk of local recurrence, neoadjuvant mFOLFOX6 + aflibercept was feasible and did not compromise surgery. Survival data were favorable in both arms, but pCR rates were not increased by the addition of aflibercept., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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Wet Age-related macular degeneration (AMD) is the leading cause of vision loss in industrialized nations, often resulting in blindness. Biologics, therapeutic agents derived from biological sources, have been effective in AMD, albeit at a high cost. Due to the high cost of AMD treatment, it is critical to determine the binding affinity of biologics to ensure their efficacy and make quantitative comparisons between different drugs. This study evaluates the in vitro VEGF binding affinity of two drugs used for treating wet AMD, monoclonal antibody-based bevacizumab and fusion protein-based aflibercept, performing quantitative binding measurements on an Interferometric Reflectance Imaging Sensor (IRIS) system. Both biologics can inhibit Vascular Endothelial Growth Factor (VEGF). For comparison, the therapeutic molecules were immobilized on to the same support in a microarray format, and their real-time binding interactions with recombinant human VEGF (rhVEGF) were measured using an IRIS. The results indicated that aflibercept exhibited a higher binding affinity to VEGF than bevacizumab, consistent with previous studies using ELISA and SPR. The IRIS system's innovative and cost-effective features, such as silicon-based semiconductor chips for enhanced signal detection and multiplexed analysis capability, offer new prospects in sensor technologies. These attributes make IRISs a promising tool for future applications in the development of therapeutic agents, specifically biologics.

Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes., (© 2024. The Author(s).)

Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished., Patients and Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model., Results: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups., Conclusion: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment., Clinical Trial Number: UMIN000028616., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Recurrent respiratory papillomatosis (RRP) is caused by human papilloma virus (HPV) infection of the aerodigestive tract that significantly impacts quality-of-life including the ability to communicate and breathe. Treatment was traditionally limited to serial ablative procedures in the O.R. with possible local adjuvant therapy, but new systemic therapies, such as Vascular endothelial growth factor (VEGF) inhibitors, are showing significant promise. This study aims to determine whether rationale exists for combination therapeutic approaches using VEGF inhibitors and/or immune checkpoint blockade., Methods: Using fresh specimens from the O.R., we performed flow cytometry on papilloma, normal adjacent tissue, and blood. Papilloma and surrounding tissue were examined for expression of PD-L1, PD-L2, Galectin-9, VEGFR2, and VEGFR3. CD8+ and CD4+ T cells were assayed for expression of PD-1, TIGIT, LAG3, and TIM3., Results: Our data shows that papilloma tissue exhibits significantly higher levels of PD-L1 and PD-L2 compared to adjacent tissue. Elevated levels of the VEGF receptor VEGFR3 were also observed in papilloma tissue. When examining T cells within the papilloma, elevated PD-1 and TIGIT expression was observed on CD8+ T cells, while levels of PD-1, TIGIT, and TIM3 were elevated on CD4+ T cells compared to PBMCs. Heterogenous marker expression was observed between individuals., Conclusions: Our analysis shows that RRP tissue shows elevated levels of multiple immune check point targets and VEGFR3, with varied patterns unique to each papilloma patient. Some of these immune checkpoint markers already have novel immunotherapies available or in development, providing molecular rationale to offer these systemic treatments to selected patients affected by RRP alongside VEGF inhibitors. Laryngoscope, 134:2819-2825, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: This study investigates the visual outcomes of neovascular age-related macular degeneration (nAMD) patients who developed intraocular inflammation (IOI) after intravitreal brolucizumab injection (IVBr)., Methods: We studied 285 eyes of 279 cases diagnosed with nAMD and focused on 18 eyes (6.3%) of 17 cases which developed IOI after IVBr. IVBr was performed either on the initial treatment or for switching of other anti-vascular endothelial growth factor agents during January 2020 to December 2021. We evaluated clinical features and the course of treatment of a 6-month follow-up after IOI occurred., Results: Of 17 cases, 9 cases were male, 8 cases were female. Baseline logarithm of the minimum angle of resolution(logMAR) best-corrected visual acuity (BCVA) was 0.36, BCVA before IOI occurred was 0.30, and BCVA when IOI occurred was 0.43. 16 eyes (88.9%) had symptoms such as visual loss or floaters when IOI occurred. On the other hand, the remaining 2 eyes (11.1%) had no symptoms. 11 eyes (61.1%) had only IOI, while the remaining 7 eyes (38.9%) had IOI and perivascular sheathing. Steroid sub-tenon injection was performed on 1 eye (5.6%), steroid eye drops were used in 11 eyes (61.1%), and 6 eyes (33.3%) were followed-up without treatment. Neovascular AMD recurred in 16 eyes (88.9%) after IOI occurred and were treated with aflibercept. VA at 3 and 6 months after IOI occurred were significantly improved to 0.34 and 0.30, respectively (P = 0.09 at 3 months and P = 0.02 at 6 months). The symptoms of patients were improved in all cases. We were able to stop steroid treatment in all cases., Conclusions: IOI occurred in 6.3% of nAMD patients after IVBr treatment. All of which showed significant improvement from logMAR of 0.43 to 0.30 with steroid treatment or without any treatment. We should consider the possibility of IOI after IVBr as a complication, however, they have a relatively good prognosis if treated at an early stage., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hirono et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/aims: To evaluate the efficacy, safety and durability of intravitreal faricimab in patients with neovascular age-related macular degeneration (nAMD) with unsatisfactory response to traditional anti-vascular endothelial growth factor (anti-VEGF) agents., Methods: Single-centre, prospective cohort study of all consecutive patients with nAMD who were switched to intravitreal faricimab from intravitreal ranibizumab or aflibercept, due to unsatisfactory treatment response (maximal fluid-free interval ≤ 8 weeks). Intravitreal faricimab was administered with a loading dose of four 4-weekly injections, followed by an 8-week extension. A treat and extend (T&E) regime was adopted thereafter. Primary outcome was the difference between the maximal fluid-free interval achieved with faricimab, and the one achieved before the switch. Morpho-functional outcomes were also assessed. Secondary outcome was accordance with clinical management when applying faricimab pivotal trial criteria versus our real-world T&E protocol, measured as a proportion., Results: Twenty-six eyes of 26 patients with a median age of 82 years (range 77-85) were included. Patients were followed for 30.2 weeks (range 26.3-33.1). Maximal fluid-free interval after switch to faricimab (Mdn = 6.0 weeks; IQR = 4-8) was longer than the maximum interval before the switch (Mdn = 4.0 weeks; IQR = 4-4), p < 0.001. Comparing real-world T&E protocol with pivotal trial criteria, 8 (30.8%) eyes received the same clinical management while 18 (69.2%) eyes were kept at a shorter interval when following our T&E protocol. No serious adverse events were recorded., Conclusions: Faricimab appears to increase the fluid-free interval and allow extension of dosing interval in patients with nAMD poorly responsive to traditional anti-VEGF drugs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this work, the cytotoxicity of monoclonal antibody (Cetuximab, Ce) and Fenbendazole (Fen), as well as their combination therapy were tested with the MTT assay. On the other side, Ce, Fen, and a combination between them were subjected to a colchicine-tubulin binding test, which was conducted and compared to Colchicine as a reference standard. Besides, Ce, Fen, and the combination of them were tested against the VEGFR-2 target receptor, compared to Sorafenib as the standard medication. Moreover, the qRT-PCR technique was used to investigate the levels of apoptotic genes (p53 and Bax) and anti-apoptotic gene (Bcl-2) as well. Also, the effect of Ce, Fen, and the combination of them on the level of ROS was studied. Furthermore, the cell cycle analysis and Annexin V apoptosis assay were carried out for Ce, Fen, and a combination of them. In addition, the molecular docking studies were used to describe the molecular levels of interactions for both (Fen and colchicine) or (Fen and sorafenib) within the binding pockets of the colchicine binding site (CBS) and vascular endothelial growth factor-2 receptor (VEGFR-2), respectively., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs). However, the specific role of VEGFB and VEGFRs in pubertal mammary gland development remains unclear. In this study, we observed that blocking the VEGF receptors with Axitinib suppressed the pubertal mammary gland development. Meanwhile, the proliferation of mammary epithelial cells (HC11) was repressed by blocking the VEGF receptors with Axitinib. Additionally, knockdown of VEGFR1 rather than VEGFR2 and NRP1 elicited the inhibition of HC11 proliferation, suggesting the essential role of VEGFR1 during this process. Furthermore, Axitinib or VEGFR1 knockdown led to the inhibition of the PI3K/Akt pathway. However, the inhibition of HC11 proliferation induced by Axitinib and or VEGFR1 knockdown was eliminated by the Akt activator SC79, indicating the involvement of the PI3K/Akt pathway. Finally, the knockdown of VEGFB and VEGFR1 suppressed the pubertal development of mice mammary gland with the inhibition of the PI3K/Akt pathway. In summary, the results showed that knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of the PI3K/Akt pathway, which provides a new target for the regulation of pubertal mammary gland development., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Purpose: Triple-negative breast cancer (TNBC) has a poor prognosis due to the absence of effective therapeutic targets. Vascular endothelial growth factor (VEGF) family are expressed in 30-60% of TNBC, therefore providing potential therapeutic targets for TNBC. Aflibercept (Abe), a humanized recombinant fusion protein specifically bound to VEGF-A, B and placental growth factor (PIGF), has proven to be effective in the treatment in some cancers. Therefore, 89 Zr/ 177 Lu-labeled Abe was investigated for its theranostic role in TNBC., Methods: Abe was radiolabeled with 89 Zr and 177 Lu via the conjugation of chelators. Flow cytometry and cell immunofluorescent staining were performed to evaluate the binding affinity of Abe. Sequential PET imaging and fluorescent imaging were conducted in TNBC tumor bearing mice following the injection of 89 Zr-labeled Abe and Cy5.5-labeled Abe. Treatment study was performed after the administration of 177 Lu-labeled Abe. Tumor volume and survival were monitored and SPECT imaging and biodistribution studies were conducted. Safety evaluation was performed including body weight, blood cell measurement, and hematoxylin-eosin (H&E) staining of major organs. Expression of VEGF and CD31 was tested by immunohistochemical staining. Dosimetry was estimated using the OLINDA software., Results: FITC-labeled Abe showed a strong binding affinity to VEGF in TNBC 4T1 cells and HUVECs by flow cytometry and cell immunofluorescence. Tumor uptake of 89 Zr-labeled Abe peaked at 120 h (SUVmax = 3.2 ± 0.64) and persisted before 168 h (SUVmax = 2.54 ± 0.42). The fluorescence intensity of the Cy5.5-labeled Abe group surpassed that of the Cy5.5-labeled IgG group, implying that Cy5.5-labeled Abe is a viable candidate monitoring in vivo tumor targeting and localization. 177 Lu-labeled Abe (11.1 MBq) served well as the therapeutic component to suppress tumor growth with standardized tumor volume at 16 days, significantly smaller than PBS group (about 815.66 ± 3.58% vs 3646.52 ± 11.10%, n = 5, P < 0.01). Moreover, SPECT images confirmed high contrast between tumors and normal organs, indicating selective tumor uptake of 177 Lu-labeled Abe. No discernible abnormalities in blood cells, and no evident histopathological abnormality observed in liver, spleen, and kidney. Immunohistochemical staining showed that 177 Lu-labeled Abe effectively inhibited the expression of VEGF and CD31 of tumor, suggesting that angiogenesis may be suppressed by 177 Lu-labeled Abe. The whole-body effective dose for an adult human was estimated to be 0.16 mSv/MBq., Conclusion: 89 Zr/ 177 Lu-labeled Abe could be a TNBC-specific marker with diagnostic value and provide insights into targeted therapy in the treatment of TNBC. Further clinical evaluation and translation may be of high significance for TNBC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To determine long-term efficacy and safety of intravitreal brolucizumab therapy for neovascular age-related macular degeneration (nAMD) in the real-world setting., Methods: Retrospective, observational, multicentric study and an extension of the REBA study (Real-world Experience with Brolucizumab in nAMD) to 24 months. The study entailed follow-up of 91 consecutive eyes (67 patients) with nAMD who received brolucizumab therapy and completed 24 months of follow-up. Both treatment-naïve and switch therapy patients were included. All relevant data were collected. The primary outcome measure was changed in best-corrected visual acuity (BCVA) over time. Secondary outcome measures included change in central subfield thickness (CST) and complications., Results: The mean (SD) baseline BCVA was 48.4 (3.5) letters and 36.2 (7.1) letters in treatment-naïve group and switch therapy group, respectively. BCVA gain was + 9.2 (3.7) letters (p = 0.01) and + 7.7 (3.4) letters (p = 0.011), respectively. The change in mean (SD) CST has shown a significant decrease in retinal thickness in treatment-naïve group (from 432.5 (68.4) to 283.0 (51.3) µm; p = 0.018) and in switch therapy group (from 452.5 (40.5) to 271.0 (43.4) µm; p = 0.011) group. One switch patient developed vascular occlusion and another a macular hole after the fifth brolucizumab injection as reported in the primary study. Both patients recovered uneventfully. Three patients demonstrated reversible intraocular inflammation between months 10 and 24., Conclusion: Patients showed a significant anatomical and functional response to brolucizumab therapy in the real world, regardless of prior treatment status, until the end of the follow-up period. Overall, 5 significant untoward events were noted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)