VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy.

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper-permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF-A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen-induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho-functional responses of the ischemic retina to anti-angiogenic therapies. Using this model, we investigated the retinal responses to VEGF-Trap (Aflibercept), an anti-angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age-related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light-responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743.

VEGF-Trap Modulates Retinal Inflammation in the Murine Oxygen-Induced Retinopathy (OIR) Model.

Anti-Vascular Endothelial Growth Factor (VEGF) agents are the first-line treatment for retinal neovascular diseases, which represent the most prevalent causes of acquired vision loss world-wide. VEGF-Trap (Aflibercept, AFL), a recombinant decoy receptor recognizing ligands of both VEGFR-1 and -2, was recently reported to be highly efficient in improving visual acuity and preserving retinal anatomy in individuals affected by diabetic macular edema. However, the precise molecular and cell biological mechanisms underlying the beneficial effects of this novel tool have yet to be elucidated. Using the mouse oxygen-induced retinopathy (OIR) model as a surrogate of retinopathies with sterile post-ischemic inflammation, such as late proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and diabetic macular edema (DME), we provide evidence that AFL modulates inflammation in response to hypoxia by regulating the morphology of microglial cells, a parameter commonly used as a proxy for changes in their activation state. We show that AFL administration during the hypoxic period of OIR leads to an increased number of ramified Iba1+ microglial cells/macrophages while subsequently limiting the accumulation of these cells in particular retinal layers. Our results suggest that, beyond its well-documented beneficial effects on microvascular regeneration, AFL might exert important modulatory effects on post-ischemic retinal inflammation.

Potential of Photon-Counting Detector CT for Radiation Dose Reduction for the Assessment of Interstitial Lung Disease in Patients With Systemic Sclerosis.

OBJECTIVE: The aim of this study was to determine the potential of photon-counting detector computed tomography (PCD-CT) for radiation dose reduction compared with conventional energy-integrated detector CT (EID-CT) in the assessment of interstitial lung disease (ILD) in systemic sclerosis (SSc) patients. METHODS: In this retrospective study, SSc patients receiving a follow-up noncontrast chest examination on a PCD-CT were included between May 2021 and December 2021. Baseline scans were generated on a dual-source EID-CT by selecting the tube current-time product for each of the 2 x-ray tubes to obtain a 100% (D 100 ), a 66% (D 66 ), and a 33% dose image (D 33 ) from the same data set. Slice thickness and kernel were adjusted between the 2 scans. Image noise was assessed by placing a fixed region of interest in the subcutaneous fat. Two independent readers rated subjective image quality (5-point Likert scale), presence, extent, diagnostic confidence, and accuracy of SSc-ILD. D 100 interpreted by a radiologist with 22 years of experience served as reference standard. Interobserver agreement was calculated with Cohen κ, and mean variables were compared by a paired t test. RESULTS: Eighty patients (mean 56 ± 14; 64 women) were included. Although CTDI vol of PCD-CT was comparable to D 33 (0.72 vs 0.76 mGy, P = 0.091), mean image noise of PCD-CT was comparable to D 100 (131 ± 15 vs 113 ± 12, P > 0.05). Overall subjective image quality of PCD-CT was comparable to D 100 (4.72 vs 4.71; P = 0.874). Diagnostic accuracy was higher in PCD-CT compared with D 33 /D 66 (97.6% and 92.5%/96.3%, respectively) and comparable to D 100 (98.1%). CONCLUSIONS: With PCD-CT, a radiation dose reduction of 66% compared with EID-CT is feasible, without penalty in image quality and diagnostic performance for the evaluation of ILD.