Efficacy of conbercept after switching from bevacizumab/ranibizumab in eyes of macular edema secondary to central retinal vein occlusion

INTRODUCTION

Macular edema (ME) secondary to central retinal vein occlusion (CRVO) is a common cause of vision loss. Vascular endothelial growth factor (VEGF) has been demonstrated to play an important role in the hypoxia course after the occlusion of the retinal vein. Numerous studies have proved that anti-VEGF agents, including bevacizumab,ranibizumab, and aflibercept, are basically safe and effective.Similar to aflibercept, conbercept (Lumitin; Chengdu Kang Hong Biotech Co., Ltd., Sichuan Province, China) is a fusion protein composed of the extracellular domain 2 of VEGF receptor 1 and extracellular domains 3 and 4 of VEGF receptor 2 combined with the Fc portion of the human immunoglobulin G1. Prior studies indicated that conbercept showed favorable safety and efficacy in the treatment of ME secondary to retinal vein occlusion. In real clinical practice, some cases trend to respond insufficiently to anti-VEGF injections or to rebound repeatedly. Although switching strategy is very common,little attention has been paid to the switching to conbercept.

Images of SCP and DCP were exported and analyzed with Image J software (1.8.0_112, http://imagej.nih.gov/ij/; National Institutes of Health, Bethesda, Maryland, USA) to acquire perfusion density (PD) and vascular length density (VLD).We calculated the parafoveal vessel densities for the SCP and DCP. The parafoveal region was set to be an annulus centeredon the fovea with inner and outer ring of diameters of 1 and 3 mm, respectively. PD was the percentage of pixels occupied by blood vessels in the binary image of the grayscale OCTA image. VLD was defined as the ratio of skeletonized vessel length to the total area. Images were imported to Image J and binarized to assign each pixel to be either “perfused” or“background”. PD was calculated from the binarized images with a vascular density plugin application. After binarizing, a skeletonized slab was created, representing vessels one pixel in width, and VLD was calculated with “Analyze Skeleton”mode in Image J.

Optical coherence tomography angiography (OCTA) is a new,noninvasive technology that provides detailed information about the retinal microvasculature with the measurements of vessel density and foveal avascular zone. The evaluation of macular perfusion makes it possible to know more about the change after intravitreal injection of anti-VEGF agents.In this study, we quantified retinal vessel density of both superficial and deep layer of retina to evaluate the change of retinal vasculature and macular thickness after switching from bevacizumab and/or ranibizumab to conbercept.

SUBJECTS AND METHODS

本文在對新課程背景下小學語文課堂教學中的合作學習進行研究時，注重的是如何提升小學語文課堂教學中合作學習模式的應用效果，這需要結合小學生的年齡特點、小學語文的教學目標、合作學習的具體方式等等來進行改進，并在這一過程中要融入新時期的教育理念，體現現代化教育觀，這樣才能保證合作學習的實效性和價值性。下面筆者結合實踐經驗以及相關方面的理論基礎，對此進行詳細論述。

From March 2016 to December 2018,medical records of cases of ME due to CRVO were retrospectively reviewed.

Including criteria: 1) Patients aged 18 years or older with diagnosed CRVO and confirmed ME through optical coherence tomography (OCT) scan; 2) Prior treatment with a minimum of three consecutive intravitreal injections of either bevacizumab(1.25 mg/0.05 mL) or ranibizumab (0.5 mg/0.05 mL); 3)Switching to conbercept (0.5 mg/0.05 mL) due to refractory ME, which was defined as persistent ME or recurrent ME that initially resolved after treatment with bevacizumab and/or ranibizumab but did not respond to following repeated injections; 4) Following conbercept injection using a(PRN) regimen; 5) With a follow-up period of at least 12mo after switching; 6) OCTA was performed before switching and in the twelfth month after switching.

Excluding criteria: 1) Eyes of primary or neovascular glaucoma and initial intraocular pressure (IOP) exceeded 21 mm Hg; 2)Vitrectomized eyes; 3) The presence of active confounding retinal or ocular disease (, severe diabetic retinopathy,exudative macular degeneration, macular hole,).

關于感性認識與理性認識之間的層次關系問題，王船山認為“由知而知所行”“并進有功”，也就是理性認識只有在實踐當中才能指導社會生活實踐，知行相輔相成就能取得事半功倍的效果。毛澤東不僅認可社會實踐是檢驗真理的唯一標準，也同時指出了“認識”對社會實踐的巨大反作用。“通過實踐而發現真理，又通過實踐而證實真理和發展真理。從感性認識而能動地發展到理性認識，又從理性認識而能動指導革命實踐，改造主觀世界和改造客觀世界。”[8]在學習的方式、方法上，毛澤東也強調理論聯系實際，在學習態度上要謙虛，要“甘當小學生”“來不得半點虛偽和驕傲”，這一觀念也同王船山的“不自圣”“不自倨”的學習態度是一脈相承的。

Over the follow-up period, no progression of diabetic retinopathy was observed in the two patients of mild non-proliferative diabetic retinopathy. Progression of posterior subcapsular cataract was found in one eye of the 20 phakic eyes during the follow-up after switching; the fellow eye had the similar progression of cataract and both eyes underwent cataract extraction and lens implantation.

This was a retrospective study that was approved by China-Japan Friendship Hospital Ethics Committee and adhered to the Declarations of Helsinki.Informed consent was obtained from all patients who were enrolled in the study.

Six eyes (25%) received only ranibizumab(9-15 injections) previously while 15 eyes (62.5%) received only bevacizumab (8-20 injections) and 3 eyes (12.5%)received injections of both, two of which were switched from bevacizumab to ranibizumab (5 and 3 injections for one subject; 4 and 4 injections for another) and one of which was switched inversely (6 and 4 injections). The number of injections ranged from 8 to 20. The mean number of injections was 14.3±5.7 within a mean follow-up duration of 16.1mo(12-29mo) and the mean interval between injections was 5.2±2.3wk.

據云南省發展改革委黨組成員、主任助理梁琦介紹，截至目前，全省特色小鎮新開工項目710個，累計完成投資633．2億元，特色小鎮實現新增就業6．5萬人，新增稅收8．6億元，新入駐企業2576家，集聚國家級大師和國家級非遺傳承人53人，特色小鎮共接待游客人數1．8億人次，其中過夜游客5832萬人，實現旅游收入1052億元。……