Comment on: Real-world outcomes of two-year Conbercept therapy for diabetic macular edema

We read with great interest the study by Cheng,which assessed the two-year outcomes in 30 (36 eyes) diabetic macular edema (DME) patients treated with intravitreal conbercept (Lumitin; Chengdu Kanghong Biotech Xo, Ltd, China; IVC) for 3mo. Additional IVC was given at subsequent monthly visits, if needed (3+). The mean improvement in best-corrected visual acuity (BCVA)was 11 letters and the central retinal thickness (CRT) was significantly reduced by 277.1 μm at 24mo with a mean number of 10.6 injections and without severe eye or systemic adverse events. The authors concluded that IVC is safe and effective for the treatment of DME. We would like to address several challenges that have arisen from this study which can be specifically summarized below.

The study was retrospectively conducted in a relatively small number of patients.

There was a selection bias attributable to inclusion and pooled analysis of 2 types of diabetic retinopathy (DR), that is,nonproliferative (=3) and proliferative (=33) DR, (although the active proliferative DR was an exclusion criterion) as well as patients with (=33) and without (=3) previous laser treatment (panretinal photocoagulation, PRP). Taken together,these findings may have confounded the final results.

3.3.3 金花茶種植管理。在種植完印度紫檀后種植金花茶。因剛種植的紫檀樹未能起到遮陰效果，金花茶種植前要架設(shè)遮陰網(wǎng)，待紫檀樹長到成蔭時(約1年)棄網(wǎng)。定點(diǎn)挖坑：坑的規(guī)格為40 cm×40 cm×40 cm，在印度紫檀樹兩旁排列成行，規(guī)格為2 m×2 m，種植密度為2 490株/hm2。

師生活動 學(xué)生獨(dú)立活動，然后全班交流.教師在此基礎(chǔ)上進(jìn)行引導(dǎo)：我們解題依據(jù)是“等腰直角三角形兩條直角邊相等”，也就是說，在直角三角形中，如果有一個角等于45°，那么不管這個三角形大小如何，這個角對邊與鄰邊的比值都等于1，是一個固定值.

“是啊，他的確……”我轉(zhuǎn)頭望了一下，他很安靜，又異常沉著，我并不害怕他會傷害我，但最終我還是附和道，“挺嚇人的。”

1) Intraretinal cysts with specification of their location if they existed (inner/outer nuclear layers or ganglion cell layers);

2) Ellipsoid zone (EZ) or external limiting membrane status;

There were no details regarding the DME defined as retinal thickening or hard exudates at or within 1 disc diameter of the macula center and which is most commonly classified into either being clinically significant or not. Moreover, the criteria used to define the clinically significant DME, if it was present in some patients, were not indicated. There were no data on the staging of diabetic maculopathy (early, advanced,severe, and atrophic maculopathy), the spectral domain-optical coherence tomography (SD-OCT) patterns of the DME (spongelike swelling/cystoid macular edema/serous neuroretinal detachment/mixed type), and the location of the cystoid type(ganglion cell layer/inner/outer nuclear layers).

The authors of this study did not considered the currently available recommendations of the European School for Advanced Studies in Ophthalmology international classificationthat classified the diabetic maculopathy based on the SDOCT microstructural alterations of the outer/inner retina and vitreoretinal interface. From the seven distinct parameters of an SD-OCT structural image going through the center of the fovea, only one was documented in this study, namely, the CRT. The remaining 6 distinct features of this classification,which should have been assessed separately in this study, are as follows:

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Nothing was stated regarding the influence which IVC can exert on the diabetic choroidopathy which consists in intrachoroidal vascular abnormalities, and which may directly induce choroidal ischemia, leading to RPE dysfunction.Notably, unlike bevacizumab, which has a protective effect against occlusion of choriocapillaris induced by photodynamic therapy, and ranibizumab, which does not impair the choroidal thickness, aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY, USA) treatment may result in a significant subfoveal choroidal thickness loss by suppressing the choroidal vascular hyperpermeability and vasoconstriction as well as by more pronounced reductions of choriocapillaris endothelium thickness and number of fenestrations.

總之，英語學(xué)習(xí)過程中詞匯對于學(xué)生的英語整體學(xué)習(xí)具有較大的影響，詞匯是英語學(xué)習(xí)中的基礎(chǔ)。如今，社會對人才的要求越來越高，人才要想提升自身的核心競爭力就需要從學(xué)習(xí)的基礎(chǔ)入手，英語的學(xué)習(xí)中努力探索詞匯積累的方法，使學(xué)生能夠利用最佳的策略來提高英語的學(xué)習(xí)效果，最終提高英語的學(xué)習(xí)能力。

The benefit of targeted PRP to areas of nonperfusion in a patient with DME is questionable. We believe that the retinal lesions that develop after PRP increase the VEGF expression, induce breakdown of the blood-retina barriers,produce destruction of normal retinal tissue, and hard exudates formation, especially in patients with high serum lipid.Laser may reduce the BCVA gains that are achieved with IVC monotherapy and causes visual field defects. The preexisting DME prior to PRP results in overburdened retinal pigment epithelium (RPE; creeping atrophy), so that PRP could aggravate DME. We favour long-term antiangiogenic treatment and add PRP only in patients with intraocular neovascularization unless this complication subsides after medical treatment.

Patients were excluded if they had intravitreal injection of corticosteroids, such as triamcinolone acetonide (Kenalog;Bayer-Bristol), within 3mo prior to the treatment or intravitreal injection of other anti-vascular endothelial growth factor(VEGF) drugs, such as bevacizumab (Avastin; Genentech,Inc., San Francisco, CA, USA) or ranibizumab (Lucentis;Genentech, Inc.), within 2mo prior to the treatment. Nothing was stated about 91.7% of patients (=33) who had previous PRP, how and when this therapy had been applied, its duration,and if a washout period existed between PRP therapy and Conbercept administration, which is essential among 2 periods of treatment in terms of aliased effects. In the absence of such a period the impact of the significant carryover effects of the PRP on previously presented patients may be confounded with direct treatment effect of Conbercept in the sense that these effects could not be estimated separately; carryover effects may bias the interpretation of data analysis.

In the assessment of the final outcomes of this study we considered the current assertionthat evaluation of outcomes should be guided by the anatomical measure data with visual changes as a secondary guide. Despite significant visual improvements in the BCVA after treatment (a mean gain of 11 letters from baseline), the structural outcomes of this study showed that 56.7% of patients had CRT＞250 μm at month 24. The persistence of high values of the CRT after treatment highlights unresolved macular edema due to insufficient macular deturgescence and indicates that the disease process is still active and progressive requiring further treatment with antiangiogenic agents. We hypothesized that a whole panoply of proinflammatory and proangiogenic cytokines, chemokines,and growth factors may be associated with the multifactorial pathophysiology of the DME. They are maximally expressed in the ischemic lesions of the long-standing DME (11.4mo duration of DME) and exacerbate the deterioration primarily caused by VEGF in the initially damaged macular ganglion cell complex.

3) Presence of disorganization of the retinal inner layers and grading of its severity (mild, severe, and severe with damaged EZ); 4) Presence and number of hyperreflective intraretinal foci; 5) Presence of subretinal fluid with serous neuroretinal detachment; 6) Patterns of vitreoretinal interface abnormalities(epiretinal membranes, vitreomacular adhesion/traction, fullthickness macular hole, lamellar macular hole, and combined epiretinal membranes and vitreomacular traction).

Altogether, the authors of this study found that Conbercept significantly improves vision, prevents severe vision loss, and rapidly reduces macular edema. The treatment efficacy was maintained for 24mo. However, the validation, extrapolation,and generalizability of these findings concerning the efficiency of Conbercept treatment and its advantages over other anti-VEGF treatments can only be made by statistical analyses including all the missing baseline potential predictive factors referred to above by us in addition to the baseline characteristics already evaluated in this study, serving to emphasize the key metrics assessing the anatomical and functional benefits of conbercept therapy in DME patients.

All authors were involved in design and conduct of the study;collection, management, analysis and interpretation of the data;and preparation, review or approval of the manuscript.

None;None.