What can we learn from negative results in clinical trials for proliferative vitreoretinopathy?

INTRODUCTION

Since the beginning of vitreoretinal surgery proliferative vitreoretinopathy (PVR) has been a constant complication.PVR is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD) resulting in multiple reoperations and vision loss. So far, there is no proven therapy to treat or prevent PVR. The incidence of PVR is estimated to be between 5% and 10% of all RRD repairs and generally occurs within 8wk of surgery. It often is difficult to predict which patients may develop PVR. A retinal break is a prerequisite for the development and almost all clinical risk factors for PVR are associated either with intravitreal dispersion of retinal pigment epithelial (RPE) cells or the breakdown of the blood-retinal barrier (BRB). Certain risk factors make the development of PVR more likely, such as the presence of intraocular hemorrhage, uveitis, preoperative or postoperative choroidal detachment, size of retinal tears,multiple retinal tears, chronic retinal detachments, and multiple previous surgeries or trauma

. Current strategies for PVR prevention are equally focused on timely and successful repair of RRD. The goal of surgical repair is to relieve traction and reattach the retina. To date, surgery remains the only management of PVR. In our current understanding PVR is a cellular reaction molded by many cytokines leading to fibrosis and scarring and redetachment and vision loss. Suitable pharmacological adjuncts moderate inflammation and cellular proliferation, thereby lessening PVR formation. The following trials tried to address the problem.

Daunomycin Trial (1998)

The 286 patients/eyes with advanced preoperative PVR in which surgery with silicone oil was planned were recruited in a prospective, randomized,controlled multicenter European clinical trial to assess the efficacy and safety of adjunctive daunorubicin during vitrectomy surgery in eyes with PVR (Grade C or higher).Standardized surgery alone (control) was compared with surgery plus adjunctive daunorubicin perfusion (study treatment). Outcomes appraised were retinal attachment without additional vitreoretinal surgery 6mo after standardized surgery, number of and time of vitreoretinal reoperations,and change in visual acuity. Six months after standardized surgery, complete retinal reattachment without additional vitreoretinal surgery was achieved in 62.7% (89/142) of eyes in the treatment group

54.1% (73/135) in the control group(

=0.07, one-sided). Although anatomic success rate after 6mo failed to show significance, some benefit of adjunctive daunomycin treatment exists, especially a tendency toward increased rates of reattachment and a significant reduction in the number of reoperations. No severe adverse effect related to daunorubicin was seen.

Ozurdex Slow-Release Dexamethasone Trial (2017)

To test the hypothesis that adjunctive slow-release dexamethasone implant (Ozurdex; Allergan Inc, Irvine, CA, USA) can improve the outcomes of surgery for established PVR a single center, prospective, masked randomized controlled clinical trial (EudraCT No.2011-004498-96) was performed.

A total of 140 patients requiring vitrectomy with silicone oil for retinal detachment with established PVR (Grade C) were randomized to standard (control) or study treatment (adjunct).Intraoperatively, the adjunct group received an injection of 0.7 mg of slow-release dexamethasone (Ozurdex) at the time of 1) vitrectomy surgery and 2) silicone oil removal. The control group received standard care.

Primary endpoint was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6mo. Secondary outcomes included 1) final visual acuity; 2) cystoid macular edema (CME), foveal thickness, and macular volume; 3)development of overt PVR recurrence; 4) complete and posterior retinal reattachment; 5) tractional retinal detachment;6) hypotony/increased intraocular pressure (IOP); 7) macula pucker/epiretinal membrane; 8) cataract; and 9) quality of life.Anatomic success between the 2 groups was similar (49.3%

46.3%, adjunct

control). Secondary anatomic outcomes(vision, complete/posterior reattachment rates and PVR recurrence) were comparable between the 2 groups. At 6mo,fewer dexamethasone patients had CME (42.7%) or an increased foveal thickness (47.6%) compared with controls(67.2% and 67.7%, respectively).

A slow-release dexamethasone implant did therefore not improve the anatomic success rate in eyes undergoing vitrectomy surgery with silicone oil for PVR.

Larger study might have had the statistical power to detect a smaller benefit. However, a too small benefit may not be clinically relevant. Some benefit of the adjunctive treatment for existing PVR exists, however: 1) a tendency toward increased rate of reattachment and a significant reduction in the number of reoperations for daunomycin and a greater reduction in CME for dexamethasone. 2) None of the treatments had major side effects, tolerable ocular concentrations can be determined.

知識(shí)經(jīng)濟(jì)和生態(tài)經(jīng)濟(jì)是不可截然分開的，它們代表未來社會(huì)經(jīng)濟(jì)發(fā)展的兩個(gè)趨勢(shì)，就像汽車的兩個(gè)輪子一樣，缺一不可。知識(shí)經(jīng)濟(jì)實(shí)際上也包含著生態(tài)經(jīng)濟(jì)，這是因?yàn)樯鷳B(tài)經(jīng)濟(jì)首先必須建立在知識(shí)的廣泛運(yùn)用和轉(zhuǎn)化的基礎(chǔ)上，建立在高科技的掌握和運(yùn)用的基礎(chǔ)上。與此同時(shí)，生態(tài)經(jīng)濟(jì)又為知識(shí)經(jīng)濟(jì)提供方向保證，只有把知識(shí)經(jīng)濟(jì)納入生態(tài)經(jīng)濟(jì)的軌道，只有在生態(tài)經(jīng)濟(jì)的規(guī)律和原則指導(dǎo)下，才能保證經(jīng)濟(jì)社會(huì)的可持續(xù)發(fā)展。換句話說，知識(shí)的運(yùn)用和轉(zhuǎn)化，科學(xué)技術(shù)的運(yùn)用和轉(zhuǎn)化，只有嚴(yán)格按照生態(tài)化的運(yùn)行模式，才能保證生態(tài)、經(jīng)濟(jì)、社會(huì)沿著可持續(xù)發(fā)展的方向進(jìn)行。

在采用高壓水力沖刷清淤時(shí)必須根據(jù)現(xiàn)場(chǎng)實(shí)際情況（管徑、淤積程度和管渠形狀等），選擇合適的噴頭、沖洗壓力(70～140 Bar)和沖洗流速。若沉積物特別密實(shí)，則需要采用銑床鉆頭進(jìn)行清理（見圖1）。

A total of 325 subjects in 13 German trial sites had been randomized (Verum:

=163; placebo:

=162). There was no significant difference in PVR rate (Verum: 28%

placebo:23%). None of the secondary endpoints showed a significant difference between treatment groups. No relevant safety risks were observed.

GUARD (Gain Understanding Against Retinal Detachment)Trial Methotrexate (2023)

The rationale for use of intravitreal methotrexate for treatment of PVR is based on its property to suppress inflammation and inhibit cellular replication, both of which are key factors in the pathogenesis of PVR. In December 2019, enrollment began in the GUARD trial, a two-part multicenter, randomized, controlled, adaptive phase 3 clinical trial in the United States investigating the efficacy of ADX-2191 (intravitreal methotrexate 0.8%,Aldeyra Therapeutics) for the prevention of PVR-associated retinal redetachment. Only PVR eyes that achieve successful retinal reattachment are randomized into the GUARD trial,with a ratio of 1:1 intraoperatively between methotrexate or control, which is standard surgery. ADX-2191 has received orphan drug designation from the US FDA. Because the PVR life cycle lasts for several weeks, the GUARD trial involves serial injections of intravitreal methotrexate throughout the entire risk period rather than as a single injection at the time of surgery. Results from part 1 of the GUARD trial is expected in the second half of 2022.

Timely diagnosis, a thoughtful surgical approach and careful postoperative management are key to successful retinal reattachment and vision preservation. Despite all the refinement and improved efficacy and safety of modern-day vitreoretinal surgery this complication still eludes us and only modest progress in the treatment of PVR has been achieved.The most important step forward was the capacity to remove quite completely the vitreous, not done and not possible at the time of the daunomycin trial.

1928年10月28日，印尼第二屆全國(guó)青年大會(huì)的“青年誓言”第3條開始提及印尼語的地位：“我們印尼兒女，尊重統(tǒng)一的語言，印尼語”。這條誓言把印尼語視作團(tuán)結(jié)各民族的語言，明確了印尼語國(guó)民語言的地位。1945年8月17日印尼獨(dú)立后，1945年憲法第15章第36條的規(guī)定將印尼語從國(guó)民語言提升至官方語言的地位。1950年臨時(shí)憲法再次規(guī)定印尼語是印尼共和國(guó)的官方語言。綜上所述，印尼語具有這樣的法律地位：既是國(guó)語(National Language)又是行政語言(Official Language)。

The primary outcome was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) within 12wk after surgery.Secondary endpoints included re-detachment rate and bestcorrected visual acuity.

What can we learn from the negative results of the above trials?

I believe there are three points:

2) The Daunomycin and Dexamethasone study treated established PVR by a single infusion during surgery or onetime repeated injection (slow release), the Privent trial tried prevention with a single perfusion. The Guard trial intends to prevent recurrence of PVR with serial injections. This may be a better approach to effectively prevent recurrent PVR.Repeated injections are no problem today but were not even thought of 30 years ago.

In the preventive PRIVENT trial the rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD considered at high PVR risk.

在九頭山漢墓中，出土了40多枚漢武帝和漢宣帝五銖錢，同時(shí)還出土了琉璃飾品，據(jù)考證可能來自東南亞或印度東海岸，從合浦登陸，經(jīng)南流江、北流江西上柳江進(jìn)口?！?br>