Assessment of Retinal Pigment Epithelium Alterations and Chorioretinal Vascular Network Analyses in Patients under Treatment with BRAF/MEK Inhibitor for Different Malignancies: A Pilot Study.

In the last two decades, an increasing number of so-called molecular-targeted therapies have become available for the treatment of patients with advanced malignancies. These drugs have included inhibitors of proteins in the MAPK pathway, such as BRAF and MEK inhibitors, which are characterized by a distinct toxicity profile. The eye is particularly susceptible to adverse effects due to MEK inhibitors, and the term MEKAR (MEK-inhibitor-associated retinopathy) indicates the presence of subretinal fluid, mimicking central serous chorioretinopathy (CSC). The pathogenesis of the retinal alterations related to MAPK pathway inhibitors is still unclear, and questions are still open. The present study aims to assess the presence of retinal pigment epithelium alterations as predictive parameters for retinal toxicity, analyzing, at the same time, the chorioretinal vascular network in patients undergoing BRAF/MEK inhibitor treatment for different malignancies.

A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors.

Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

Choroidal and Choriocapillaris Morphology in Pan-FGFR Inhibitor-Associated Retinopathy: A Case Report.

Emerging anticancer agents such as the pan-FGFR Inhibitor have achieved remarkable improvements in the survival of patients with metastatic malignancies. Nevertheless they are still associated with specific ophthalmic toxicities. Understanding their pathophysiology can lead us to better clinical practice of life-threatening and vision-threatening circumstances. To investigate choroidal alterations as a potential pathophysiological mechanism of a serous detachment in bilateral pan-FGFR Inhibitor-Associated Retinopathy (FGFRAR), the morphology of the choroid and choriocapillaris were assessed. The choroidal thickness (ChT) and choriocapillaris flow void were measured by macular optical coherence tomography (OCT) and angiography (OCT-A), respectively. Data were collected at the baseline, then at one-month and two-months follow-ups after starting erdafitinib, in a single case of pulmonary angiosarcoma. Choroidal and choriocapillaris morphology showed stable ChT and choriocapillaris flow void at FGFRAR onset and relapse. To the best of our knowledge, this is the first analyzed case reported with flow-void OCT-angiography. Considering these results, FGFRAR in this patient does not seem to match the pachychoroid spectrum disorder definition; rather, an intracellular mechanism based on intracellular transduction pathways may be at work.

Non-arteritic anterior ischaemic optic neuropathy sequential to SARS-CoV-2 virus pneumonia: preventable by endothelial protection?

We present a case of non-arteritic anterior ischaemic optic neuropathy (NAION) with no ocular or systemic risk factors in a patient who recovered from a recent SARS-CoV-2 pneumonia. NAION is the most common acute optic neuropathy among individuals over 50 years of age. It results from a transient hypoperfusion of the optic nerve head circulation, especially in patients with low vascular compliance due to ocular or systemic risk factors. We attribute the ophthalmological condition to a SARS-CoV-2 virus-associated endotheliopathy that can be prevented with timely protection of endothelial function with vitamins D and K2.

Acute exudative polymorphous vitelliform maculopathy during pembrolizumab treatment for metastatic melanoma: a case report.

BACKGROUND: The use of immunomodulating therapy to treat various cancers has been on the rise and these immune checkpoint inhibitors are known to cause ocular side effects. In this article a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) is reported which developed during a first line treatment with pembrolizumab. CASE PRESENTATION: A 54-year-old woman was referred because of blurry vision in both eyes with a yellow spot in the central visual field of the left eye. These symptoms started after four treatments with pembrolizumab (a monoclonal antibody against the programmed cell death receptor-1) for a metastatic recurrent vaginal mucosal melanoma. Her best corrected visual acuity was 10/10 in both eyes with a correction of + 2.00 bilaterally. There were no inflammatory findings in the anterior segment or the vitreous. Fundoscopy revealed an attenuation of the foveal reflex with subtle yellow-white subretinal macular deposits (vitelliform lesions) in both eyes. Fluorescein angiography did not show staining or leakage in the mid-phase, neither a late staining. Spectral-domain optical coherence tomography of the macula illustrated bilateral neurosensory retinal detachment with a thick, highly reflective band at the outer photoreceptor segment. En face structural OCT at the level of the photoreceptors showed focal areas of increased signal corresponding to hyperreflective vitelliform material. The treatment with pembrolizumab was ceased immediately. During the following visits we slowly saw an improvement of the neurosensory retinal detachment. After almost four months a total resolution of the subretinal fluid was visualized in both eyes without the use of additional treatment, though the vitelliform deposits persisted. CONCLUSIONS: The development of AEPVM in melanoma patients could be triggered by treatment with Pembrolizumab. Pembrolizumab has the potential to disturb indirectly the retinal pigment epithelium homeostasis with accumulation of lipofuscin deposits and subretinal fluid, both signs of AEPVM.

A Phase 2 Clinical Trial of Trametinib and Low-Dose Dabrafenib in Patients with Advanced Pretreated NRASQ61R/K/L Mutant Melanoma (TraMel-WT).

BACKGROUND: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. METHODS: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. RESULTS: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. CONCLUSIONS: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.

Choriocapillaris Assessment In Patients Under Mek-Inhibitor Therapy For Cutaneous Melanoma: An Optical Coherence Tomography Angiography Study.

PURPOSE: The present study investigates by optical coherence tomography angiography (OCTA) the retinal capillary plexus and choriocapillaris flow voids and their possible correlation with MEKAR. METHODS: 34 eyes of 17 patients (61.5 years [30.4-77.4]) with stage IV cutaneous melanoma were included prospectively. All patients showed disease progression under treatment with Nivolumab/Ipilimumab and were subsequently treated with the MEK-inhibitor Trametinib 2 mg once daily. At the start and every 6 weeks during follow-up of 4 months, patients underwent a complete ophthalmologic exam, OCTA and when needed fluorescein angiography. RESULTS: Statistical analysis was performed on 17 eyes of 9 patients. Eight patients were excluded due to missing OCTA images or due to drop-out because of decease or change of treatment. Comparing vessel area density (P = .625 and 0.681, respectively), vessel skeleton density (P = .996 and 0.766, respectively) of the superficial and deep capillary plexus, flow void number and total flow void area (mm2 and %) (P = .495; 0.197 and 0.298, respectively) of choriocapillaris slab, before and after treatment, revealed no significant difference. The evolution of choriocapillaris flow void parameter did not significantly differ in patients, who developed MEKAR compared to patients who did not. CONCLUSION: In patients receiving MEK-inhibitor with and without MEKAR, no significant different characteristics of the retinal capillary plexus and choriocapillaris were found. These data suggest that the development of MEKAR, has no correlation with vascular alteration.

A randomized trial of intravitreal bevacizumab vs. ranibizumab for myopic CNV.

AIMS: The aim was to compare the efficacy of intravitreal therapy with bevacizumab and ranibizumab for choroidal neovascularization (CNV) in pathologic myopia (PM). METHODS: This was a prospective multicenter randomized nonblinded trial. RESULTS: In seven centers, 78 eyes were randomized 1:1 to treatment with bevacizumab (group B, 40 eyes) or ranibizumab (group R, 38 eyes) given with an "on demand" regimen (PRN). The mean follow-up was 19 months (SD 2, range 12-24). The mean BCVA at baseline was 0.60 logMAR (20/80 Snellen equivalent, Seq) and 50 letter score (ls). Mean final BCVA was 0.51 LogMAR (20/63 Seq) and 57 ls (p = 0.0009 and p = 0.0002, respectively). In group B, mean basal BCVA was 0.52 logMAR (20/63 Seq) and 54 ls, and final BCVA was 0.51 logMar (20/63 Seq) and 57 ls. In group R, mean basal BCVA was 0.62 logMAR (20/80 Seq) and 45 ls, and the final values were 0.50 logMAR (20/63 Seq) and 58 ls. Statistical comparison of the two groups showed no significant difference (logMAR p = 0.90 and letters p = 0.78). Multivariate analysis showed no influence of age or previous photodynamic treatment (PDT) on final visual changes. The mean number of treatments in the first year was 2.7 in group B and 2.3 in group R (p = 0.09). CONCLUSION: Myopic CNV equally benefits from on-demand intravitreal injection of either bevacizumab or ranibizumab; the therapeutic effect is independent of previous PDT and age.

Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study.

AIM: To assess the efficacy and safety of ranibizumab in the treatment of choroidal neovascularisation (CNV) caused by pathologic myopia (PM). DESIGN: Prospective, multicentre, interventional case series. METHODS: 40 eyes of 39 consecutive patients with PM and CNV were treated with 'on demand' intravitreal injection of ranibizumab 0.5 mg. Final best corrected visual acuity (BCVA) and its change from baseline were the main outcome measures. Changes in optical coherence tomography (OCT) central retinal thickness (CRT) were a secondary outcome. RESULTS: Mean age was 53±13 years and mean refractive error -13.5±6.5 D. Median follow-up was 13.3±2 (range 12-18) months. Fifteen eyes (37.5%) had previously been treated with photodynamic therapy (PDT). The mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (Early Treatment Diabetic Retinopathy Study (ETDRS) vision chart) was 0.68±0.34 (Snellen equivalent 20/131) and 21±16 letters. The final mean logMAR BCVA was 0.27±0.2 (p = 0.008) (20/42) and 40.5±14 letters (p = 0.01). Mean final VA improved in 82.5% of patients, in 60% by 3 or more lines (median number of lines gained 2.9). Even six out of seven cases of low vision (≤1.1 logMAR) at the final examination has improved vision. Mean OCT CRT reduced from 218±70 to 175±46 µm (p 0.02). Age and previous PDT did not influence the results (p>0.05). The mean number of injection was 2.8±1.2 (range 1-6). No ocular or systemic side effects were observed. CONCLUSION: Ranibizumab was an effective treatment for stabilising and improving vision with a low number of injections in 92.5% of patients with myopic CNV in a long-term follow-up.

25-gauge macular surgery: results and complications.

PURPOSE: To report the safety and surgical outcome of 25-gauge transconjunctival sutureless vitrectomy for macular conditions. METHODS: In a single-center, retrospective, noncomparative case series, 160 eyes of 150 patients underwent 25-gauge vitrectomy for different macular conditions: 108 eyes for idiopathic macular pucker, 24 for idiopathic macular hole, and 28 for tractional diabetic macular edema. Main outcome measures were surgical time, preoperative and 1-day intraocular pressure (IOP), preoperative and 1-month, 3-month, and 6-month visual acuity, intraoperative and postoperative complications, anatomical results, and cataract progression. All patients were observed up for at least 6 months. RESULTS: Mean follow-up was 10 months (range, 6-20 months). Mean operative time +/- SD was 21 +/- 11 minutes. Mean 1-day IOP was 14 +/- 4 mmHg. No IOP was <8 mmHg on postoperative day 1. Mean overall preoperative visual acuity was 20/70, and mean overall postoperative visual acuity was 20/40 (P or=2 Snellen lines of visual acuity at 1 month; 74%, at 3 months; and 67%, at 6 months (P

Time course of changes in retinal thickness and visual acuity after intravitreal triamcinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment.

PURPOSE: To describe the changes in retinal thickness (RT) and visual acuity over time in patients with clinically significant diffuse diabetic macular edema (DME) after intravitreal injection of triamcinolone acetonide (IVTA) and to compare patients with and without previous laser treatment. METHODS: A total of 23 eyes with clinically significant DME received a 4-mg IVTA injection. Twelve eyes were refractory to macular laser treatment (group 1), and 11 eyes received IVTA as primary therapy (group 2). Visual acuity and changes in macular thickening shown by optical coherence tomography were evaluated 48 hours after injection, every 7 days for 1 month, and at 3 months and 6 months of follow-up. RESULTS: RT decreased in all eyes in both groups. The reduction of edema was maximal in the first 7 days after IVTA and tended to remain stable for 3 months. The decrease in RT over time was significant in both groups (P < 0.001). At 6 months, RT had increased in almost all eyes. Visual acuity improved quickly, to a maximum at 2 weeks in both groups, after which it remained stable for 3 months and then decreased. Improvement in visual acuity over time was significant in both groups (P < 0.001). The temporal characteristics of the changes in RT and visual acuity were similar in the two groups (P < 0.05). CONCLUSIONS: IVTA was effective in reducing clinically significant DME and improving visual acuity in eyes with and without previous laser treatment. Its action was maximal in the first week and lasted approximately 3 months in this study.

Optical coherence tomography evaluation of macular edema after radial optic neurotomy in patients affected by central retinal vein occlusion.

PURPOSE: To evaluate the characteristics of macular edema (ME) before and after radial optic neurotomy (RON) detected by optical coherence tomography (OCT), in patients with central retinal vein occlusion (CRVO). DESIGN: Interventional case series. METHODS: Five eyes of 5 patients affected by CRVO underwent RON. Complete ocular examination including best corrected snellen visual acuity (VA), fluorescein angiography (FA) and OCT were performed before RON and at 1, 3 and 6 months of follow-up. RESULTS: The OCT characteristics of macular edema are similar in all the eyes affected by CRVO. Mean retinal thickness (RT) before RON was 858 microns, mean VA was 20/640. By FA 3 eyes were evaluated as being perfused and 2 as indeterminate. No complications occurred during and after surgery. At 6 months of follow-up the RT decreased in all the patients (100%) with a mean value of 289 microns. The VA increased in 3 patients and remained stable in 2. CONCLUSIONS: OCT demonstrated resolution of the macular edema in all the eyes. This resolution is not always accompanied with an improvement in VA. Further studies are needed to better understand the efficacy of this procedure.