A study using this method found that contrast sensitivity function measured in both standard and low luminance conditions decreased with increasing severity of dry AMD and was better in normal controls compared with the dry AMD subgroup representing the earliest stage of disease.



AMD, DED most common retinal conditions in the United States

“AMD is a leading cause of vision loss in the elderly, although visual acuity tends to be spared until late in the disease course,” said William C. Ou, a researcher at the Retina Foundation of the Southwest in Dallas, Texas. “However, patients with earlier stage AMD often have visual complaints, especially under low luminance conditions. Thus, there is a need to identify alternative measures of visual dysfunction that may better reflect the true degree of visual impairment.”

According to Ou, the study suggests that the tool investigators evaluated may be useful as a supplemental visual function measure in patients with AMD.

Although contrast sensitivity has been considered a more sensitive indicator of visual dysfunction in early AMD compared with visual acuity, measuring contrast sensitivity with traditional methods is difficult outside research settings. 

The method investigated in the present study uses an active learning approach to estimate a model of the contrast sensitivity function’s global shape. 

The algorithm, known as the quick contrast sensitivity function (qCSF), measures the full spatial contrast sensitivity function in just 5 to 10 minutes, which makes it practical for use in clinical settings.



For the testing, patients are asked to identify 25 consecutive optotype triplets varying in size and contrast. The software generates contrast sensitivities at individual spatial frequencies. 

Testing for the study was done under standard photopic conditions and then repeated at low luminance created using a 2.0 log neutral density filter.

A total of 65 patients with dry AMD and 23 age-matched controls participated in the study. Those with AMD had disease in at least 1 eye and a visual acuity of 20/80 or better. To investigate correlations between AMD severity and contrast sensitivity, the patients with dry AMD were divided into 3 subgroups defined based on the presence of soft drusen only (ie, intermediate AMD, n = 26), subretinal drusenoid deposits (n = 19), and geographic atrophy (n = 20).

A plot of the qCSF data from testing at standard photopic luminance showed decreasing function with increasing AMD severity across all spatial frequencies. Losses in contrast sensitivity were greatest at low to intermediate spatial frequencies (3 and 6 cycles per degree, equivalent to Snellen sizes of 20/200 and 20/100).



Vision-related quality of life: Impacts of advanced AMD

“Our finding that the group with subretinal drusenoid deposits fell in between the intermediate AMD and geographic atrophy groups is consistent with previous studies that indicated patients with subretinal drusenoid deposits appear to be phenotypically distinct from patients with soft drusen alone,” Ou said.

The results from testing under low luminance conditions were similar, although some significant floor effects were seen at the highest spatial frequencies.

To allow for a statistical analysis of the results, the investigators calculated the area under the log CSF (AULCSF). The AULCSF gives a single value for each contrast sensitivity function.

Qualitatively, the data showed that the AULCSF decreased with increasing AMD severity under both standard photopic and low luminance conditions. 

Pairwise comparisons between the AMD severity groups showed statistically significant differences for most but not all comparisons.

William C. Ou presented this research at the 2020 Association for Research in Vision and Ophthalmology virtual annual meeting. He has no financial interests to disclose.

Articles

Using active learning approach can help gauge visual function loss in patients

Platform for measuring contrast sensitivity shows potential for AMD


The visual outcomes of the SMILE Xtra (Carl Zeiss Meditec) study of small-incision lenticule extraction with accelerated corneal cross-linking were comparable from 1 week to 2 years postoperatively, as were the safety, stability, and predictability—important findings for patients at moderate risk of ectasia.

The study was undertaken to evaluate the long-term effects of the procedure in patients who had abnormal topography, low residual stromal bed thickness, higher refractive errors, and thin preoperative corneal thickness, according to Sung Min Kim, MD, from the NUNEMISO Eye Center in Seoul, South Korea. In addition, investigators wanted to determine the safety and clinical effect of the Xtra energy protocol in various patient subgroups.



Is the time right for corneal crosslinking?

The study included patients who underwent the SMILE Xtra treatment from March 2016 to February 2017 and had been followed for 2 years postoperatively.

The Xtra protocol included soaking with a 0.25% riboflavin solution for 90 seconds, followed by ultraviolet A light exposure at 30 mW/cm

 for 60 seconds. This approach provided 1.8 J/cm2 of total energy, Kim said.

The inclusion criterion for the SMILE Xtra candidates was moderate-risk patients determined based on the Randleman Ectasia Score System. 

The patients were divided into 4 subgroups based on their characteristics: abnormal topography, low residual stromal bed thickness under 300 μm, high refractive errors exceeding -9.5 D or lenticule thickness exceeding 130 μm, or a thin preoperative central corneal thickness under 510 μm.

Patients were excluded if they were under 18 years old, had keratoconus or suspected they had keratoconus, had a central corneal thickness under 480 μm, had a residual stromal bed under 290 μm, had been lost to follow-up, or had undergone a reoperation.



Estimating the total power in keratoconus patients

Included were 130 eyes of 65 patients (mean age, 26.4 years). The mean preoperative sphere was -6.22 D, and the mean cylinder was -1.59 D.

“The efficacy index for the SMILE Xtra treatment was 1.13, which was comparable to that of the patients who underwent the SMILE procedure in the same clinic. Only 61% of patients achieved a visual acuity of 1.08 1 day after the procedure, but at 2 years that increased to 1.08 or better in 95% of patients,” Kim explained.

Kim noted that when the SMILE Xtra procedure was compared with the SMILE procedure, the vision on the first day postoperatively was significantly lower in the Xtra group; however, from the 1-week time point out to 2 years, the results of the 2 procedures were comparable.

The safety, stability, and predictability of the Xtra procedure were all good. The safety index was 1.16. Only 1 line of vision was lost at 2 years among all the study patients. 

Two eyes were enhanced with PRK at 1 year; these eyes were excluded from the study. 

Finally, at the final visit at 2 years, 97.7% were within ± 0.05 D of the targeted refraction.


ASCRS 2020: Corneal CXL outcomes in children with progressive keratoconus

The analysis of the 4 subgroups did not find any significant differences in the visual recovery and refractive change over the 2 year course of study. 

The patients in the group characterized by a high refractive error tended toward slight regression and lower vision at the final evaluation compared with the other 3 groups. However, the differences were not significant.

The differences in the endothelial cell counts from preoperatively to postoperatively were not significant in the entire study cohort or among the subgroups.

“The Xtra corneal crosslinking did not result in significant endothelial cell loss over the long term,” Kim said.



CXL imperative in treatment of pediatric keratoconus

The investigators concluded that with the exception of the early postoperative period, the SMILE Xtra treatment demonstrated comparable visual outcomes from 1 week to 2 years. The safety, stability, and predictability also were stable. 

Finally, the characteristics of the subgroups did not affect the clinical outcomes after SMILE Xtra.

“SMILE, in combination with the 1.8 J/cm

 Xtra protocol, seems to be an effective, safe, and predictable treatment strategy in patients who are at moderate risk,” Kim concluded.


Researchers evaluate effects of procedure on patients with abnormal topography

Study: Patients at moderate risk of ectasia stable 2 years after treatment


This article was reviewed by Sophia El Hamichi, MD

Retinoblastoma (RB) is the most frequently seen intraocular cancer in children, a complication of which is retinal detachment (RD). 

While the main focus of treatment is curing the cancer and preserving the eye, the visual function is important to the patient’s quality of life.

These cases are not without potential hurdles. The RDs can prove to be complex problems that are persistent, and therein lies the challenge to ophthalmologists, according to Sophia El Hamichi, MD, from Murray Ocular Oncology and Retina in Miami, Florida.


Retinal pathologies challenging to image with current technologies


El Hamichi and her colleagues conducted a retrospective study in which they reviewed and described persistent RDs in eyes with RBs, the etiologies, treatment attempts, and outcomes in this patient population between June 2012 and December 2019.

A review of the medical records identified 62 patients with RB during the study period. Persistence of RDs was defined as the presence of subretinal fluid after the patients had been treated for RB and achieved complete tumor regression. 

Of these patients, a RD developed in 42 (67%), of which 35 resolved successfully. 

The other 7 patients (5 boys, 2 girls) had a persistent RD; in these patients, the RB was bilateral in 3 patients and unilateral in 4. 

In all patients, the RB and RD presented simultaneously during the first ophthalmologic assessment. The mean age at diagnosis of RB was 11 months (range, 2 days-24 months). 


NR600 retinal prosthesis: Safe with promising visual results​ 

​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 

The ages at diagnosis of RD ranged from 2 days to 24 months. All eyes had an advanced stage of RB, ie, state 5B in 8 eyes and stage 4 in 2 eyes.

Intraarterial chemotherapy was applied in 6 eyes of 5 patients and systemic chemotherapy in 3 patients; 1 patient was treated with intraarterial chemotherapy bilaterally and systemic chemotherapy. One patient underwent external beam radiation therapy and a periocular injection of carboplatin. Cryotherapy and intravitreal chemotherapy were not used on any patients.

The RDs were complex in all eyes. In 9 eyes, the detachment had exudative and tractional components. One eye had a pure tractional RD as the result of persistent fetal vasculature. The RDs were not repaired surgically in any eyes, El Hamichi said.

Following treatment, the tumors did not recur in any eyes. The eyes were anatomically stable. One patient had a globe phthisis in 1 eye, and another patient had a globe pre-phthisis; both patients had bilateral RBs and bilateral retinal detachments with poor visual outcomes.



Micropulse laser therapy a safe treatment for retinal disorders


In RB, exudative, rhegmatogenous, and tractional RDs can develop. The exudative type tends to occur when an exophytic RB is present subretinally and generally is associated with subretinal tumor seeding.

In these cases, when the tumor responses to chemotherapy, the RD was reported to resolve spontaneously.

Another study found that the first round of chemotherapy caused exudative RDs when eyes did not receive focal consolidation treatment, possibly because of excessive inflammation from chemoreduction or rapid tumor reduction.

Intra-arterial chemotherapy resolves 43% of total RDs and all partial RDs associated with RB.3 Exudative RDs have developed after intra-arterial chemotherapy that never resolved despite tumor regression.

Rhegmatogenous RDs probably develop as the result of focal retinal necrosis and retinal breaks that resulted from cryotherapy applied to the tumor area. The area around the tumor usually has an exudative RD present. 



Harnessing regeneration of retinal tissues: An option almost within reach



Another theory about rhegmatogenous RDs is that focal inflammation increases in response to cryotherapy in eyes with inflammation because of the tumor. 

Traction and breaks in weakened retinal zones result. These patients, most of whom undergo chemoreduction, are more susceptible to complications.

Some rhegmatogenous RDs have developed after intraarterial chemotherapy as a result of rapid tumor regression that leaves an atrophic retinal hole. Rhegmatogenous RDs seem to occur mostly in eyes with advanced disease with extensive endophytic tumors.



Intravitreally injected hRPCs improve vision in retinitis pigmentosa cases


The caveat in these eyes is that surgery in the presence of active RB carries a high risk of tumor metastasis.

Pars plana vitrectomy can be an option in cases of RD of more than 1 mechanism in an attempt to restore the retinal anatomy and possibly vision. 

However, the investigators pointed out that the risk of tumor dissemination outweighs the benefit of repairing the RD. 

The investigators recommended that surgery not be performed until 2 years after the patient underwent their last treatment for RB. If the RB is not controlled, enucleation is mandatory.

Based on the study findings, the investigators concluded, “the development of RD can be challenging in cases of RB, especially when it has a complex configuration leading to persistence of the RD. These RDs are difficult to treat, and the visual outcomes can be compromised. Vitrectomy should not be performed until the patient is free of RB for 2 years to avoid spreading the tumor and metastatic disease. This waiting period affects the surgical results and even calls into question its necessity.” 



El Hamichi has no financial interest in this subject matter.

1. Shields JA, Shields CL. Management of retinoblastoma. In: Shields JA, Shields CL, eds. 

Intraocular Tumors: An Atlas and Textbook.

 Lippincott Williams Wilkins; 2008:334-351.

2. Elaraoud I, Ch’ng S, Karl D, Kalogeropoulos D, Chavan R, Sharma A. Management of retinal detachment in retinoblastoma with globe conserving treatment. 

. 2018;31(1):43-48. doi:10.1016/j.joco.2018.09.002

3. Shields CL, Kaliki S, Shah SU, Bianciotto CG, Jabbour P, Shields JA. Effect of intraarterial chemotherapy on retinoblastoma-induced retinal detachment. 

. 2012;32(4):799-804. doi:10.1097/IAE.0b013e31823d8e1e

Watchful waiting may prove to be beneficial in complicated cases

Persistent retinal detachment connected to retinoblastoma


This article was reviewed by Aaron Y. Lee, MD, MSCI



Artificial intelligence (AI) screening systems of 

 are not all created equal, and as a result, their performances differ.

Researchers compared several AI screening systems using the US Department of Veterans Affairs (VA) screening program. The results highlight the need for independent validation studies before clinical use, according to Aaron Y. Lee, MD, MSCI, from the University of Washington in Seattle.



Artificial intelligence: The good, the bad, and the scary


Initially, 23 companies were invited to participated in the masked study. Several agreed to participate and contributed AI models: ADCIS (Advanced Concepts in Imaging Software), Airdoc, Eyenuk, Retina-AI Health, and Retmarker.

The investigators extracted data from the VA teleretinal screening program for VA Puget Sound in Seattle and the Atlanta VA Health Care System in Georgia, including the images and the original VA teleretinal grades. 

This created a data set of 311,604 images from 23,724 patients with diabetes for the full data set and a subset of about 7000 images that was set aside for arbitration. All the patients had type 2 diabetes and no previous diagnoses of the disease. 

The 7 algorithms were run, and the output indicated whether the patients should be referred. The performances were then compared with the VA teleretinal grades. 

In the subset used for arbitration, 2 ophthalmologists graded the images independently and a retinal specialist performed masked arbitration, according to Lee.



 Teaching AI algorithms to identify corneal pathology: The future is now

A few baseline differences were seen between the Atlanta and Seattle groups. Investigators found a 10-fold difference in the proliferative DR (PDR) rate between the 2 locations. 

In Atlanta, dilatation is a routine practice, but, Lee noted, that is not the case in Seattle. This resulted in a large discrepancy in the rate of ungradable images between the 2 sites.

The algorithm output, he explained, was set for no DR versus the presence of any degree of DR because of the VA’s practice pattern.



Analysis of the full data sets from both sites showed an overall high negative predictive value and a low positive predictive value.

In the arbitrated data set, the VA teleretinal grader was compared directly with the AI models: Algorithm A had a significantly lower sensitivity but higher specificity, B had lower sensitivity and specificity, C and D had the same sensitivity but lower specificity, E and F had significantly higher sensitivity and lower specificity, and G could not be differentiated from the VA grader.

Lee explained what he considers to be the most important finding: the performance of the sensitivity of the various algorithms with different severities of retinopathy.



Blockchain technology aims to drive big data to 'train' AI

“The VA grader demonstrated 100% sensitivity for moderate and severe non-PDR [NPDR] and PDR. Algorithms E, F, and G were statistically similar to the VA grader for moderate NPDR or higher, and these algorithms were carried forward for future analysis,” he said.

The investigators simulated a 2-stage screening system to measure the amount of labor savings in a cost analysis if the 3 algorithms were implemented within the VA. The cost of an ophthalmologist reading the images would be about $15 per encounter.

A limitation of this study is that some analyses, including cost, are applicable to the VA setting.

According to Lee, the investigators found that dilation may be important to reduce the rate of ungradable images.

“The algorithms varied tremendously in performance despite having regulatory approval and/or having been clinically deployed somewhere,” he concluded. “It is important to understand that the AI models in the context of the underlying disease prevalence in order to understand the negative and positive predictive values. We believe that external, independent validation with real-world imaging is crucial before deployment, even after algorithms receive regulatory."
approval.”



Lee is a consultant to Genentech, Verana Health, and Topcon.

Dilation may be an important step to reduce the rate of ungradable images

AI algorithms: a work in progress

This article was reviewed by Russell N. Van Gelder, MD, PhD

Neuronal cell replacement therapies remain a challenge in retinal diseases. Some fish and salamanders have the innate ability to regenerate retinal tissue after injuries and, as Russell N. Van Gelder, MD, PhD, pointed out, if researchers could harness this ability in humans, the possibilities would be great for repairing or replacing damaged tissue in a wide variety of retinal diseases. Stem cells are the key to cell replacement therapies.

“Stem cells are cells that have not terminally differentiated and still have the potential to become many types of terminal cells,” said Van Gelder, from the Department of Ophthalmology at the University of Washington in Seattle. “We all started as embryonic stem cells in the earliest phases of development.”



Van Gelder went on to explain that there are now methods to create equivalently totipotent stem cells from individual induced progenitor stem cells derived from an individual’s blood or epithelial cells.

“The overarching goal is to create a cell type that needs replacement from a stem cell precursor,” he said.

A major achievement in this quest for regenerative ability occurred in 2014 when an entire eye cup was grown from progenitor stem cells.

Van Gelder also described a study1 in which green fluorescent protein–labeled retinal precursors derived from embryonic stem cells were transplanted into the subretinal space of macaques. Three months after the procedure, the researchers demonstrated that the bolus of cells persisted and had outgrowth of axons that were seen going to the optic nerve and on to the brain.

“This result establishes the validity of a stem cell-based approach for doing regenerative medicine in primates,” he said.



Persistent retinal detachment associated with retinoblastoma


As of now, however, no stem cell-based replacement treatment has received FDA approval. The problems preventing establishment of a treatment have been technical in nature and include correct cellular differentiation as well as generating adequate numbers of cells for large transplantation experiments, establishing correct cell polarity and connectivity, and ensuring the safety of these approaches regarding tumor or hamartoma formation, Van Gelder explained.

Managing inflammatory responses is a problem after cell transplantation. He cited a Japanese study2 of individual progenitor cell-derived retinal progenitor cells transplanted subretinally in monkey models.

“Even with an immune HLA-matched donor, there was still a marked inflammatory response at the site of the transplantation,” Van Gelder said. “This and other inflammatory responses will have to be managed for cell transplantation to be successful.”


There are regulatory hurdles to clear. The FDA Center for Biologics Evaluation and Research regulates cellular therapy products, human gene therapy products, and certain devices related to cell and gene therapy.

Van Gelder recalled the well-publicized case of transplantation of fat-derived mesenchymal cells into patients’ eyes, resulting in loss of vision bilaterally. He pointed out that it is important to temper patient expectations regarding these therapies and to ensure that the work is being done with the highest degree of ethical integrity.

“While great progress has been made in this field, significant barriers remain to the successful adoption in the clinical setting in the coming years,” Van Gelder concluded. “The barriers to cell replacement should be overcome.”


Van Gelder has no financial interests in this subject matter. He serves on the advisory committee for the National Eye Institute Audacious Goals Initiative.

1. Chao JR, Lamba DA, Kiesert TR, et al. Transl Vis Sci Technol. 2017;6:4; doi:10.1167/tvst/6/3/4

2. Fujii S, Sugita S, Futatsugi Y, et al. A strategy for personalized treatment of iPS-retinal immune rejections assessed in cynomolgus monkey models. Int J Mol Sci. 2020;21(9):3077. doi:10.3390/ijms21093077

This ability would unlock possibilities for repairing tissue damaged by disease



This article was reviewed by Charles Wykoff, MD, PhD

The results achieved with intravitreally injected gene therapy for neovascular 

 with ADVM-022 (Adverum Biotechnologies) indicate that the treatment is well tolerated and exhibited robust efficacy and durability in the patient population.

ADVM-022 may help solve the significant treatment burden associated with the treatment of neovascular AMD that includes frequent trips by patients to undergo intravitreal injections of various anti-vascular endothelial growth factor (VEGF) agents.

“Perhaps most important is the finding that the frequency needed to achieve optimal outcomes is often not realized in the real world,” noted Charles Wykoff, MD, PhD, who is in private practice in Houston, Texas.



Same-day exams with anti-VEGF therapy key to QoL, cost savings for wet AMD

This adeno-associated virus (AAV) gene therapy vector comprises an AAV7m8 capsid, a promoter to achieve protein expression, and a codon-optimized cDNA to drive aflibercept (Eylea, Regeneron Pharmaceuticals) that is delivered to the intravitreal space. 

Two preclinical studies have demonstrated the long-term protein expression in nonhuman primates that extended up to 21 and 30 months after 1 intravitreal injection.

Wykoff suggested that 1 solution to this undertreatment is the establishment of an intraocular biofactory that produces an anti-VEGF agent using gene therapy to deliver long-term efficacy, which is what ADVM-022 was designed to do.



Easing patient comfort, pain perception of intravitreal injections


Wykoff reported the updated 24-week results on behalf of the OPTIC investigators. OPTIC (NCT03748784) is a phase 1, 2-year multicenter dose-ranging study of ADVM-022 in neovascular AMD with the primary assessment of safety and tolerability of 1 intravitreal injection. 

Patients in cohorts 1 and 2 received oral steroid prophylaxis to prevent ocular inflammation and respective doses of ADVM-022 of 6 x 1011 vg/eye and 2 x 1011 vg/eye. 

Patients in cohorts 3 and 4 received a topical steroid for prophylaxis; cohorts 3 and 4 were treated with doses of ADVM-022 of 2 x 1011 vg/eye and 6 x 1011 vg/eye. Patients could receive rescue therapy, if needed.

The durations of the follow-up periods differed among cohorts: 6 patients in cohort 1 were followed for a median of 60 weeks, 6 patients in cohort 2 a median of 36 weeks, and cohort 3 a median of 20 weeks.

The current evaluation, which extended to April 1, 2020, showed no serious safety issues at 24 weeks. Low-grade inflammation associated with treatment was seen often and responded to topical steroids. The patients in cohort 3 had fewer adverse events compared with the others, he noted.



Taking a deeper dive: Novel gene therapy approaches to treat ocular disease

The inflammatory events in the 6 patients in cohorts 1 and 2 were low grade and responsive to oral steroids; 2 patients in both cohorts remained on topical steroids for extended periods. 

In cohort 3, treated with topical prophylaxis, 1 of the 6 patients continues steroid treatment at week 20; 3 patients were still taking the initial prophylactic steroid.

Regarding the best-corrected visual acuity (BCVA), the mean change in cohort 1 was -2.7 letters over a median of 60 weeks and the central subfield thickness (CST) decreased by 26.2 μm; no patients needed rescue therapy. 

In cohort 2, the mean BCVA change was -2.8 letters over 36 weeks and the CST improved by 40.8 μm; 2 of the 6 patients received rescue therapy. 

In cohort 3, the mean change in the BCVA was an increase of 6.8 letters over 20 weeks and the CST improved by 137.8 μm; 1 of the 5 patients who completed 20 weeks received rescue therapy.

Subjects in cohorts 1, 2, and 3 had been treated with frequent anti-VEGF injections before treatment with ADVM-022. Only 3 patients received rescue injections.



ASRS 2020: Trial shows faricimab blocks Ang-2 and VEGF-A

The study demonstrates that ADVM-022 is well tolerated and shows robust efficacy; the low-grade inflammation that develops frequently is responsive to steroid eye drops, and there is no need for oral baseline prophylaxis. It further shows that 1 office-based dose of ADVM-022 could reduce the anti-VEGF patient burden in neovascular AMD.

The ADVM-002 Infinity double-masked phase 2 study of recent-onset diabetic macular edema is underway with patients randomly assigned to 1 intravitreal injection of the treatment compared with 1 aflibercept injection. Patients’ conditions will be followed.

Wykoff reported performing research for and serving as a consultant to Adverum Biotechnologies.

Intravitreal gene therapy continues to be well tolerated and shows robust efficacy

Targeting AMD patient treatment burden



This article was reviewed by Justine S. Paradis, PhD



The results of a preclinical study indicate there is hope for an effective treatment for the GNAQ-driven metastatic uveal melanoma, an aggressive form of the disease.

The treatment relies on 2 components, the MEK inhibitor trametinib or the second generation RAF/MEK inhibitor VS-6766 (Verastem Oncology) combined with defactinib, a focal adhesion kinase (FAK) inhibitor (Verastem Oncology), that work better together than apart for controlling uveal melanoma.



Light-activated agent novel option for uveal melanoma 

The importance of this potential treatment is underscored by the fact that uveal melanoma is the most frequently occurring ocular cancer in adults, and it becomes metastatic in 50% of patients in whom it develops. The survival rate currently is 2 years, with only 8% surviving following metastasis to the liver.

“To date there is no effective treatment for metastatic uveal melanoma, and there is an urgent need to identify novel precision therapies for advanced and metastatic uveal melanoma patients,” according to Justine S. Paradis, PhD, a postdoctoral fellow at the Moores Cancer Center at the University of California San Diego.


Trametinib is an inhibitor of MEK kinase activity, and VS-6766 is a second-generation RAF/MEK inhibitor blocking both the MEK kinase activity and the ability of RAF to phosphorylate MEK. 

The investigators explained that VS-6766 blocks MEK signaling without the compensatory activation of MEK, which differs from how other inhibitors work.

Defactinib (VS-6063) is an oral small-molecule inhibitor of FAK and PYK2 that is being evaluated as a potential combination therapy for various solid tumors.



Pearls for managing care of high-risk uveal melanoma patients

The combination of the 2 inhibitors induces apoptosis of the uveal melanoma cells, which in turn leads to rapid tumor regression in the uveal melanoma xenografts. When the 2 agents were used alone, the tumor growth was inhibited, but the size of the tumors did not shrink. 

In addition, this combination approach also decreased the tumor burden in models of uveal melanoma liver metastasis.

The investigators described that FAK and MEK inhibition combined showed “synergistic cytotoxic effects” in metastatic uveal melanoma cells.



The investigators used the combination of the MEK and FAK inhibitors in a xenograft mouse model in which the animals were treated for 20 days and found that the tumor volume decreased when the 2 were used together. 

In contrast, when used alone, the inhibitors only stabilized the tumor size, with a limited apoptotic response.



Conjunctival melanoma: Unlocking mysteries of disease

In a mouse model of liver metastasis, in which the animals were treated for 21 days, the investigators reported that the metastatic burden in the animals was reduced. The combination of the 2, they reported, very importantly “nearly eliminated all metastatic lesions.”

The team is evaluating residual disease and tumor burden progression after the treatments were stopped.

J. Silvio Gutkind, PhD, distinguished professor of pharmacology and associate director for Basic Science at Moores Cancer Center at the University of California San Diego, and senior investigator of the study, said results should lead to human trials.

“The study identified and reinforced FAK as a viable pathway to inhibit downstream from the GNAQ pathway, which is constitutively active in uveal melanoma,” he said. “We observed that cotargeting of FAK and RAF/MEK signaling led to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.”



Liquid biopsies: Not yet ready for prime time in uveal melanoma 

Pharmacological inhibition of FAK and MEK inhibited the growth of uveal melanoma cells and had cytotoxic effects leading to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.

The results emphasized the importance of cotargeting with FAK and RAF/MEK to provide a new network-based precision therapeutic strategy.

The signal-transduction-based precision therapy data support clinical testing of the combination inhibition in metastatic uveal melanoma.

VS-6766 and defactinib are also being studied clinically to treat low-grade serous ovarian and 

 mutant non–small cell lung cancers and colorectal cancer.

A phase 2 study of VS-6766 and defactinib in uveal melanoma is expected to commence in late 2020. 


Paradis has no financial interest in this subject matter.

Combining RAF/MEK signaling pathway inhibitor with FAK inhibitor raises bar

Options give 1-2 punch to metastatic uveal melanoma


This article was reviewed by Ariana Levin, MD



The current preoperative requirement for a short evaluation regarding patient histories and physicals may offer an opportunity to streamline the preoperative process for patients scheduled to undergo a 

. 

In many cases, excess travel time and associated costs of lost work, food, and lodging place an unnecessary burden on patients who are not at high-risk of a complication associated with the surgery.



Improving surgical safety, efficiency, and outcomes for patients

“One of our goals is to maximize accessible, affordable, and efficient care, and to do so we should reevaluate the requirement for preoperative histories and physicals for patients undergoing cataract surgery,” according to Ariana Levin, MD, a resident at the Moran Eye Institute at the University of Utah in Salt Lake City.

The preoperative requirements for this patient group have decreased over time in order to decrease unnecessary costs and waste. The savings positively impact the patients, physicians, surgery system, and the health care system.

The American Academy of Ophthalmology (AAO) stated “routine medical tests performed on patients before cataract surgery are unnecessary, because they do not increase the safety of the procedure.”

What remains now is the mandate for histories and physicals to be performed within 30 days of the scheduled cataract surgery. Levin pointed out that this is generally a 15-minute appointment that does not include an ocular examination, receipt of eye drops, or discussion of cessation of medications.


Perioperative medications can eliminate postoperative drops after cataract surgery

Considering the limits of this 15-minute appointment, Levin emphasized, some patients who attend the Veterans’ Administration facility in Salt Lake City can travel up to 5.5 hours for what is likely an unnecessary visit and suggested that telemedicine could play a future role in such an evaluation.

This 15-evaluation is not required in all VA facilities and some schedule it for the day of the cataract evaluation with an update on the surgical day. 

However, despite this, Dr. Levin emphasized that the preoperative requirement must be streamlined even further. 

A recent publication reported what should seem obvious, i.e., that cataract surgery is very safe for most patients, the few patients who do need further screening can be screened before the surgery, and the interventions that take place on the day of the surgery are generally for hypertension or bradycardia.

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Another study that compared the before-and-after effects of the preoperative history and physicals requirement based on a risk stratification questionnaire; in this study low-risk patients did not undergo the history/physical evaluation.



The investigators reported that there was no difference found in the major medical events, and no events were associated with elimination of the history/physical visit.

“These observations show that the value of the history/physical evaluation is questionable, and our patients can travel a long distance,” she said and noted that the important consideration is not so much the burden on the health care system, although that is a concern, but the burden on the patients.

Surveys of patients treated at the Salt Lake City VA indicate that patients have a mean 1-way travel time of 96 minutes over 72 miles and a median 1-way travel time 60 minutes over 33 miles.


Robotics: Allowing surgeons to perform the seemingly impossible


 The other data are equally impressive in that 6.2% missed work, 23% had a family member who missed work. 8.6% had associated child and pet care costs, and 32% expressed concern about the cost of medical care. Patients tallied the costs of food, time, and time off work equaling about $300, Levin said.

“This is an opportunity to restructure preoperative requirements to decrease the burden on patients while maintaining superb patient care,” the investigators concluded. “While our institution is inside the VA system in Salt Lake City, these points likely apply to patients outside the VA system, especially in rural areas.”


e: Ariana.levin@hsc,utah.edu
Levin has no financial interest in this subject matter.


1. Schein O, Pronovost PJ. A preoperative medical history and physical should not be a requirement for all cataract patients. 

2. Benoit BA, Wallace M, Toth G, et al. 529-39. Does eliminating the preoperative history and physical make a difference in low-risk cataract surgery patients? A before and after study of 30-day morbidity and mortality. 

Streamlining preoperative process can offer some relief during stressful time

Reducing burden on veterans undergoing cataract surgery

This article was reviewed by Manjool Shah, MD



In uncertain times, it is important to remain in contact with fellow surgeons in order to continue learning, growing, and developing.

“As I train my residents [and] fellows and work with my colleagues, we all recognize both the importance of maintaining surgical skills and how difficult this may be when the surgical volume dries up,” Manjool Shah, MD, emphasized, and provided some pearls that can help alleviate this situation.

Pearls for practicing in the COVID-19 era

Shah, a clinical assistant professor at the University of Michigan Kellogg Eye Center in Ann Arbor, equated being a surgeon and maintaining skills to being a member of a football team. The majority of players are off the field most of the time. 

He pointed out that coaches use certain strategies for those players not on the field to keep them prepared and ready to perform when called upon.

Surgeons can prepare themselves for action by creating mental representations of themselves “in the game” through mindful and direct observation. They also can play the “anticipation game” by imagining what they would do next when faced with the current situation, he explained.

Additionally, Shah advised that surgeons have hands-on tasks that they can work on while sidelined; these tasks are directly related to the anticipated surgeries.

“These steps enable players to maintain a direct connection with what is happening in the operating room,” he said.

Protecting cataract patients and their surgeons' practices


“Surgical skills start in your head and not in your hands,” Shah said. He pointed out that one way for surgeons to refine their skills is by watching videos of routine cases, such as a cataract procedure.

Shah suggested starting from the beginning without fast-forwarding the recording, even when nothing remarkable is happening.

“Feel that agony of stasis,” he said. “Watch actively, take notes, draw diagrams, imagine hand placement during the procedure and place incisions; pause, rewatch, rewind. Focus on fundamentals such as hand and phaco positions and second instrument position. Be critical of yourself and seek the ‘why’ behind every action or inaction that may occur and try to understand every nuance of the procedure.”

Ophthalmologists remain in touch with colleagues while maintaining social distancing

Ophthalmology Times: September 15, 2020

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