The most rigorous data in evidence-based medicine is considered to be that generated by prospective, randomized, controlled trials (RCTs). 

RCTs are essential for evaluating the therapeutic impact of a drug or device while eliminating potential confounding factors. 

However, there are many situations in which these gold standard clinical trials are not practical or cost effective.



Clinical trial outcomes for macular edema don’t translate to ‘real-world’ settings

RCTs evaluate outcomes for very tightly defined groups of patients with highly standardized care and optimal adherence and follow-up. 

In the real world, however, patients present with a variety of underlying systemic conditions, prior surgery, and adherence patterns that muddy the picture. This is where retrospective, observational studies can help to fill the knowledge gap with real-world evidence (RWE).

RWE can help to answer key clinical questions, such as how a treatment works in patients who are already on other medications, and whether switching to or adding a new pharmaceutical agent would be more beneficial. 

Real-world studies can demonstrate how a new 

 therapy compares with the prostaglandin analogues (PGAs) that most clinicians rely on for first-line therapy, rather than with timolol, the typical control used in FDA studies. 

In cardiology, a major ongoing RWE study, the ADAPTABLE trial (NCT02697916), is trying to settle the debate over whether patients with coronary artery disease do better on low- or high-dose aspirin.

Developing a new therapy: Where do we go from here?


Increasingly, RWE researchers are looking at big data for answers. Very large data registries permit analysis of records from representative patient populations that are orders of magnitude larger than the number of subjects typically found in a phase 3 clinical trial.

Verana Health, through our partnership with the American Academy of Ophthalmology, is actively engaged in curating and analyzing data from the IRIS Registry (Intelligent Research in Sight) to better inform clinical practice in ophthalmology. 

The IRIS Registry is the largest specialty clinical database in medicine, with 343 million patient visits and billions of data points reported by more than 15,000 ophthalmologists through their electronic health records (EHR) systems. 

Large registries like this offer the opportunity to gather RWE about clinical outcomes. They facilitate research on questions that are critical to patient care but may be less likely to garner industry support such as head-to-head comparisons of new and long-established treatments.



IRIS Registry study: Overall anti-VEGF injection intervals for wet AMD similar at 1, 2 years of treatment


Large registry studies are relatively new but have already led to changes in ophthalmic practice. 

For example, a retrospective analysis of all procedures in the Swedish national cataract registry over a multi-year period revealed that intracameral antibiotics were an important factor in reducing the rate of endophthalmitis.

 

This led to a prospective European study of intracameral antibiotics

 and widespread adoption of this method of infection prophylaxis in Europe. A large health maintenance organization (HMO) in the United States also reached similar conclusion about the value of injected antibiotics in cataract surgery after reviewing a large data set from its own EHR system.

Another national registry helped to establish corneal collagen cross-linking as the standard of care for keratoconus. 





In this case, analysis of healthcare resource utilization in the Netherlands before and after the introduction of crosslinking showed that the procedure was associated with a 25% reduction in corneal transplantation over three years.

We have been able to use the IRIS Registry data to evaluate real-world anti-VEGF injection intervals in 56,672 treatment-naïve patients with 

 

In this study, the authors found that the mean number of injections per eye was approximately five per year.

By the end of year 1, approximately 40% of eyes continually treated with anti-VEGF medications needed injections more frequently than every 8 weeks, including 17%-18% who still needed monthly injections.

In another retrospective review of IRIS Registry data for 12.5 million patients seen by an eye care provider in 2017, researchers evaluated the relationship between smoking and IOP.

 

After adjusting for many factors, including age and glaucoma diagnosis, smokers (both current and those with a history of smoking) had higher mean IOP than those who had never smoked. 

In fact, smoking was the most important predictor of IOP after the glaucoma diagnosis (

IOP homeostasis in glaucoma: Looking below the surface


The ability to access large amounts of information to improve medicine is very exciting. But large data sets can be quite challenging to interpret. Imagine a spreadsheet with billions of rows and columns. 

No human can realistically check it over for errors; sophisticated algorithms are needed to catch and remove errors in a systematic way. The raw data must be cleaned, harmonized, and structured in such a way that it can be used for clinical research.

To better understand this, consider something as simple as visual acuity (VA)—an important outcome measure in ophthalmic studies. 

Data comes into the IRIS Registry every day from thousands of doctors using more than 50 different EHR platforms, each of which collects VA in slightly different fields or formats.



Apps now online to aid patients with visual impairment

VA may have been measured using a Snellen or ETDRS (Early Treatment Diabetic Retinopathy Study) chart, autorefraction, or a pinhole test. The patient may have been tested with or without correction, monocularly or binocularly. 

All of that VA data needs to be harmonized so that “20/20” has the same meaning across millions of records.

At Verana, we are using machine-learning techniques to refine algorithms that characterize important information from “unstructured” data, such as free text and images. 

Imaging is very important in ophthalmology, so the ability to develop algorithms that can mine images for precalculated measurements such as retinal nerve fiber layer thickness, as well as pathological features (eg, drusen) is highly relevant for future research.



In fact, real-world data from large registries opens up many new avenues for clinical research and the advancement of medicine. 

The sheer volume of patients offers a chance to drill down into specific subgroups that are underrepresented in clinical trials and to better understand how a disease process or treatment response might vary by gender, race or ethnicity.

We are also passionate about the opportunity to use RWE from the IRIS Registry and other large registries to develop more personalized patient care. 



Pearls to educate patients about ocular telemedicine options



Currently, a new glaucoma patient is typically treated first with a prostaglandin analog—the best available treatment, based on the literature. 

But what if we had a robust algorithm that could take into account not just the basic diagnosis, but age, ethnicity, gender, and comorbidities, to identify the best treatment paradigm for that individual patient? Ironically, big data has the power to change how we approach small, daily decisions.

And as large as these registries are, there are opportunities to deepen them further through data linking. If we link records from pharmacy prescription databases or serum testing laboratories to the IRIS Registry data, we could get a much clearer picture of diabetic patients’ glycemic control, and potentially be able to evaluate how glycated hemoglobin levels or metformin usage correlate with diabetic retinopathy changes.

We now have the ability to access large volumes of real-world data from very broad patient populations. The possibilities for using that data to improve patient care and drive scientific insights are limitless. 


Roe is chief medical officer of Verana Health. A cardiologist by training, he spent 20 years at Duke University and as an investigator at the Duke Clinical Research Institute in Durham, North Carolina, where he focused on research initiatives leveraging real-world data. He was a principal investigator in the ADAPTABLE trial.


Leng is a practicing retinal specialist, assistant professor of ophthalmology and director of Clinical and Translational Research at Stanford University Medical School in Stanford, California. He has a research background in image analysis, machine learning algorithms, and clinical trial design and execution. He serves as a medical adviser to Verana Health.


Johnston A, Jones WS, Hernandez AF. The ADAPTABLE trial and aspirin dosing in secondary prevention for patients with coronary artery disease. 

. 2016;18(8):81. doi:10.1007/s11886-016-0749-2

Friling E, Lundström M, Stenevi U, Montan P. Six-year incidence of endophthalmitis after cataract surgery: Swedish national study. 

. 2013;39(1):15-21. doi:10.1016/j.jcrs.2012.10.037

Endophthalmitis Study Group, European Society of Cataract and Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. 

. 2007;33(6):978-988. doi:10.1016/j.jcrs.2007.02.032

Herrington LJ, Shorstein NH, Paschal JR, et al. Comparative effectiveness of antibiotic prophylaxis in cataract surgery. 

. 2016;123(2):287-294. doi:10.1016/j.ophtha.2015.08.039

Godefrooij DA, Gans R, Imhof SM, Wisse RP. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. 

. 2016;94(7):675-678. doi:10.1111/aos.13095

MacCumber M, Yu, JS, Sagkriotis A, et al. Injection intervals in treatment-naïve neovascular AMD patients who received anti-VEGF agents: an analysis of the IRIS Registry. Paper presented at: American Academy of Ophthalmology Annual Meeting October 12-15, 2019; San Francisco. 2019: PO471.

Lee CS, Owen JP, Yanagihara RT, et al. Smoking is associated with higher intraocular pressure regardless of glaucoma.

. 2020;3(4)253-261. doi: 10.1016/j.ogla.2020.03.008

Articles

Evidence-based medicine can lead to personalized care, better results for patients

Big data drives opportunity for real-world evidence

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.”

Importantly, Shah also suggested trying to devise at least 1 actionable change that can be implemented during the next surgery in the operating room.



PPE packs helping ophthalmologists restore patient confidence amid COVID-19

After mastering a simple case, surgeons can advance to a more complicated surgery, such as a case of a dropped nucleus, in which things do not necessarily proceed as expected. The same steps outlined previously can be applied to these cases, too.

“Focus on the complications but instead [move] forward and backward in time in the video to determine how it happened, starting from the beginning, and how it was managed,” Shah said. “Find the cause before the root cause and imagine all the steps from the initial event to the complication and then beyond.”

Most importantly, the surgeon can determine productive tasks to work on to avoid this in the future in the operating room.

“Learn from others by standing on the shoulders of giants,” Shah said.

This can be tackled by reading the steady stream of surgical techniques that have been described in the literature.

“The act of reading a description before watching an accompanying video is useful. 

The Journal of Cataract & Refractive Surgery

 may be a good place to begin,” Shah noted.



Perioperative medications can eliminate postoperative drops after cataract surgery

Following reading, now is the time to watch the videos. This can facilitate the learning of new techniques and how to manage challenging cases. 

The American Society of Cataract and Refractive Surgery clinical education site and YouTube are all good sources.

“Be critical and [apply] those same watching skills. Pause the video at key intervals and ask ‘What would I do next?’” he suggested.

Shah also pointed out that surgeons can share the information they gained with colleagues and the community and discuss best practices, challenges, complications, and resources.

“We have opportunities to leverage teleconferencing options to build bonds and practice [distance] socializing,” he said.

Finally, Shah advised working on technical skills using a microscope or surgical supplies.



Assessing the right angle: Surgeons getting back to basics

“Devices and implants are often available from reps, and model eyes can be made specifically for many surgical techniques and can be reused,” he said.

The current environment will change, and ophthalmologists must be prepared for it.

“The crisis will end and we will be called off the bench,” Shah said, pointing out that the reduced surgical volume and delayed care can translate into some cases that may present increased complexity.

“Stay safe, stay sane, stay healthy, and stay sharp,” he concluded. “These directives apply with and without a pandemic.”




Shah has no financial interest in this subject matter.

Ophthalmologists remain in touch with colleagues while maintaining social distancing

Surgery during the COVID-19 pandemic: Staying sharp

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 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 related to retinoblastoma

Reviewed by Richard B. Rosen, MD, DSC (HON)

Medical robots are revolutionizing medicine. Their applications can facilitate superhuman dexterity, enabling the performance of surgical steps otherwise considered impossible and automating repetitive tasks.

The benefits include high positional stability, precision, and accuracy along the x-, y-, and z-axes, removal of time constraints on subretinal and intraretinal drug delivery, and reduction of surgeon fatigue, according to Richard B. Rosen, MD, DSC(HON), of the New York Eye and Ear Infirmary of Mount Sinai in New York, New York.



Robotic technology in surgery: Surgeon's eye of the future

The robotic approaches being developed in ophthalmology include assistive handheld devices, such as the steady-hand stabilizer (Johns Hopkins Group); a comanipulation strategy to stabilize the surgeon’s movement (University of California, Los Angeles); and telemanipulation, which uses a separate robotic manipulator operated by the surgeon (Einhoven Group).

Rosen presented study findings that showed the advantages of robotics over manual procedures during retinal surgery. 

The study was conducted by his associates, Reza Ladha, MD, of the Department of Ophthalmology at the Centre Hospitalier Universitaire (CHU) Saint-Pierre and CHU Brugmann in Brussels, Belgium, and Marc D. de Smet, MD, of Microinvasive Ocular Surgery Center in Lausanne, Switzerland, and an employee of Preceyes in Eindhoven, the Netherlands. 

The investigators used the Preceyes surgical robot with Zeiss Microscopy with integrated optical coherence tomography.

The robot filters tremors to under 10 µm, which is 10 times better than the human performance. The arm of the robot permits intuitive motion with positional stability and memory and allows exchange of instruments, Rosen said.

When the investigators compared the accuracy and precision of the robotic and manual performances, improvement with the robot was markedly greater. Rosen showed that the robot improves precision and accuracy by at least an order of magnitude. 

Improving surgical safety, efficiency, and outcomes for patients


The manual static task performed by an experienced surgeon with minimal tremors of about 100 µm, with additional microjerks reaching 200 µm, became more intense the longer the surgeon remained static.

Other research also supports the use of robotics in ophthalmology. In an Eyesi simulator experiment, retinal injuries were decreased substantially using the robot compared with manual peeling.

In addition, a simulation study looked at manual and robot bleb creation, with the goal of elevating a retinal membrane and avoiding reflux. 



The manual injection created a great deal of reflux and an enlarging bubble of fluid on the membrane’s surface compared with the robotic injection, which formed no bubble.

The investigators also performed subretinal injections in a porcine eye manually and with robotic assistance. 

Rosen reported a 40% success rate of bleb creation with the manual procedure, with leakage in all cases during injection and when the needle was withdrawn; all cases were considered failures. 

3D cataract surgery: Keeping the eye in focus


In contrast, the robotic-assisted technique had a 100% success rate in bleb creation; there was leakage in 20% of cases when the needle was withdrawn, considered an 80% success rate.

“Bleb generation with robotic assistance was more precise and more consistent. Robotic assistance prevented motion and leakage during injection,” Rosen said. “Static manual subretinal positioning showed repeated contact with the underlying retinal pigment epithelium.”

Based on the above results, the investigators noted that robotic assistance removes the time constraints of delivery and allows high-precision positioning for controlled subretinal drug delivery.

“Robotic assistance controls tremor, reduces fatigue, and helps avoid inadvertent injury in tight spaces,” they concluded. “Robotic-assisted ocular surgery shows promise for advancing the surgeon’s ability to perform more complex maneuvers necessary for the next generation of retinal interventions."



Rosen has no financial interest in this subject matter.

Robotic-assisted procedures are proving more precise in every way when compared with manual procedures: automated assistance controls tremor, reduces fatigue, and helps avoid inadvertent injury. 


Robotics: Allowing surgeons to perform the seemingly impossible



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.



“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.


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.

Streamlining preoperative process can offer some relief during stressful time

Ophthalmology Times: September 15, 2020