Cheryl Guttman Krader, BS, Pharm

Chance of getting, dying from non-ocular malignancies differs between men, women

The 10-year survival rate for patients with hereditary retinoblastoma is excellent, but these individuals are at increased risk for developing secondary cancers and have elevated mortality compared to age-matched individuals in the general population.
	
	According to analyses of data for retinoblastoma patients in the United States, there are gender-related differences in both the incidence of the different types of second non-ocular malignancies and cause-specific mortality, said Ruth Kleinerman, PhD.
	
	

Retinoblastoma screening rules set foundation for care


	
	“Based on this information, evidence-based guidelines for longterm surveillance and follow-up of retinoblastoma survivors should take gender into account,” said Dr. Kleinerman, deputy branch chief, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD. “International pooling of second cancer data for retinoblastoma survivors will increase the number of cases of second cancers and provide statistical power to further investigate gender disparity in risk with greater precision.”
	
	Information on the incidence of second cancers in retinoblastoma survivors and rates of mortality related to the subsequent cancers is available from the National Cancer Institute Long-term Follow-up Study of Retinoblastoma Survivors.
	
	It includes data on 1,129 patients with hereditary retinoblastoma diagnosed between 1914 through 2006, of whom approximately 50% were still alive in 2016.
	
	Dr. Kleinerman said that the most common second cancers in the hereditary retinoblastoma survivors are bone cancer, soft tissue sarcoma, and melanoma. Analyses of cause-specific mortality compare the rates of death among retinoblastoma survivors with those reported for the U.S. population.
	
	The data show that female retinoblastoma survivors have a higher risk of dying of bone cancer, melanoma, and brain tumors and a slightly higher risk of dying of nasal cavity cancers compared with females in the general population.
	
	Rates of death due to lung, bladder, and colon cancer among female retinoblastoma survivors also appear to be higher than females in the general population. Male retinoblastoma survivors are at higher risk of dying of pancreatic cancer than males in the general population.
	
	

Retinoblastoma survival rates high; secondary cancer a risk


	Genetic susceptibility, treatment, and other factors might contribute to the increased risk of second cancers in patients with hereditary retinoblastoma.
	
	Hereditary retinoblastoma is caused by germline mutations in

, and the location of the mutation or the type of the mutation may be involved in the risk of some secondary cancers, including lung, bladder, and brain tumors. In addition, the patients may be carrying mutations in other related pathways.
	
	The RB1 gene is the spark for the creation of a protein called pRB, which acts as a tumor suppressor, meaning that it regulats cell growth and keeps cells from dividing to fast or in an uncontrolled way. The 

gene provides instructions for making a protein called pRB.
	
	This protein acts as a tumor suppressor, which means that it regulates cell growth and keeps cells from dividing too fast or in an uncontrolled way.
	
	“For example, 

 is in the same cell cycle control pathway as 

, which is a susceptibility gene for familial melanoma and pancreatic cancer,” Dr. Kleinerman said. Host characteristics, such as age and sex, as well as lifestyle and environmental factors, such as smoking history and sun exposure, may also play a role.
	
	Host characteristics, such as age and sex, as well as lifestyle and environmental factors, such as smoking history and sun exposure, may also play a role.
	
	


	This article is based on a presentation given by Dr. Kleinerman at the Ocular Oncology/Pathology Subspecialty Day meeting. The mortality data were subsequently published in the Journal of the National Cancer Institute (Kleinerman RA, et al. Patterns of causespecifi c mortality among 2053 survivors of retinoblastoma, 1914-2016. 

t. 2019 Jan 30. Doi: 10.1093/jnci/djy227 [Epub ahead of print]).
	

Dr. Kleinerman has no relevant financial interests to disclose.

Articles

Research eyes risk of second cancers occurring in retinoblastoma patients 

Neither the need for unplanned postoperative visits for complications nor the incidence of visually disturbing cystoid macular edema (CME) was significantly reduced by adding a topical NSAID to postoperative topical steroid treatment, finds a recent study.

A retrospective population-based controlled study analyzing data from an unselected patient population undergoing phacoemulsification surgery found that neither the need for unplanned postoperative visits for complications nor the incidence of visually disturbing 

 was significantly reduced by adding a topical 

 to postoperative topical steroid treatment.

The research, however, did highlight increased susceptibility to postoperative CME in eyes with preexisting vitreoretinal conditions.

“Results of randomized controlled trials indicate that the occurrence of CME is reduced in eyes treated with an NSAID, either in combination with a steroid or alone,” said Jan GÃ¤rdin, MD, resident, 

Department of Ophthalmology, LinkÃ¶ping University

However, it is sometimes difficult to relate study results to what is perceived as clinical reality. In our investigator-initiated study including a large number of eyes from an unselected patient population, we were not able to demonstrate a clear benefit for the cohort that received combination therapy, Dr. GÃ¤rdin added.

Intracamerally injected mydriatic agents in cataract surgery: Good safety profile

“Although randomized controlled studies remain the gold standard for evaluating the efficacy of new treatments, adequately designed and conducted clinical studies such as our retrospective population-based trial are an important complement to clarify how medical and surgical treatments are used in an optimal fashion in unselected clinical populations," said 

, coinvestigator in the study and associate professor of ophthalmology, LinkÃ¶ping University. "The findings from such studies may have both medical and economic impact.”

The population-based controlled study analyzed data from two groups of consecutive patients operated on in the eye clinics of Vrinnevi Hospital, NorrkÃ¶ping, Sweden and LinkÃ¶ping University Hospital, LinkÃ¶ping, Sweden.

The two facilities are in the same county, publicly financed, and under the same regional clinical center, and they use the same electronic patient record system. However, they use different standard protocols for controlling postoperative inflammation, Dr. GÃ¤rdin explained.

Novel delivery system shows positive performance in phase II trial

At Vrinnevi Hospital, patients are treated for 3 weeks after surgery with a topical steroid and a topical NSAID, each given 3 times daily. Patients undergoing cataract surgery at the eye clinic of LinkÃ¶ping University Hospital are treated only with a tapering dose of a steroid for 3 weeks.

Using the electronic medical record system and beginning the search in January 2015, the investigators identified a total of 500 consecutive eyes from each hospital. The selected eyes were from patients aged 20 years and older.

Patients were excluded if they had posterior capsular rupture and/or zonular damage preventing in-the-bag IOL placement, deviation from the center’s standard protocol for topical anti-inflammatory treatment, or a pre-existing ocular malformation. Data were extracted on baseline characteristics and unplanned postoperative visits within 6 months after surgery.

The two study groups were balanced with respect to gender and right/left eye distribution. Each group had a predominance of females over males and included a majority of right eyes. Mean age was about 75 years and similar in the two study groups.

Mean logMAR BCDVA was also similar in the two groups preoperatively.

Managing ophthalmic surgery patients on antithrombotic drugs

A review of preoperative ocular comorbidities showed the percentage of eyes with pseudoexfoliation was higher in the group that received the steroid alone compared with those treated with combination therapy. The group receiving combination therapy had higher percentages of eyes with an epiretinal membrane (ERM) and with diabetic maculopathy or 

. The number of patients with diabetes and with 

Although a higher rate of unplanned postoperative visits was found for the group receiving combination treatment than among eyes treated only with a steroid, the difference was not statistically significant (16.6% versus 12.6%; 

 = 0.073). CME occurred in eight eyes (1.6%) in the combination treatment group and in six eyes (1.2%) treated with the steroid alone.

“The overall incidence of CME in our total cohort was 1.4%, but when patients with diabetes or an ERM were removed, the overall incidence of CME decreased to 0.8%,” Dr. GÃ¤rdin noted.

Clinically significant CME occurred in 2.9% of eyes in patients with diabetes mellitus and in 8.2% of eyes with an ERM.

“The incidence of clinically significant CME among patients in our study who had an ERM was 10-fold higher than in our patients without diabetes and no ERM, indicating patients with an ERM had a drastically increased risk,” Dr. GÃ¤rdin said.

Prevention of CME, infection in lens-based surgery: Evidence-based approaches


	Dr. GÃ¤rdin has no relevant financial interests to disclose.


	Dr. Johansson is a consultant to companies that market topical anti-inflammatory medications.

This article is based on a paper presented at the 2019 meeting of the American Society of Cataract and Refractive Surgery.

Large population-based study questions value of routine NSAID use after cataract surgery

Retinal disease and glaucoma can be overlapping conditions which present opportunities for collaboration among subspecialties.

Anita Agarwal, MD, discussed diagnostic and management considerations for patients with hypertensive uveitis, central retinal vein occlusion (CRVO), narrow angles, and retinal dystrophy, and the need for pars plana tube shunt surgery. She outlined these opportunities at the 23rd annual Glaucoma Symposium, held during the 2019 

Elevated intraocular pressure (IOP) is a feature of certain types of uveitis.

Reminding glaucoma specialists to conduct a thorough examination to establish an accurate diagnosis that will guide appropriate treatment, Dr. Agarwal underscored her point with several case presentations.

One case involved a HIV-positive patient who presented with elevated IOP and anterior uveitis.

“Cytomegalovirus was suspected to be the cause of the uveitis because the patient was HIV-positive, but the posterior segment examination showed widespread Toxo-plasma retinitis,” said Dr. Agarwal, 

, San Francisco, and adjoint professor of ophthalmology, Vanderbilt University, Nashville, TN. “This patient needed treatment for the ocular inflammation and elevated IOP, but also needed systemic treatment for the toxoplasmosis.”

Another case involved a female patient presenting with hypertensive anterior uveitis in the left eye due to herpes zoster, based on the presence of vesicular cutaneous lesions over a V1 distribution.

The patient was treated with topical corticosteroids, pressure-lowering medication, and oral acyclovir, which she was taking infrequently. She returned after two weeks complaining of blurred vision in the right eye.

On exam-nation, the right eye was found to have keratitic precipitates, 2+ anterior chamber cells, significant vitritis, and acute retinal necrosis. “In patients with anterior uveitis, it is important to think about the potential for involvement of the posterior segment and also the fellow eye,” Dr. Agarwal said.

To prevent complications that can cause permanent vision loss, treatment for patients with hypertensive uveitis requires aggressive intervention to control both the inflammation and elevated IOP. Corticosteroid therapy remains the mainstay for suppressing inflammation, and in certain chronic situations, such as sarcoidosis, it has been revolutionized by the availability of long-acting intraocular implants, Dr. Agarwal said.

“Treat the inflammation fully and don’t worry about an IOP-steroid response,” Dr. Agarwal said. “If using a steroid implant, advise patients that they have a 100% chance of developing a cataract and persistently elevated IOP that may require cataract surgery and a glaucoma tube shunt.”

The risks of iris neovascularization and neovascular glaucoma (NVG) developing in eyes suffering an ischemic CRVO have been reduced because of the advent of effec-tive pharmacotherapy. Current CRVO management involves intravitreal, anti-VEGF injections and steroids as needed to reduce or resolve cystoid macular edema (CME).

Patients are carefully monitored for natural evolution to development of collaterals and for the development of iris neovascularization and NVG. However, there is no clearly defined treatment endpoint, and iris neovascularization and NVG can develop as patients fail to return for follow-up.

Dr. Agarwal discussed a patient who eventually returned with count-fingers vision and was found to have massive CME, an atrophic retina, and iris neovascularization. Treatment at this stage was to restart the anti-VEGF injections and perform panretinal photocoagulation.

Autosomal recessive bestrophinopathy, a macular dystrophy caused by a mutation of the Bestrophin gene (VMD2) gene, is something to think about in a relatively young patient who presents with narrow angles and elevated IOP, said Dr. Agarwal.

First described in 2008, age of onset for the condition ranges from 4 to 40 years. The retinal findings include multiple yellow flecks, increased fundus autofluorescence from lipofuscin deposition, islands of retinal pigment epithelium loss, and intraretinal fluid accumulation. Many patients also have elevated IOP that is related to a narrow angle.

In affected children, elevated IOP may be the initial manifestation.

“Because the mutation is a null defect and the protein coded for by the gene is absent, the consequences are severe,” Dr. Agarwal said. "Since it is a recessive condition, patients may not have a positive family history.”

There are several situations where glaucoma and retinal specialists may meet in the operating room.

Patients needing pars plana placement of a tube shunt is one setting. Indications for a pars plana shunt include NVG, uveitic glaucoma, traumatic aphakia with glaucoma, pediatric aphakic glaucoma, aniridia, corneal scarring, and the post-corneal transplant state.

Depending on the indication, pars plana placement may be preferred to achieve more durable success or for greater safety, Dr. Agarwal explained.

Retinal disease and glaucoma can be overlapping conditions which present opportu-nities for collaboration among subspecialties.

Glaucoma, retinal diseases present collaborative opportunities

Uveitic glaucoma presents a treatment challenge because of the need to control two conditions. Furthermore, side effects of conventional treatments for uveitis-corticosteroids and systemic immunomodulatory agents-limit their use.

Fortunately, new treatments for uveitis are enabling safer and effective management of uveitic glaucoma, and others are on the horizon, said Terri Pickering, MD.

Speaking at the 23rd Annual Glaucoma Symposium during the 2019 

 meeting, Dr. Pickering reviewed the etiology, diagnosis, and management of uveitic glaucoma. She is a clinical instructor, 

Dr. Pickering said there are multiple classification systems for uveitis, but it is most often categorized as infectious or non-infectious, and the latter group may be further divided according to whether it is associated with a systemic disorder.

With so many possible causes for uveitis, the work-up for a patient with intraocular in-flammation may seem daunting, but establishing the etiology is important to avoid overlooking a treatable cause for uveitis (i.e., infection) or a concurrent systemic disease that needs treatment. A targeted work-up is facilitated based on the patient’s demographics and findings from the history and physical examination.

“Identifying the cause for the uveitis can also help with counseling patients about their prognosis,” Dr. Pickering said.

She recommended, however, that all patients be tested for syphilis, which is considered “the great masquerader,” and have a chest X-ray or CT scan to look for sarcoidosis or tuberculosis.

Dr. Pickering said glaucoma can develop in patients with uveitis through several path-ogenic pathways and may represent open-angle or closed-angle disease. Inflamma-tion control is critical, and steroids are the cornerstone of treatment for non-infectious uveitis.

The risk for intraocular pressure (IOP) elevation and other side effects, howev-er, create a need for steroid-sparing therapy.

(MUST) trial showed that systemic immunosuppressive therapy was superior to the use of the fluocinolone acetonide steroid implant for controlling uveitis over the long-term,” said Dr. Pickering.

Prednisone is still the mainstay for systemic immunosuppressive treatment of uveitis, but antimetabolites, alkylating agents, and T-cell inhibitors have been used as steroid-sparing therapy instead of or in combination with prednisone to limit steroid-induced adverse events.

Biologic therapy was first used to treat uveitis about 15 years ago.

“Now, the biologics are revolutionizing treatment of uveitis because compared with traditional immunomodulatory treatments, the biologics tend to be more effective, better tolerated, and easier to comply with because of a less frequent administration schedule,” Dr. Pickering said. “But as with everything, there are cons associated with the biologics.”

Dr. Pickering noted that the response to biologic treatment can be variable, there is potential for long-term toxicity, more long-term safety data are needed, and while the situation is improving, insurance coverage can be difficult to obtain.

“Methotrexate is still much less expensive,” Dr. Pickering added. Biologics may be most useful for treating uveitis in patients with HLA-B27 disease, BehÃ§ets disease, or juvenile idiopathic arthritis. In addition, they may be considered for patients who fail or cannot tolerate traditional immunomodulatory treatments.

), which is a tumor necrosis factor (TNF) antagonist, is the only biologic approved by the FDA for treating noninfectious uveitis. It is indicated for the treatment of noninfectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

Studies with adalimumab and other TNF antagonists showed benefit for improving uveitis control and decreasing steroid dependency. It appears that earlier treatment initiation is helpful for minimizing irreversible tissue damage.

However, there is evidence that efficacy may decline over time and compared to their use in treating systemic diseases, biologics may need to be given at a higher dose or more frequently to control uveitis, said Dr. Pickering.

“Combination treatment with a biologic and nonbiologic is also commonly done, but two biologics should not be used together because of toxicity and infection risk,” Dr. Pickering said.

Potential side effects of the TNF antagonists include infection or infection reactivation, malignancy development, particularly non-melanoma skin cancers, a lupus-type syn-drome, and a systemic drug sensitivity allergic reaction.

In addition, the TNF antago-nists are contraindicated in patients with advanced congestive heart failure, any type of demyelinating disease, and women who are pregnant or nursing. Patients on a TNF antagonist should not be given a live vaccine.

“In the interest of minimizing toxicity, most uveitis specialists will use a biologic in a pulse regimen, treating patients for two or three years and then try to stop the biologic,” Dr. Pickering said. “In the future we may see different classes of biologics emerge for the treatment of uve-itis because there are many potential targets in the eye, and there are some agents already in development."

Medical management is considered first-line of treatment for controlling IOP in eyes with uveitic glaucoma, although prostaglandins and laser trabeculoplasty should be avoided if the uveitis is not well controlled and alpha agonists should be avoided in children.

Ideally, surgery for glaucoma should be performed only after the eye has been quiet for at least three months.

“The problem is that surgical intervention is often indicated because of high IOP, and so there may not be the luxury of time,” Dr. Pickering said.

A glaucoma drainage device is considered the surgical intervention of choice for adults.

Dr. Pickering cautioned that cycloablative procedures can lead to phthisis, especially in the setting of active inflammation.

Goniotomy may be the best choice for surgical intervention in children and teens. Trabeculectomy should not be performed in the pediatric population, Dr. Pickering said.

Novel therapeutic target The gut microbiome has become a new target of interest for treating noninfectious au-toimmune uveitis based on the theory that it plays a key role in any disease involving the immune system.

Dr. Pickering explained that cross-reactive antigens of gut bacte-ria can trigger an autoimmune attack in the eye by activating T-cells that pass through the intestine and cross the blood-brain barrier.

“HLA-B27 shares a short peptide sequence with some bacterial molecules, and be-cause HLA-B27 disease accounts for 40% of anterior uveitis cases, treatments directed at the gut microbiome or T-cells open up a large avenue for potential future therapy based on the goal of restoring immune homeostasis,” she concluded.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Research eyes risk of second cancers occurring in retinoblastoma patients

Large population-based study questions value of routine NSAID use after cataract surgery

Glaucoma, retinal diseases present collaborative opportunities

New options address challenges of managing uveitic glaucoma