Consensus Guidelines for Ocular Surveillance of von Hippel-Lindau Disease.

PURPOSE: To develop guidelines for ocular surveillance and early intervention for individuals with von Hippel-Lindau (VHL) disease. DESIGN: Systematic review of the literature. PARTICIPANTS: Expert panel of retina specialists and ocular oncologists. METHODS: A consortium of experts on clinical management of all-organ aspects of VHL disease was convened. Working groups with expertise in organ-specific features of VHL disease were tasked with development of evidence-based guidelines for each organ system. The ophthalmology subcommittee formulated questions for consideration and performed a systematic literature review. Evidence was graded for topic quality and relevance and the strength of each recommendation, and guideline recommendations were developed. RESULTS: The quality of evidence was limited, and no controlled clinical trial data were available. Consensus guidelines included: (1) individuals with known or suspected VHL disease should undergo periodic ocular screening (evidence type, III; evidence strength, C; degree of consensus, 2A); (2) patients at risk of VHL disease, including first-degree relatives of patients with known VHL disease, or any patient with single or multifocal retinal hemangioblastomas (RHs), should undergo genetic testing for pathologic VHL disease gene variants as part of an appropriate medical evaluation (III/C/2A); (3) ocular screening should begin within 12 months after birth and continue throughout life (III/C/2A); (4) ocular screening should occur approximately every 6 to 12 months until 30 years of age and then at least yearly thereafter (III/C-D/2A); (5) ocular screening should be performed before a planned pregnancy and every 6 to 12 months during pregnancy (IV/D/2A); (6) ultra-widefield color fundus photography may be helpful in certain circumstances to monitor RHs, and ultra-widefield fluorescein angiography may be helpful in certain circumstances to detect small RHs (IV/D/2A); (7) patients should be managed, whenever possible, by those with subspecialty training, with experience with VHL disease or RHs, or with both and ideally within the context of a multidisciplinary center capable of providing multiorgan surveillance and access to genetic testing (IV/D/2A); (8) extramacular or extrapapillary RHs should be treated promptly (III/C/2A). CONCLUSIONS: Based on available evidence from observational studies, broad agreement was reached for a strategy of lifelong surveillance and early treatment for ocular VHL disease. These guidelines were endorsed by the VHL Alliance and the International Society of Ocular Oncology and were approved by the American Academy of Ophthalmology Board of Trustees. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

PURPOSE: To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. METHODS: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 µm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ophthalmoplegia Associated With Extramedullary Multiple Myeloma: Case Series From a Tertiary Cancer Center.

BACKGROUND: Multiple myeloma (MM) is a malignant disorder of plasma cells that results in tumor cells replacing the bone marrow. In extramedullary MM (EMM), however, tumor cells proliferate outside the bone marrow. EMM may produce ophthalmoplegia through direct invasion of the superior orbital fissure, cavernous sinus, and/or sphenoidal sinus. Several mechanisms have been proposed including cranial nerve palsies, direct infiltration of bone, extraocular muscle metastasis, myelomatous meningitis, and parenchymal or paraneoplastic effects. METHODS: We retrospectively reviewed the medical records of 7 patients at MD Anderson Cancer Center who suffered from ophthalmoplegia secondary to extramedullary MM between 2019 and 2021. We collected information regarding the symptoms, signs, radiographic and laboratory findings, management, complications, and prognosis of these patients throughout their disease course. RESULTS: Skull base MRI revealed 4 patients with ophthalmoplegias secondary to superior orbital fissure invasion, 2 patients with ophthalmoplegias secondary to cavernous sinus invasion, and 1 patient with ophthalmoplegia secondary to sphenoid sinus invasion. CONCLUSIONS: This is a case series describing 7 patients with ophthalmoplegias secondary to EMM. Our article is unique because of the size of the included cohort, which is large when compared with most English language publications detailing such ophthalmoplegias.

Overview of Ocular Side Effects of Selinexor.

BACKGROUND: The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator-initiated trial. METHODS: We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed. RESULTS: A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment-related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment-related adverse event was the progression of age-related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation. CONCLUSION: Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation. IMPLICATIONS FOR PRACTICE: Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Immune-Related Oral, Otologic, and Ocular Adverse Events.

Emerging immunotherapeutic agents, including immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), have revolutionized cancer treatment. The first immune checkpoint inhibitor (ICI) ipilimumab, an anti-CTLA-4, was approved in 2011. Since then, the US Food and Drug Administration (FDA) has approved more than half a dozen immune checkpoint inhibitors to treat various malignancies. These agents are part of a broader class of chemotherapy agents termed immunotherapy, which selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. While the effects of traditional chemotherapy are well known, the toxicity profile of emerging immune therapies is not fully elucidated. They have been associated with atypical side effects labeled collectively as immune-related adverse events (irAEs).

Immune-Related Oral, Otologic, and Ocular Adverse Events.

Emerging immunotherapy agents, such as immune checkpoint inhibitors, have shown remarkable promise in the treatment of various malignancies. These drugs selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. Due to the novelty of these therapeutic agents, their toxicity profile is less well understood.Meta-analysis results reveal that the overall prevalence of oral mucositis, stomatitis, and xerostomia is lower with checkpoint inhibitors compared to conventional chemotherapy, and head and neck radiation therapy. However, the widespread use of immunotherapy reveals new oral mucosal barrier adverse events, including bullous pemphigoid, mucous membrane pemphigoid, and lichenoid mucositis. Audiovestibular dysfunction can occur from autoimmune-mediated pathways of immunotherapy (adoptive cell) with limited treatment options. Such auditory complications can lead to speech recognition deficits and sensorineural hearing loss. Ocular toxicities are among the most common adverse events resulting from the use of these agents. The majority of ocular immune-related adverse events (irAEs) are mild, low-grade, non-sight threatening, such as blurred vision, conjunctivitis, and ocular surface disease. Serious and sight-threatening events, including corneal perforation, optic neuropathy, and retinal vascular occlusion, can occur but are infrequent. In this chapter, we review the current evidence on the clinical manifestations of oral, audiovestibular, and ocular immune-related adverse events (i.e., irAEs).

DICER1 Syndrome: Characterization of the Ocular Phenotype in a Family-Based Cohort Study.

PURPOSE: To characterize the ocular phenotype of DICER1 syndrome. DESIGN: Prospective, single-center, case-control study. PARTICIPANTS: One hundred three patients with an identified germline pathogenic DICER1 variant (DICER1 carriers) and 69 family control participants underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016. METHODS: All participants were evaluated with a comprehensive ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain OCT, color fundus photography, fundus autofluorescence imaging, visual field testing, full-field electroretinography, and genetic testing for inherited retinal degenerative diseases. MAIN OUTCOME MEASURES: Visual acuity and examination findings. RESULTS: Most DICER1 carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty-three DICER1 carriers (22%) showed ocular abnormalities compared with 4 family controls (6%; P = 0.005). These abnormalities included retinal pigment abnormalities (n = 6 [5.8%]), increased cup-to-disc ratio (n = 5 [4.9%]), optic nerve abnormalities (n = 2 [1.9%]), epiretinal membrane (n = 2 [1.9%]), and drusen (n = 2 [1.9%]). Overall, we observed a significant difference (P = 0.03) in the rate of retinal abnormalities in DICER1 carriers (n = 11 [11%]) versus controls (n = 1 [1.5%]). One patient demonstrated an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and 1 showed optic nerve elevation in the setting of increased intracranial pressure (ICP) of unclear cause. Three patients (3%) demonstrated DICER1-related ciliary body medulloepithelioma (CBME), 2 of which were identified during routine examination, a higher rate than that reported previously. CONCLUSIONS: Ophthalmologists should be aware of the ophthalmic manifestations of DICER1 syndrome, and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those younger than 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased ICP, and perhaps changes in the retinal pigment epithelium.

Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial.

BACKGROUND: No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease. METHODS: In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual. FINDINGS: Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1-2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed. INTERPRETATION: Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation. FUNDING: Novartis Inc and NIH National Cancer Institute core grant.

Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists.

PURPOSE: To provide a set of surveillance guidelines for children at risk for development of retinoblastoma. DESIGN: Consensus panel. PARTICIPANTS: Expert panel of ophthalmic oncologists, pathologists, and geneticists. METHODS: A group of members of the American Association of Ophthalmic Oncologists and Pathologists (AAOOP) with support of the American Association for Pediatric Ophthalmology and Strabismus and the American Academy of Pediatrics (AAP) was convened. The panel included representative ophthalmic oncologists, pathologists, and geneticists from retinoblastoma referral centers located in various geographic regions who met and discussed screening approaches for retinoblastoma. A patient "at risk" was defined as a person with a family history of retinoblastoma in a parent, sibling, or first- or second-degree relative. MAIN OUTCOME MEASURES: Screening recommendations for children at risk for retinoblastoma. RESULTS: Consensus statement from the panel: (1) Dedicated ophthalmic screening is recommended for all children at risk for retinoblastoma above the population risk. (2) Frequency of examinations is adjusted on the basis of expected risk for RB1 mutation. (3) Genetic counseling and testing clarify the risk for retinoblastoma in children with a family history of the disease. (4) Examination schedules are stratified on the basis of high-, intermediate-, and low-risk children. (5) Children at high risk for retinoblastoma require more frequent screening, which may preferentially be examinations under anesthesia. CONCLUSIONS: Risk stratification including genetic testing and counseling serves as the basis for screening of children at elevated risk for development of retinoblastoma.

Metastatic Melanoma of the Optic Nerve Sheath.

A 23-year-old man with a history of metastatic melanoma developed painful vision loss to counting fingers with enhancement of optic nerve on contrast-enhanced magnetic resonance imaging (MRI) and received a diagnosis of optic neuritis from an outside hospital. Despite empiric corticosteroid therapy, the patient worsened and developed secondary central retinal vein occlusion with further deterioration of vision. Repeat MRI demonstrated optic nerve sheath (ONS) involvement suggestive of optic perineuritis (OPN) and an ONS biopsy confirmed a rare case of isolated metastatic melanoma. Our case highlights the clinical and radiographic features that can mimic OPN and delay diagnosis and treatment.

Vitreous Seeds in Retinoblastoma: Clinicopathologic Classification and Correlation.

PURPOSE: A recent classification scheme for retinoblastoma vitreous seeds has shown promise in predicting treatment response. For the first time, we correlate this clinical classification scheme with its histopathologic features. DESIGN: Retrospective review. PARTICIPANTS: Enucleated eyes received at the pathology department of the Retinoblastoma Center of Houston from 2010 to 2015. METHODS: Macroscopic photographs of the enucleated eyes of patients with retinoblastoma were analyzed to select those with vitreous seeds. Cases with adequate material for clinicopathologic correlation were selected for further analysis, and clinical photographs were reviewed. Routine histopathologic slides were reviewed and compared with the clinical and macroscopic photographs. Seeds were classified as type 1 ("dust"), type 2 ("sphere"), or type 3 ("cloud"). To confirm the presence of macrophages, CD68 immunohistochemical staining was used. Synaptophysin was used to stain retinoblastoma cells. MAIN OUTCOME MEASURES: To correlate clinical vitreous seed type with histopathologic features. RESULTS: A total of 14 eyes with adequate amounts of tumor seeds along with clinical and macroscopic photographic correlation were selected from a total of 138 eyes reviewed. Type 1 seeds consisted of individual viable tumor cells and scattered macrophages. Type 2 seeds consisted of 2 submorphologies: spheres with viable cells throughout and spheres with an outer rim of viable cells but necrotic cells centrally. Type 3 seeds were composed of more than 90% necrotic material admixed with few macrophages and viable cells at their outer rim. Untreated (8/14) and previously treated (6/14) eyes showed similar histopathologic features for each type of seeds. Treated eyes had more type 1 and 3 seeds. CONCLUSIONS: We provide the first histopathologic correlation of the clinical classification scheme for vitreous seeds in retinoblastoma. "Dust" is formed by scattered single cells alternating with macrophages. "Spheres" with translucent centers contain multiple layers of viable tumor cells that shed single cells and may be more clinically aggressive. "Cloud" seeds are mostly composed of necrotic material, explaining their lack of therapeutic response. Pretreated eyes showed tumor seeds morphologically similar to untreated eyes. Knowledge of the underlying histopathology of vitreous seed types is a fundamental component of classification and may aid in understanding clinical response to treatment.

Uveal melanoma: From diagnosis to treatment and the science in between.

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

Effects and Safety of 5% Lifitegrast Ophthalmic Solution in Patients With Dry Eye Disease Associated With Ocular Graft-Versus-Host Disease.

Introduction Graft-versus-host disease (GVHD) is a common sequela of hematopoietic stem cell transplant (HSCT). While HSCT is often curative for certain hematologic malignancies, acute and chronic GVHD remains an important cause of morbidity and mortality in post-transplant patients. Ocular involvement is one manifestation of chronic GVHD that can present similarly to chronic dry eye with tear film abnormalities, aqueous deficiency, and corneal epithelial defects through melting and perforation. Current management includes frequent use of artificial tears and oral or topical glucocorticoids as tolerated. There is a need for long-term, steroid-sparing therapeutics in the management of ocular GVHD (oGVHD). Lifitegrast is approved for the treatment of chronic dry eye and may have therapeutic potential in the treatment of oGVHD. The aim of this study was to investigate the efficacy and safety of topical lifitegrast in the management of oGVHD. Methodology A prospective randomized clinical trial (NCT04792580) was performed on 32 enrolled patients with diagnosed oGVHD. Subjects underwent a two-week washout period consisting of preservative-free artificial tears dosed twice a day, after which they were randomized to the treatment arm (5% lifitegrast ophthalmic solution) or placebo arm (vehicle solution) for four weeks. Endpoints included Symptom Assessment iN Dry Eye (SANDE) score, unanesthetized Schirmer score, Ocular Surface Disease Index questionnaire score, fluorescein staining, tear film breakup time, meibum quantity, and turbidity. Safety endpoints included intraocular pressure, visual acuity, and rate of treatment-related adverse effects. Statistical analysis was done with a t-test or Wilcoxon rank-sum test. Results The primary and secondary efficacy endpoints were met, with statistically significant reductions in mean SANDE and unanesthetized Schirmer score observed at four weeks post-randomization. No serious adverse events related to the use of either lifitegrast or vehicle were observed, and no worsening of visual acuity or intraocular pressure occurred in the intention-to-treat analysis. However, further inference was limited due to insufficient statistical power owing to significant washout and a 50% dropout rate from the all-enrolled analysis set. The most common causes of study dropout were worsening of unrelated medical conditions (not GVHD) and improvement of SANDE score or Schirmer score outside of the inclusion criteria range during the washout period. Conclusions Lifitegrast may be a useful steroid-sparing agent in the long-term management of oGVHD. This study provides further support for the clinical evidence of lifitegrast in the management of dry eye signs and symptoms, although further sufficiently powered clinical trials are warranted to better understand its efficacy in the oGVHD population. Personalized treatment options targeting distinct manifestations of oGVHD in the cornea, tear film, lid margin, and conjunctiva are needed in the effective management of this multifaceted and complex disease.

Mineralocorticoid receptor expression and the effects of the mineralocorticoid receptor antagonist spironolactone in a murine model of graft-versus-host disease.

PURPOSE: The topical administration of spironolactone, a mineralocorticoid receptor antagonist (MRA) improves dry eye symptoms in patients with ocular graft-versus-host disease (GVHD); however, the detailed mechanism remains unclear. This study aimed to investigate the effects of spironolactone eyedrops on the ocular surface using a chronic GVHD (cGVHD) mouse model and to determine the expression of the mineralocorticoid receptor (MR). METHODS: A cGVHD mouse model was established by allogeneic bone marrow transplantation (BMT) from B10.D2 mice to BALB/c mice. Subsequently, cGVHD mice were treated with either 0.005 % spironolactone or vehicle eyedrops. The eyelids, cornea and conjunctiva of the recipients were analyzed at 4-week intervals post-BMT in both groups. RESULTS: Signs of ocular GVHD, such as corneal epithelial damage, depletion of meibomian glands, and inflammatory cell infiltration onto the ocular surface, were significantly decreased in cGVHD mice treated with spironolactone eyedrops. The expression of the MR NR3C2 in the corneal and conjunctival epithelia was significantly increased in cGVHD mice. HSP47+NR3C2+ MR-expressing fibroblasts, CD45+NR3C2+ MR-expressing leukocytes, and CD4+NR3C2+ MR-expressing T cells infiltrated the ocular surface tissue of cGVHD mice significantly more than that of syngeneic controls. CONCLUSIONS: MR expression is increased in epithelial cells, fibroblasts, and T cells in a murine cGVHD model, whereas MRA and spironolactone eyedrops could attenuate the severity of ocular GVHD. These findings suggest that MR signaling partially contributes to the development of ocular GVHD in this mouse model.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier.MATERIALS AND METHODSThis study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.CONCLUSIONIn the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Association of choroidal invasion with retinoblastoma survival rates.

PURPOSE: To assess the impact of varying levels of choroidal invasion on survival from retinoblastoma. METHODS: A retrospective nationwide analysis of retinoblastoma cases diagnosed between 2004-2016 using the Surveillance, Epidemiology, and End Results database was conducted. Overall survival, cause-specific survival, and all-cause mortality risk were assessed as primary outcomes. RESULTS: A total of 393 retinoblastoma patients were included, of whom 268 (68.2%) had no choroidal invasion, 91 (23.2%) had focal choroidal invasion, and 34 (8.7%) had massive choroidal invasion on enucleation. A total of 6 deaths occurred throughout an average follow-up period of 72.2 ± 47.1 months: 4 deaths were cancer related. Adjusted Cox regression demonstrated higher all-cause mortality in patients with massive choroidal invasion (HR, 41.29; 95% CI, 4.05-420.49; P = 0.002) relative to those without choroidal invasion; however, those with focal choroidal invasion (HR, 2.69; 95% CI, 0.17-43.09; P = 0.484) demonstrated no difference in all-cause mortality. On further stratification by level of optic nerve invasion (ONI), all cancer-related deaths (4/4) were found to have occurred in patients with massive choroidal invasion and concomitant postlaminar ONI (PLONI). Patients with massive choroidal invasion without PLONI demonstrated 5-year overall and cause-specific survival of 100%, whereas patients with massive choroidal invasion and PLONI demonstrated 5-year overall and cause-specific survival of 80.2%. CONCLUSIONS: All retinoblastoma-related deaths occurred in patients with both massive choroidal invasion and PLONI. These findings could not establish that massive choroidal invasion is an independent risk factor for poor outcome.