Enhancing Diversity in the Ophthalmology Workforce.

Health care teams are most effective at addressing complex problems and improving health outcomes for underserved populations when team members bring diverse life experiences and perspectives to the effort. With rates of visual impairment expected to increase in the United States by 2050, especially among minority populations, diversification of the ophthalmology workforce will be critical in reducing disparities in access to and quality of vision health care. Currently, ophthalmology is less diverse with respect to race, ethnicity, and gender than graduating medical classes and other medical specialties, as well as the general US population. In addition, data on diversity in sexual orientation and gender identity, socioeconomic status, and disability are lacking in ophthalmology. The Minority Ophthalmology Mentoring and Rabb-Venable Excellence in Ophthalmology Programs are examples of initiatives to increase racial and ethnic diversity in the workforce and can serve as models for increasing other aspects of inclusiveness. Other strategies for improving vision health care for all Americans include continuing to support existing diversity programs and creating new ones; addressing unconscious and implicit bias in medical school, residency, and faculty selections; conducting holistic reviews of medical school and residency applications; diversifying selection committees and leadership; and encouraging faculty development of underrepresented groups.

Ophthalmic Immune-Related Adverse Events after Anti-CTLA-4 or PD-1 Therapy Recorded in the American Academy of Ophthalmology Intelligent Research in Sight Registry.

PURPOSE: Detailed study of ophthalmic immune-related adverse events (AEs), including determination of incidence and recurrence rates, is of integral importance in cancer immunotherapy to inform management and treatment guidelines. DESIGN: Retrospective registry study. PARTICIPANTS: Patients newly diagnosed with ophthalmic immune-related AEs between January 1, 2013, and December 31, 2017, in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS®) Registry. METHODS: Data were collected from electronic health records of IRIS® Registry participating ophthalmology practices. Patients with select ophthalmic immune-related AEs were identified by International Classification of Diseases diagnosis codes. The primary exposure of interest was prior initiation of immune checkpoint inhibitors (ICIs). MAIN OUTCOME MEASURES: Incidence of ophthalmic immune-related AEs within 1 year after initiation of ICI therapy was determined. Incidence rate ratios (IRRs) were derived by comparing incidence of ophthalmic immune-related AEs after ICIs versus rates of the same ocular complications in patients not taking ICIs in the entire registry population. Rates of ophthalmic immune-related AEs in patients with a past history of ocular inflammation or other specific ophthalmic condition before initiation of ICIs were examined further. RESULTS: A total of 3123 patients who received anti-CTLA-4 or anti-programmed cell death 1 (PD-1) therapy were identified, 112 of whom demonstrated an ophthalmic immune-related AE. Incidence rates for anterior uveitis, the most common ophthalmic immune-related AE, were 8209 per 100 000 for ipilimumab (anti-CTLA-4), 2542 per 100 000 for nivolumab (anti-PD-1), 2451 per 100 000 for pembrolizumab (anti-PD-1), 5556 per 100 000 for ipilimumab plus nivolumab, and 3740 per 100 000 among all ICIs. Rates of ophthalmic immune-related AEs among patients receiving ICI therapy were higher compared with baseline rates in the general registry population (anterior uveitis IRR, 13.9; other uveitis IRR, 43.0; papilledema IRR, 38.3). Patients with a history of uveitis or other ocular inflammatory condition demonstrated high recurrence rates of ophthalmic immune-related AEs after initiating ICIs (up to 51.1%). CONCLUSIONS: For patients initiating ICI therapy, early coordination with ophthalmic subspecialist care is important because rates of ophthalmic immune-related AEs are elevated compared with ocular complication rates in the entire registry population and patients with a history of prior autoimmune ocular disease are at high risk of recurrence of ocular complications.

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

BACKGROUND: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. METHODS: A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. RESULTS: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. CONCLUSION: This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

Bullying, harassment and sexual discrimination among ophthalmologists in Australia and New Zealand.

BACKGROUND: Discrimination, bullying and sexual harassment (DBSH) impact the psychological well-being of doctors and contribute to poor health outcomes. The Royal Australian and New Zealand College of Ophthalmologists (RANZCO) commissioned independent surveys to evaluate DBSH among members/trainees. METHODS: Anonymous online surveys by Best Practice Australia were undertaken in 2015 and 2018. Cross-sectional analysis was prevalence of perceived DBSH, rates of reporting, intervention and resolution undertaken. Response rate was 50% (658/1319) in 2015 and 40% (557/1401) in 2018. In both surveys, 29% were female. This is representative of the distribution of the RANZCO members. RESULTS: In a 2015 survey, 37.6% of respondents experienced DBSH, with prevalence being the highest for females (62.3%; N = 104 cf males 27.7%; N = 167) and trainees (49.2%; N = 61). In 2018, 49.2% of respondents reported DBSH with rates low for all forms of DBSH (22%-29%). Sexual harassment was reported by 12% and the least discussed or reported. Respondents strategy for taking action included draw on personal support network (25-43%), official complaints to supervisors (16-22%), human resources (2%-10%) and RANZCO (0%-6%). Reasons for not taking action included fear of impact of future career options (54.1%-60.7%), fear of victimization (35.7%-50.4%) and afraid of not being believed (31.9%-52.4%). Satisfactory resolution rates were 6% to 25%. A majority of respondents (77%) were positive about RANZCO initiatives. CONCLUSIONS: DBSH is commonly reported by RANZCO members with female ophthalmologists more than two times more likely to experience any one of the four behaviours, three times more likely to experience discrimination and six times for sexual harassment. Fear of compromising personal and career progression contribute to low levels of reporting.

Identification of epithelial membrane protein 2 (EMP2) as a molecular marker and correlate for angiogenesis in meningioma.

PURPOSE: Although intracranial meningiomas are the most common primary brain tumor in adults, treatment options are few and have traditionally been limited to surgical resection and radiotherapy. Additional targeted therapies and biomarkers are needed, especially as complete surgical resection is frequently not feasible in many patients. METHODS: Non-pathologic brain tissue from 3 patients undergoing routine autopsies and tumor specimens from 16 patients requiring surgical resection for meningioma were collected. EMP2 protein expression was evaluated by immunohistochemistry and western blot analysis. EMP2 mRNA expression was also investigated using surgical specimens and validated by analysis of several independent NCBI GEO databases. RESULTS: EMP2 mRNA expression levels were found to be higher in meningioma relative to non-pathologic meninges (P = 0.0013) and brain (P = 0.0011). Concordantly, strong EMP2 protein expression was demonstrated in 100% of meningioma specimens from all 16 patients, with no observable protein expression in normal brain tissue samples from 3 subjects (P < 0.001). EMP2 expression was confirmed by western blot analysis in five samples, with EMP2 protein intensity positively correlating with histologic staining score (R2 = 0.780; P = 0.047). No association was found between EMP2 mRNA or protein levels and WHO grade or markers of proliferation. However, EMP2 expression was positively associated with an angiomatous pattern on histologic evaluation (P = 0.0597), VEGF-A mRNA expression (P < 0.001), and clinical markers of tumor vascularity such as operative blood loss (P = 0.037). CONCLUSIONS: EMP2 is not found in normal brain tissue, yet has shown consistently high mRNA and protein expression in meningiomas, and may serve as a useful molecular marker for these tumors.

Gender-based differences in letters of recommendation written for ophthalmology residency applicants.

BACKGROUND: To determine whether gender-based differences may be present in letters of recommendation written for ophthalmology residency applicants. METHODS: All applications submitted through SF Match to the UCLA Stein Eye Institute Residency Training Program from the 2017-2018 application cycle were analyzed using validated text analysis software (Linguistic Inquiry and Word Count (Austin, TX)). The main outcome measures were differences in language use in letters of recommendation by gender of applicant. RESULTS: Of 440 applicants, 254 (58%) were male and 186 (42%) were female. The two gender groups had similar United States Medical Licensing Exam (USMLE) Step 1 scores, undergraduate grade point averages (uGPA's), proportions of underrepresented minority (URM) applicants and Gold Humanism Honor Society members, numbers of academic and service activities listed, and gender distributions of their letter writers (all P values > 0.05). However, letters written for male applicants were determined to use more "authentic" words than those written for female applicants (mean difference, 0.800; 95% CI, 0.001-1.590; P = 0.047). Letters written for male applicants also contained more "leisure" words (mean difference, 0.056; 95% CI, 0.008-0.104; P = 0.023) and fewer "feel" words (mean difference, 0.033; 95% CI, 0.001-0.065; P = 0.041) and "biological processes" words (mean difference, 0.157; 95% CI, 0.017-0.297; P = 0.028). CONCLUSIONS: There were gender differences detected in recommendation letters in ophthalmology consistent with prior studies from other fields. Awareness of these differences may improve residency selection processes.

Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is associated with an extremely poor clinical prognosis. One pathologic hallmark of GBM is excessive vascularization with abnormal blood vessels. Extensive investigation of anti-angiogenic therapy as a treatment for recurrent GBM has been performed. Bevacizumab, a monoclonal anti-vascular endothelial growth factor A (VEGF-A), suggests a progression-free survival benefit but no overall survival benefit. Developing novel anti-angiogenic therapies are urgently needed in controlling GBM growth. In this study, we demonstrate tumor expression of epithelial membrane protein-2 (EMP2) promotes angiogenesis both in vitro and in vivo using cell lines from human GBM. Mechanistically, this pro-angiogenic effect of EMP2 was partially through upregulating tumor VEGF-A levels. A potential therapeutic effect of a systemic administration of anti-EMP2 IgG1 on intracranial xenografts was observed resulting in both significant reduction of tumor load and decreased tumor vasculature. These results suggest the potential for anti-EMP2 IgG1 as a promising novel anti-angiogenic therapy for GBM. Further investigation is needed to fully understand the molecular mechanisms how EMP2 modulates GBM pathogenesis and progression and to further characterize anti-EMP2 therapy in GBM.

Optic Nerve.

Optic nerve diseases arise from many different etiologies including inflammatory, neoplastic, genetic, infectious, ischemic, and idiopathic. Understanding some of the characteristics of the most common optic neuropathies along with therapeutic approaches to these diseases is helpful in designing recommendations for individual patients. Although many optic neuropathies have no specific treatment, some do, and it is those potentially treatable or preventable conditions which need to be recognized in order to help patients regain their sight or develop a better understanding of their own prognosis. In this chapter several diseases are discussed including idiopathic intracranial hypertension, optic neuritis, ischemic optic neuropathies, hereditary optic neuropathies, trauma, and primary tumors of the optic nerve. For each condition there is a presentation of the signs and symptoms of the disease, in some conditions the evaluation and diagnostic criteria are highlighted, and where possible, current therapy or past trials are discussed.

Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma.

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvß3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush.

Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury.

Paraneoplastic Syndromes in Neuro-Ophthalmology.

BACKGROUND: Paraneoplastic syndromes that affect the visual pathways and present with neuro-ophthalmologic signs or symptoms may involve the afferent or efferent systems. Afferent syndromes may involve the optic nerve or retina and, in some cases, these may be associated with systemic neurologic disease. Efferent symptoms typically affect eye movements and may involve the neuromuscular junction or involuntary eye movements. EVIDENCE ACQUISITION: Literature review and personal clinical and research experience. RESULTS: Diagnosis of paraneoplastic syndromes relies on clinical and laboratory evaluations. In the appropriate clinical setting, the presence of specific antibodies may help confirm the diagnosis. CONCLUSIONS: In some cases, the visual pathway disturbance precedes a diagnosis of malignancy. Astute observation and selective evaluation and management are critical to establish the correct diagnosis and institute therapeutic approaches that can be sight or life saving.

Satisfaction of Women Faculty in Academic Medicine.

Purpose: Research about academic medicine women faculty has focused on comparisons of men and women or specific groups who achieved leadership. To better understand the low percentages of women in academic medicine leadership, attention should be paid to the career continuum within genders. Study findings will inform policies and programs to support women in building careers and acquiring leadership positions. Materials and Methods: Association of American Medical Colleges (AAMC) StandPoint Faculty Engagement Survey data are used to describe and compare women assistant, associate and full professors' perceptions of (1) career development and advancement opportunities, and (2) a culture and climate that fosters diversity, equity, and inclusion. Specific similarities and differences with men are highlighted. Results: Fifty-nine percent of women respondents were assistant, 25% associate, and 16% full professors. Associate professors of both genders were the least satisfied on the main measures. Women were less satisfied than men at each career stage across the majority of variables. Among women, fewer than half of full and associate professors, and 52% of assistant professors believe they can express their opinions without fear of retribution. While the majority at all ranks (69%-75%) report feeling respected in the workplace, among those who did not, the highest percentage of disrespect based on gender was among associate professors. Conclusions: The perceptions of >7,500 academic medicine women faculty, representing different generations and ranks, underscore the need to broadly address gender inequity and sexism throughout the career continuum. It identifies the mid-career stage as a challenging experience for both men and women. Women, especially at the associate professor rank, remain a critically dissatisfied and underresourced group that is at risk for underutilization and potentially exit from academic medicine. All ranks of women need career development and equitable policies to support their sense of belonging and career advancement.

89Zr-ImmunoPET for the Specific Detection of EMP2-Positive Tumors.

Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for mAb-based therapy. In the current study, image-guided therapy for an anti-EMP2 mAb was evaluated by PET in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2-expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2-positive tumors within 24 hours after injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, and U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02 and Ramos). Biodistribution at 5 days after injection revealed that the tumor uptake ranged from 2 to approximately 16%ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 Ab fragments may be useful to track EMP2-positive tumors for subsequent therapeutic interventions.

EMP2 Serves as a Functional Biomarker for Chemotherapy-Resistant Triple-Negative Breast Cancer.

Breast cancer (BC) remains among the most commonly diagnosed cancers in women worldwide. Triple-negative BC (TNBC) is a subset of BC characterized by aggressive behavior, a high risk of distant recurrence, and poor overall survival rates. Chemotherapy is the backbone for treatment in patients with TNBC, but outcomes remain poor compared to other BC subtypes, in part due to the lack of recognized functional targets. In this study, the expression of the tetraspan protein epithelial membrane protein 2 (EMP2) was explored as a predictor of TNBC response to standard chemotherapy. We demonstrate that EMP2 functions as a prognostic biomarker for patients treated with taxane-based chemotherapy, with high expression at both transcriptomic and protein levels following treatment correlating with poor overall survival. Moreover, we show that targeting EMP2 in combination with docetaxel reduces tumor load in syngeneic and xenograft models of TNBC. These results provide support for the prognostic and therapeutic potential of this tetraspan protein, suggesting that anti-EMP2 therapy may be beneficial for the treatment of select chemotherapy-resistant TNBC tumors.

Anti-EMP2 diabody blocks epithelial membrane protein 2 (EMP2) and FAK mediated collagen gel contraction in ARPE-19 cells.

Epithelial membrane protein 2 (EMP2) regulates collagen gel contraction by the retinal pigment epithelium cell line ARPE-19 by modulating FAK activation. Collagen gel contraction is one in vitro model for an aberrant wound healing response, proliferative vitreoretinopathy (PVR), which occurs as a complication of severe ocular trauma. The purpose of this study is to investigate whether EMP2 specific recombinant diabody decreases activation of FAK and collagen gel contraction in ARPE-19. Anti-EMP2 diabody was recombinantly constructed from a human phage library-derived clone selected for reactivity against an extracellular domain of human EMP2. ARPE-19 cells were exposed to an anti-EMP2 or control diabody, and toxicity, adhesion, and migration were assessed respectively through toluidine blue exclusion, binding to collagen type 1, and a migration assay. Collagen gel contraction was assessed using an in vitro assay. FAK activation was evaluated using Western blot. Exposure to anti-EMP2 diabody, resulted in a 75% reduction in EMP2 protein levels at 4 h. No significant toxicity was observed with anti-EMP2 diabody at levels that maximally reduced EMP2. Anti-EMP2 diabody, but not control diabody, significantly reduced collagen gel contraction (p < 0.001), without changes in adhesion or migration. Concordantly, anti-EMP2 diabody as compared to a control diabody reduced collagen stimulated FAK activation (p = 0.01). Anti-EMP2 diabody decreases EMP2 protein levels, FAK activation, and collagen gel contraction by ARPE-19 cells without an adverse effect on cell survival. Modulation of EMP2 using anti-EMP2 diabody could be a new approach for targeting EMP2 and pathologic consequences associated with EMP2.

Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice.

OBJECTIVES: During mouse retina maturation, the final number of retinal ganglion cells (RGCs) is determined by highly regulated programmed cell death. Previous studies demonstrated that the immunoregulatory receptor programmed cell death-1 (PD-1) promotes developmental RGC death. To identify the functional signaling partner(s) for PD-1, we identified retinal expression of PD-1 ligands and examined the effect of PD-1 ligand expression on RGC number. We also explored the hypothesis that PD-1 signaling promotes the development of functional visual circuitry. METHODS: Characterization of retinal and brain programmed cell death-1 ligand 1 (PD-L1) expression were examined by immunofluorescence on tissue sections. The contribution of PD-ligands, PD-L1, and programmed cell death-1 ligand 2 (PD-L2) to RGC number was examined in PD-ligand knockout mice lacking 1 or both ligands. Retinal architecture was assessed by spectral-domain optical coherence tomography, and retinal function was analyzed by electroretinography in wild-type and PD-L1/L2 double-deficient mice. RESULTS: PD-L1 expression is found throughout the neonatal retina and persists in adult RGCs, bipolar interneurons, and Müller glia. In the absence of both PD-ligands, there is a significant numerical increase in RGCs (34% at postnatal day 2 [P2] and 18% in adult), as compared to wild type, and PD-ligands have redundant function in this process. Despite the increased RGC number, adult PD-L1/L2 double-knockout mice have normal retinal architecture and outer retina function. CONCLUSION: This study demonstrates that PD-L1 and PD-L2 together impact the final number of RGCs in adult mice and supports a novel role for active promotion of neuronal cell death through PD-1 receptor-ligand engagement.