Comparative Analysis of Alternative Calcium Chelators for the Treatment of Calcific Band Keratopathy.

PURPOSE: In this study, we compared clinically relevant biochemical properties of each chelator for pH, osmolarity, and calcium chelation potential. METHODS: In total, 0.2 M K 2 EDTA and K 3 EDTA (BD vacutainer tubes by Becton, Dickinson and Company) and Na 2 EDTA (Sigma Aldrich) solutions were made. The pH of each solution was measured (Mettler Toledo pH meter), and the theoretical osmolarity was calculated. Next, we determined the calcium chelation potential of each EDTA salt by titrating it with 10 µmol of calcium hydroxyapatite or CaCl 2 containing Patton-Reeder colorimetric indicator. Statistical significance was analyzed using analysis of variance. RESULTS: The 0.2 M solutions of Na 2 EDTA, K 2 EDTA, and K 3 EDTA have pH values of 4.43, 5.71, and 9.191 and theoretical osmolarities of 600, 600, and 800 mOsm/L, respectively. Calcium chelation ability was similar among all 3 solutions: 0.94 to 0.98 mol of EDTA was needed to fully chelate 1 mol calcium ions of CaCl 2 ( P = 0.296), 0.100 to 0.108 mol of EDTA for 1 mol calcium ions of the hydroxyapatite aqueous suspension ( P = 0.296), and 0.992 to 0.996 mol for 1 mol calcium ions of hydroxyapatite in acidic solution ( P = 0.178). Compared with the clinical standard of 3% (30 mg/mL) Na 2 EDTA, approximately 3.3% (33 mg/mL) K 2 EDTA and 3.6% (36 mg/mL) K 3 EDTA are needed to chelate an equivalent amount of calcium. CONCLUSIONS: In this article, we provide clinically relevant biochemical properties of 2 alternatives to Na 2 EDTA and demonstrate comparable calcium chelation ability among all 3 solutions. In situations where sterile sources of Na 2 EDTA are unavailable, potassium EDTA may provide a convenient and equally effective method of treatment for band keratopathy.

Differential Detection of O-GlcNAcylated proteins in the heart using antibodies.

Thousands of mammalian intracellular proteins are dynamically modified by O-linked ß-N-acetylglucosamine (O-GlcNAc). Global changes in O-GlcNAcylation have been associated with the development of cardiomyopathy, heart failure, hypertension, and neurodegenerative disease. Levels of O-GlcNAc in cells and tissues can be detected using numerous approaches; however, immunoblotting using GlcNAc-specific antibodies and lectins is commonplace. The goal of this study was to optimize the detection of O-GlcNAc in heart lysates by immunoblotting. Using a combination of tissue fractionation, immunoblotting, and galactosyltransferase labeling, as well as hearts from wild-type and O-GlcNAc transferase transgenic mice, we demonstrate that contractile proteins in the heart are differentially detected by two commercially available antibodies (CTD110.6 and RL2). As CTD110.6 displays poor reactivity toward contractile proteins, and as these proteins represent a major fraction of the heart proteome, a better assessment of cardiac O-GlcNAcylation is obtained in total tissue lysates with RL2. The data presented highlight tissue lysis approaches that should aid the assessment of the cardiac O-GlcNAcylation by immunoblotting.

Consultations in Eye Pathology: Experience at the Ophthalmology Specialty Hospital.

CONTEXT.­: Ophthalmic pathology is a discipline that relies heavily on a knowledge of clinical ophthalmology. The diagnosis of ocular and periocular lesions can be challenging because some lesions and diseases are unique to this region, whereas others may demonstrate site-specific differences from nonocular counterparts. Because of these challenges, ocular and periocular biopsies are frequently referred to specialized ophthalmic pathology centers for second opinion diagnoses. OBJECTIVE.­: To analyze the referral patterns, diagnostic challenges, and diagnostic discrepancies for second opinion referrals at a dedicated ophthalmic pathology laboratory with an emphasis on lesions of special interest in ophthalmic pathology. DATA SOURCES.­: Data sources included the pathology records of all slides and blocks received in consultation at the referral eye pathology center between December 1, 2015, and December 1, 2022, the personal experience of senior authors, and published peer-reviewed literature. CONCLUSIONS.­: Corneal, intraocular, and conjunctival biopsies are the most common types of cases received in consultation without the referring pathologist's diagnosis, likely reflecting diagnostic challenges. Degenerative intraocular processes occasionally raise concern for a neoplasm. Conjunctival melanocytic lesions are the most common conjunctival biopsies referred for second opinion diagnosis and require careful tissue sampling and clinical-pathologic correlation. Careful clinical-pathologic correlation, a high level of suspicion, and adequate sampling also are required for the accurate diagnosis of periocular sebaceous carcinoma. The diagnostic discrepancies involving uveal, retinal, conjunctival, eyelid, and temporal artery biopsies are most likely to adversely influence patient management and possible outcome. Such specimens may benefit from referral to specialized ophthalmic pathology laboratories.

The impact of primary repair timing on longitudinal visual outcomes after open globe injury.

BACKGROUND: The urgency with which to repair open globe injuries is a debated topic that lacks grounding in longitudinal visual outcomes data. We aim to test the association between primary repair timing and visual recovery potential following OGI. SUBJECTS/METHODS: We performed a retrospective cohort study of medical records from a US academic medical center (7/2017 to 11/2021). We included all patients with a principal diagnosis of OGI, a documented date and time of injury, presentation, repair, and ≥ 3 months of complete follow-up data on visual outcomes. We excluded those with prior OGI in the same eye. We also tested the correlation of injury to repair time (ITR) in hours with best corrected visual acuity (BCVA, in logMAR units) at last follow-up in the general cohort and select subpopulations and the impact of repair delay on visual improvement over the follow-up period. RESULTS: One hundred twenty-nine patients with OGI were analyzed (91 patients with ≥ 3 months of follow-up). The majority were male (105/129, 81%) with a median age of 45 years. Most OGI involved zone 1 (57%), followed by zone 3 (24%), and zone 2 injuries (19%). Median ocular trauma score (OTS) was 60 (IQR 37-70); mean presenting BCVA was logMAR 1.9 (median 2.3, IQR 1.0-2.7). Median ITR was 22 h (IQR 15-30 h, range 5-199 h). ITR time did not significantly correlate with final BCVA (n = 91, ß = - 0.003, 95% CI - 0.009-0.002, P = 0.233), nor did it significantly increase the odds of developing ocular complications or requiring secondary ocular surgeries (OR 0.985, 95% CI 0.967-1.002, P = 0.085). Additionally, the rate of BCVA improvement over subsequent months of follow-up did not significantly differ based on ITR time. Presenting BCVA (R2 = 0.701, P < 0.001) and OTS (R2 = 0.477, P < 0.001) significantly correlated with final BCVA, independent of repair delays. CONCLUSIONS: In this cohort of OGI patients, repair timing does not significantly correlate with final BCVA, and delays beyond 24 h do not significantly correlate with worse visual recovery potential. Repair time alone should be emphasized to a lesser extent as a prognosticator of visual potential, in favor of significant predictors such as the ocular trauma score and presenting visual acuity.

Educational quality and content of YouTube videos on diabetic macular edema.

PURPOSE: Diabetic macular edema (DME) is a vision-threatening complication of diabetes mellitus due to increased vascular permeability. Patients are increasingly using YouTube videos to educate themselves about DME. This study analyzes the content and quality of YouTube videos about DME. METHODS: Videos were searched in December 2021 for "diabetic macular edema." The first 100 videos sorted by both relevance and view count were reviewed (n = 200). Quantitative metrics and content were collected. Two reviewers assessed videos using the JAMA (0-4), modified DISCERN (1-5), and Global Quality Scale (GQS, 1-5). Videos were sorted into author groups: 1 (academic institutions/organizations), 2 (private practices/organizations), and 3 (independent users; ophthalmologist users noted). Statistical analyses were deemed significant at a = 0.05. RESULTS: One hundred four videos were included after applying exclusion criteria. Overall mean + standard deviations were 2.25 ± 0.83 (JAMA), 3.47 ± 0.55 (DISCERN), and 3.95 ± 0.95 (GQS). 51.9% of videos stated a definition, 32.7% mentioned screening, and 50% mentioned any DME risk factor. Healthcare professional-targeted videos had higher JAMA and DISCERN scores than patient-targeted videos (p < 0.05). Videos using ophthalmologists had higher JAMA and DISCERN scores than those lacking their presence (p < 0.05). JAMA scores significantly varied between author groups; within group 3, ophthalmologist-authored videos had higher DISCERN scores (p < 0.05). CONCLUSION: Videos without ophthalmologists or targeted toward patients had poor quality and content coverage. The rising prevalence of diabetes, coupled with increased internet use for acquiring medical information, creates a strong need for high-quality information about DME.

The Impact of Frailty Syndrome on Endogenous Endophthalmitis Development and Outcomes: A Population-Level Analysis.

PURPOSE: Characterize the impact of frailty on endogenous endophthalmitis (EE) development and clinical outcomes among septicemic patients. DESIGN: Population-level, retrospective cohort study. PARTICIPANTS: Adult inpatients within the National Inpatient Sample (years 2002-2014) diagnosed with bacterial septicemia. METHODS: Septicemic patients were classified as frail or nonfrail using the previously validated Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator, and diagnosis of EE was abstracted from International Classification of Diseases 9 codes. We used multivariable logistic regression to generate odds ratios (ORs) for rates of EE development and in-hospital mortality based on frailty status. We also examined the association between frailty and blood culture-proven organism class, inpatient length of stay, and total charges billed to insurance. MAIN OUTCOME MEASURES: Incidence of EE among septicemic patients; rates of EE development among frail and nonfrail patients; blood culture-proven microbe type, length of stay, and total charges billed to insurance. RESULTS: 9294 of 18 470 658 (0.05%) inpatients with bacteremia developed EE, 2102 (22.6%) of whom had at least 1 frailty-defining feature (predominantly malnutrition [68%]). Odds of developing EE were 16.7% higher for frail patients (OR, 1.167; 95% confidence interval, 1.108-1.229) when controlling for age, sex, race, concomitant human immunodeficiency virus/AIDS, pyogenic liver abscess, infectious endocarditis, cirrhosis, and diabetes with chronic complications. Frail EE patients had a 27.9% increased odds of in-hospital death, independent of age, sex, race, and Elixhauser comorbidity score (OR, 1.279; 95% confidence interval, 1.056-1.549). Higher rates of methicillin-resistant Staphylococcus aureus bacteremia (14.3% vs. 10.9%, P = 0.000016), gram-negative bacteremia (7.6% vs. 4.9%, P = 0.000003), and concomitant candidemia (10.4% vs. 7.0%, P = 0.0000004) were associated with frailty. Hospital stays were significantly longer (median, 14 days; interquartile range, 19 days; P < 0.00001) and total charges billed to insurance were significantly greater (median, $96 398; interquartile range, $154,682; P < 0.00001) among frail EE patients. CONCLUSIONS: Frailty syndrome is independently associated with development of EE in the setting of bacterial septicemia; frailty-associated EE may occur in patients with malnutrition and particular bacterial subtypes, and it predisposes to higher rates of in-hospital death and health care resource usage.

Cyclin D1 Expression and Molecular Genetic Findings in Periocular Histiocytoses and Neoplasms of Macrophage-Dendritic Cell Lineage.

PURPOSE: Frequent activating mutations in the mitogen-activated protein kinase (MAPK) pathway genes have been identified in histiocytoses. MAPK signaling consistently upregulates cyclin D1. The goal of this study was to determine whether cyclin D1 expression by immunohistochemistry is a useful diagnostic marker for periocular histiocytoses and to further characterize their genetic basis. DESIGN: Retrospective observational case series. METHODS: Pathology records were searched for all patients with histiocytoses diagnosed between 1995 and 2020. Eleven histiocyte-rich inflammatory lesions and 10 xanthelasma served as controls. Cyclin D1 immunohistochemistry was performed on all tissues. A subset of histiocytoses was evaluated by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). RESULTS: There were 36 patients, 15 males (42%) and 21 females (58%), with histiocytoses: 9 juvenile xanthogranuloma (25%), 8 adult-onset asthma and periocular xanthogranuloma (22%), 7 Langerhans cell histiocytosis (19%), 5 Rosai-Dorfman disease (14%), 5 xanthogranuloma-not otherwise specified (14%), 1 Erdheim-Chester disease (3%), and 1 histiocytic sarcoma (3%). Moderate to strong nuclear cyclin D1 expression was present in ≥50% of lesional cells in histiocytoses (23/36, 64%), significantly more when compared to histiocyte-rich inflammatory lesions (0/11, 0%, P<.001) and xanthelasma (0/10, 0%, P<.001). Cyclin D1 was expressed in <10% of lesional cells in all 11 histiocyte-rich inflammatory lesions (P<.001) and all 10 xanthelasma lesions (P<.001). MAPK pathway gene mutations were detected in 12 of 14 (86%) histiocytoses successfully assayed by NGS and/or ddPCR. CONCLUSIONS: Our study confirms that the cyclin D1 immunohistochemical stain is a useful diagnostic marker for periocular histiocytoses, correlating with underlying mutations in MAPK pathway genes.

Double-hit and triple-hit high-grade B-cell lymphoma of the ocular adnexa.

High-grade B-cell lymphoma (HGBL) with c-MYC and BCL2 and/or BCL6 rearrangements, also known as a double-hit and triple-hit lymphoma, is an aggressive non-Hodgkin lymphoma affecting older adults. After formal recognition of this entity in the 2017 revision of the World Health Organization Classification of lymphoid neoplasms, only two well-documented cases of triple-hit lymphoma of the orbit appear in the literature. Herein, we describe a 70-year-old man with progressive diplopia, ophthalmoplegia, and rapidly enlarging temporal mass. Biopsy revealed a tumor morphologically consistent with HGBL, coexpressing CD20, CD10, BCL6, BCL2, and c-MYC on immunohistochemical analysis. Fluorescence in-situ hybridization showed rearrangements in c-MYC and BCL-2 genes, confirming double-hit HGBL. Systemic workup revealed Ann Arbor stage IV disease. This report reviews the existing literature on ocular adnexal double-hit and triple-hit lymphoma and provides an update on the diagnostic ancillary studies, prognostic implications, and latest management for this aggressive hematolymphoid malignancy.

Frailty as a Predictor of Postoperative Complications Following Skull Base Surgery.

OBJECTIVE/HYPOTHESIS: Frailty has emerged as a powerful risk stratification tool across surgical specialties; however, an analysis of the impact of frailty on outcomes following skull base surgery has not been published. The aim of this study was to assess the validity of the 5-factor modified frailty index (mFI-5) as a predictor of perioperative morbidity and mortality in patients undergoing skull base surgery. METHODS: A mFI-5 score was calculated for patients undergoing skull base surgeries using the National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2018. Multivariate logistic regression analysis was used to evaluate the association of increasing frailty with complications in the 30-day postoperative period, with a subanalysis by operative location. RESULTS: A total of 17,912 patients who underwent skull base procedures were identified, with 45.5% of patients having a frailty score of one or greater; 44.9% were male and the mean age was 52.0 (±16.1 SD) years. Multivariable regression analysis revealed frailty to be an independent predictor of overall complications (odds ratio [OR]: 1.325, P < .001), life-threatening complications (OR: 1.428, P < .001), and mortality (OR: 1.453, P < .001). Higher frailty also correlated with increased length of stay. When procedures were stratified by operative location, frailty correlated significantly with overall complications for middle, posterior, and multiple-fossae operations but not the anterior fossa. CONCLUSIONS: Frailty demonstrates a significant and stepwise association with life-threatening postoperative morbidity, mortality, and length of stay following skull base surgeries. mFI-5 is an objective and easily calculable measure of preoperative risk, which may facilitate perioperative planning and counseling regarding outcomes prior to surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1977-1984, 2021.

Ocular adnexal lymphoma: A single-institution retrospective study.

PURPOSE: To characterize demographic, clinical, and histopathologic features of ocular adnexal lymphoma (OAL) at a single institution. METHODS: Retrospective review of all patients with pathologic diagnosis of OAL between 2015 and 2020. RESULTS: There were 133 patients with OAL, with a median age of 65 years (range 23-97) and a slight female predominance (male: female = 1:1.46), (n = 79, 59%). The majority of tumors were non-Hodgkin B-cell lymphomas (n = 131, 99%), most frequently Extranodal Marginal Zone B-Cell Lymphoma (EMZL, n = 93, 70%), followed by follicular lymphoma (n = 21, 16%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7, 5%), diffuse large B-cell lymphoma (n = 5, 4%), and mantle cell lymphoma (n = 5, 4%). The most frequently involved sites included the orbit (n = 85, 64%) and conjunctiva (n = 43, 32%). Information was available on oncologic staging in 78 (59%), treatment in 82 (62%), and follow-up in 75 (56%) patients. By the Ann-Arbor classification system, patients were classified as IE (54/78, 69%), IIE (9/78, 12%), IIIE (6/78, 8%), and IVE (9/78, 12%). The most common treatments included external beam radiotherapy (standard and ultra-low-dose) (48/82, 59%), biologics (22/82, 27%), and surgical excision with cryotherapy (14/82, 17%) (some patients had >1 therapy). Median follow-up time was 24 months (range 0-221 months). Recurrence was observed in 13% (10/75) with a median time to recurrence of 60 months (95% confidence interval 47-73 months). Excision with cryotherapy as a sole treatment modality was associated with earlier recurrence (P = 0.003). CONCLUSION: In this largest single-center study of OAL, we found that most OAL were Ann-Arbor Stage IE EMZL, occurring in older patients with a female predominance. Early recurrence was noted in tumors treated with excision and cryotherapy alone.

Validation of the Newly Proposed World Health Organization Classification System for Conjunctival Melanocytic Intraepithelial Lesions: A Comparison with the C-MIN and PAM Classification Schemes.

PURPOSE: We sought to compare the sensitivity, specificity, accuracy, and interobserver agreement of the two most commonly used classification systems for conjunctival melanocytic intraepithelial lesions with the new World Health Organization (WHO) classification. DESIGN: Retrospective case series and evaluation of classification systems. METHODS: We reviewed the pathology and medical records of all patients who underwent a primary biopsy procedure for conjunctival primary acquired melanosis (PAM) at Wills Eye Hospital between 1974 and 2002 who had ≥36 months of follow-up. Data collected included age, sex, clinical findings, recurrence, and progression to melanoma. Twelve ophthalmic pathologists analyzed scanned hematoxylin and eosin-stained virtual microscopic slides using 3 classification systems: PAM, conjunctival melanocytic intraepithelial neoplasia, and the WHO 4th edition classification of conjunctival melanocytic intraepithelial lesions. Observer agreement, sensitivity, specificity, and diagnostic accuracy of each classification system were assessed. RESULTS: There were 64 patients who underwent 83 primary excisions with cryotherapy for conjunctival PAM who had adequate tissue for histopathologic evaluation. The interobserver agreement in distinction between the low- and high-grade lesions was 76% for PAM, 67% for conjunctival melanocytic intraepithelial neoplasia, and 81% for WHO classification system. Low-grade lesions provided the greatest interpretative challenge with all 3 classification systems. The 3 classification systems had comparable accuracy of 81%-83% in their ability to identify lesions with potential for recurrence. CONCLUSIONS: This study highlights the comparable strengths and limitations of the 3 classification systems for conjunctival melanocytic intraepithelial lesions and suggests that the simplified WHO classification scheme is appropriate for evaluation of these lesions.

Orbital and Ocular Adnexal Manifestations of Adult T-Cell Leukemia/Lymphoma: a Case Report and Systematic Review.

PURPOSE: To describe a patient with orbital adult T-cell leukemia/lymphoma (ATLL) and to review the literature on presentation, diagnostics, management, and clinical course of this rare disease. METHODS: A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of orbital/ocular adnexal ATLL. RESULTS: Sixteen patients were included in the final analysis. The median age at diagnosis was 47 years (range, 20-85), 9/16 patients (56%) were male, and patients were of Japanese (10/16, 63%), Caribbean (5/16, 31%), or African (1/16, 6%) origin. Proptosis (6/15, 40%) and visual loss (5/15, 33%) were the most common presenting signs. Involvement of adjacent structures was documented in 8 of 16 (50%) patients. All patients had evidence of systemic ATLL, which was identified concurrently with orbital/ocular adnexal disease in 9 of 15 (60%) patients. Management included multi-agent chemotherapy with steroids (9/13, 69%), antivirals (2/13, 15%), biologic agents (4/13, 31%), and umbilical cord blood transplantation (1/13, 8%). Most patients (8/12, 67%) experienced at least partial remission with disease relapse occurring in 6 of 8 patients (75%). The median survival time was 28 months (95% CI, 5.5-50.5 months). CONCLUSIONS: Adult T-cell leukemia/lymphoma should be considered in the differential diagnosis of orbital and ocular adnexal space-occupying lesions, particularly in male patients from endemic regions. Orbital disease is frequently locally aggressive and presents concurrently with systemic ATLL, highlighting the importance of comprehensive multimodal work-up and multidisciplinary management. Emerging targeted therapies and hematopoietic stem cell transplant may prolong survival.

Ocular adnexal manifestations of neuroendocrine neoplasms: a case report and a major review.

PURPOSE: To describe a patient with orbital neuroendocrine neoplasm (NEN)/carcinoid tumor and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported ocular adnexal (OA) NENs. METHODS: A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of OA NENs. RESULTS: Final analysis yielded 94 patients with OA NENs, 50 females (53%) and 44 (47%) males with an average age of 63 years (range 14-86). Of 91 patients with known information, the most common presenting signs were proptosis (56/91, 61%) and visual disturbances (42/91, 47%), induced by a mass most commonly associated with an extraocular muscle (49/63, 78%). The majority of tumors (88/94, 94%) were metastases, most commonly from the gastrointestinal tract (52/88, 59%). OA NEN metastasis presented following detection of primary tumor in 73/94 (78%) patients (median time to metastasis 36 months, range 0-288 months) and as an initial manifestation of disease in 15/94 (16%) patients (median time to primary detection 18 months, range 1-108 months). Systemic work-up included extra-OA NEN biopsy (37/54, 69%), multimodal imaging (42/54, 78%), and other laboratory studies (32/54, 59%). Resection with or without adjuvant chemotherapy, radiotherapy, and biologics was the most common intervention for OA NENs (36/82, 44%). Of 67 patients with available follow-up, the median survival was 108 months (95% CI 55-161 months) and the absolute 5-year survival rate was 68%. CONCLUSIONS: OA NENs are almost exclusively metastases and can precede detection of primary tumor by many months, requiring appropriate diagnostic work-up.