Intrinsic disorder in PRAME and its role in uveal melanoma.

INTRODUCTION: The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM. METHODS: A bioinformatics study to characterize PRAME's propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the protein structure of PRAME. Then we used the Compositional Profiler and a set of per-residue intrinsic disorder predictors to quantify the intrinsic disorder. The Database of Disordered Protein Prediction (D2P2) platform, IUPred, FuzDrop, fIDPnn, AUCpred, SPOT-Disorder2, and metapredict V2 allowed us to evaluate the potential functional disorder of PRAME. Additionally, we used the Search Tool for the Retrieval of Interacting Genes (STRING) to analyze PRAME's potential interactions with other proteins. RESULTS: Our structural analysis showed that PRAME contains intrinsically disordered protein regions (IDPRs), which are structureless and flexible. We found that PRAME is significantly enriched with serine (p-value < 0.05), a disorder-promoting amino acid. PRAME was found to have an average disorder score of 16.49% (i.e., moderately disordered) across six per-residue intrinsic disorder predictors. Our IUPred analysis revealed the presence of disorder-to-order transition (DOT) regions in PRAME near the C-terminus of the protein (residues 475-509). The D2P2 platform predicted a region from approximately 140 and 175 to be highly concentrated with post-translational modifications (PTMs). FuzDrop predicted the PTM hot spot of PRAME to be a droplet-promoting region and an aggregation hotspot. Finally, our analysis using the STRING tool revealed that PRAME has significantly more interactions with other proteins than expected for randomly selected proteins of the same size, with the ability to interact with 84 different partners (STRING analysis result: p-value < 1.0 × 10-16; model confidence: 0.400). CONCLUSION: Our study revealed that PRAME has IDPRs that are possibly linked to its functionality in the context of Class 1 UM. The regions of functionality (i.e., DOT regions, PTM sites, droplet-promoting regions, and aggregation hotspots) are localized to regions of high levels of disorder. PRAME has a complex protein-protein interaction (PPI) network that may be secondary to the structureless features of the polypeptide. Our findings contribute to our understanding of UM and suggest that IDPRs and DOT regions in PRAME may be targeted in developing new therapies for this aggressive cancer. Video Abstract.

Subpalpebral Antibiotic Lavage for the Treatment of Refractory Infectious Scleritis.

Infectious scleritis is a potentially devastating condition that can result in severe vision loss. When traditional management fails, a subpalpebral antibiotic lavage system (SAL) can be considered to bathe the infected area with a high volume and concentration of antibiotics. Several reports show that this method can be curative for infectious scleritis, otherwise refractory to care. However, surgical approaches for this technique are either not well described, advocate for transecting the levator aponeurosis, or do not expose the entire width of the superior fornix, which can lead to postoperative ptosis. The authors describe a case where a novel approach was utilized, using a fenestrated angiocather in the superior lateral fornix, to maximize outcomes and minimize postoperative complications. In the setting of infectious scleritis refractory to traditional management, a SAL can be safely and effectively placed with the technique detailed in this report.

The role of imaging technologies for ocular surface tumors.

PURPOSE OF REVIEW: This review will discuss the utility of high-resolution anterior segment optical coherence tomography (HR-OCT), in-vivo confocal microscopy (IVCM) and ultrasound biomicroscopy (UBM) in characterizing and diagnosing various ocular surface tumors, namely ocular surface squamous neoplasia (OSSN), conjunctival lymphoma and conjunctival melanoma. The strengths and limitations of each imaging modality will be discussed along with the characteristics findings of each lesion on each imaging platform. RECENT FINDINGS: HR-OCT can consistently be utilized in the clinic setting to distinguish between epithelial ocular surface tumors such as OSSN as compared with subepithelial tumors such as conjunctival lymphoma and conjunctival melanoma given their distinctive findings. IVCM can be used as an adjunct to HR-OCT to obtain cellular and surface characteristics, whereas UBM can be used to assess tumor depth and thickness for larger and highly pigmented lesions as well as to detect intraocular invasion. SUMMARY: HR-OCT, IVCM and UBM are all helpful imaging modalities to diagnose and characterize various ocular surface tumors and can serve as valuable adjuncts to monitor treatment response and assess for recurrence ocular surface tumors.

Case Series: High-resolution Optical Coherence Tomography as an Optical Biopsy in Ocular Surface Squamous Neoplasia.

SIGNIFICANCE: Ocular surface squamous neoplasias are superficial tumors of the cornea and conjunctiva that can be sight threatening if neglected. Therefore, accurate noninvasive diagnostic modalities are needed. PURPOSE: The purpose of this case series was to describe the hallmark features of ocular surface squamous neoplasia on high-resolution optical coherence tomography (HR-OCT) imaging and its use in the evaluation and management of superficial ocular tumors. CASE SERIES: Five eyes of four patients with ocular surface squamous neoplasia are described. Whereas two eyes displayed the classic clinical features of ocular surface squamous neoplasia, three of the five eyes had more subtle atypical features. However, all shared features on HR-OCT of epithelial thickening and hyperreflectivity with abrupt transitions between normal and abnormal tissue, classic features of ocular surface squamous neoplasia. All lesions ultimately underwent incisional or excisional biopsy and were confirmed to be ocular surface squamous neoplasia on histopathology. CONCLUSIONS: Ocular surface squamous neoplasia may present as a classic tumor but can also have subtle features or masquerade. Accurate methods to diagnose and manage patients with ocular surface squamous neoplasia are necessary. With recent advancements in technology, HR-OCT has been demonstrated to accurately identify ocular surface squamous neoplasia with the repeatable optical findings of (1) epithelial thickening, (2) epithelial hyperreflectivity, and (3) abrupt transition zone between normal and abnormal tissue. This case series demonstrates how HR-OCT can help provide an optical biopsy to guide appropriate diagnosis and management of this neoplastic lesion.

Blue Nevi of the Ocular Surface: Clinical Characteristics, Pathologic Features, and Clinical Course.

PURPOSE: Blue nevus is a melanocytic tumor that is commonly found in the skin. Extracutaneous presentations, including the ocular surface, are rare. As such, the purpose of this study was to characterize the clinical features and clinical course of congenital melanocytic tumor (blue nevus) of the conjunctiva. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Twenty-one patients with 23 blue nevi of the ocular surface that were excised surgically between 2000 and 2016. METHODS: Chart review of patients identified from a database search of the Florida Lions Ocular Pathology Laboratory records. Pathologic diagnoses were confirmed by 2 pathologists (S.R.D. and G.E.). All specimens were bleached and, tissue permitting, stained using SOX10 (MilliporeSigma, Darmstadt, Germany) and CD68 (Leica Biosystems, Nussloch, Germany). MAIN OUTCOME MEASURES: Clinical characteristics, pathologic features, and clinical course. RESULTS: Mean age of the population was 55±15 years; 71.4% (n = 15) were white and 57.1% (n = 12) were men. One patient had 3 lesions, for a total of 23 lesions examined. Clinically, 13 lesions were on the bulbar conjunctiva, 3 were on the tarsal conjunctiva, 3 were in the fornix, 2 were caruncular, 1 was episcleral, and 1 was at the limbus. Before excision, 8 patients were thought to have primary acquired melanosis, 4 with concern for primary conjunctival melanoma, and 1 thought to have metastatic disease from a plantar melanoma. Five lesions were thought to be benign, and in 8 patients, the lesions were identified incidentally after other ocular surgeries, with no diagnosis of the lesions before excision. Pathologic features were consistent with simple blue nevi in 21 lesions and cellular blue nevus in 2 lesions. No malignant transformations were noted in any patient over the mean 20.2-month follow-up period (range, 2 weeks-103 months). CONCLUSIONS: Blue nevus is a rare deeply pigmented congenital melanocytic lesion with a benign clinical course that can appear clinically similar to primary acquired melanosis or melanoma.

Neuropathic-Like Ocular Pain and Nonocular Comorbidities Correlate With Dry Eye Symptoms.

OBJECTIVE: To evaluate the association between dry eye (DE) symptoms and neuropathic-like ocular pain (NOP) features, chronic pain conditions, depression, and anxiety in patients presenting for routine ophthalmic examinations. METHODS: Two hundred thirty-three consecutive patients ≥18 years of age presenting to a comprehensive eye clinic between January and August 2016 were included in this study. Information on demographics, chronic pain conditions, medication use, DE symptoms (dry eye questionnaire, DEQ5), NOP complaints (burning; wind, light, and temperature sensitivity), depression, and anxiety indices (patient health questionnaire 9, PHQ-9 and symptom checklist 90-revised, SCL-90-R) were collected for each individual. Pearson correlation was used to evaluate strengths of association. Logistic regression analysis examined risk factors for any (DEQ5≥6) and severe (DEQ5≥12) DE symptoms. RESULTS: The mean age of the population was 46.3 years (±13.0); 67.8% (n=158) were female. Per the DEQ5, 40.3% (n=94) had mild or greater DE symptoms and 12% (n=24) had severe symptoms. Severity of DE symptoms correlated with NOP complaints: burning (Pearson r=0.37, P<0.001); sensitivity to wind (r=0.37, P<0.001), sensitivity to light (r=0.34, P<0.001), and sensitivity to temperature (r=0.30, P<0.001). Sex, race, and ethnicity were not significant risk factors for DE symptoms. Risk factors for mild or greater DE symptoms included a greater number of chronic nonocular pain conditions (odds ratio [OR]=1.38, P<0.001), arthritic pain (OR=6.34, P<0.001), back pain (OR=2.47, P=0.004), headaches (OR=2.14, P=0.02), depression (OR=1.17, P<0.001), and anxiety (OR=1.13, P=0.02). CONCLUSION: Dry eye severity positively associated with NOP complaints, comorbid chronic pain conditions, and symptoms of depression and anxiety.

Sub-basal Corneal Nerve Plexus Analysis Using a New Software Technology.

PURPOSE: To study sub-basal corneal nerve plexus (SCNP) parameters by in vivo corneal confocal microscopy using a new software technology and examine the effect of demographics and diabetes mellitus (DM) on corneal nerves morphology. METHODS: A Confoscan 4 (Nidek Technologies) was used in this cross-sectional study to image the SCNP in 84 right eyes at the Miami Veterans Affairs eye clinic. Images were analyzed using a new semiautomated nerve analysis software program (The Corneal Nerve Analysis tool) which evaluated 9 parameters including nerve fibers length (NFL) and nerve fibers length density (NFLD). The main outcome measure was the examination of SCNP morphology by demographics, comorbidities, and HbA1c level. RESULTS: Interoperator and intraoperator reproducibility were good for the 9 parameters studied (Intraclass Correlations [ICCs] 0.73-0.97). Image variability between two images within the same scan was good for all parameters (ICC 0.66-0.80). Older individuals had lower SCNP parameters with NFL and NFLD negatively correlating with age (r=-0.471, and -0.461, respectively, P<0.01 for all). Patients with diabetes had lower mean NFLD 10987.6 µm/mm (±3,284.6) and NFL 1,289.5 µm/frame (±387.2) compared with patients without diabetes (mean NFLD 15077.1 µm/mm [±4,261.3] and NFL 1750.0 µm/frame [±540.7]) (P<0.05 for all). HbA1c levels in patients with diabetes were inversely correlated with NFL and NFLD (r= -0.568, and -0.569, respectively, P<0.05 for all). CONCLUSIONS: The Corneal Nerve Analysis tool is a reproducible diagnostic software technique for the analysis of the SCNP with confocal microscopy. Older age, DM, and higher level of HbA1c were associated with a significant reduction in SCNP parameters.

Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears.

PURPOSE: To report a case of filamentary keratitis (FK) successfully treated with autologous serum tears and to review the pathogenesis and management of FK. METHODS: Case report including high-resolution anterior segment optical coherence tomography and filament histopathology. CASE REPORT: A 61-year-old Hispanic man presented with pain and photophobia of the right eye. He was found to have a corneal epithelial defect and a small peripheral infiltrate 4 months after Laser Assisted in situ Keratomileusis. After resolution of the epithelial defect, he developed FK. Over a 4-month period, conservative management with aggressive lubrication, lid hygiene, topical corticosteroids, topical cyclosporine, bandage contact lenses, and oral doxycycline failed to resolve the corneal filaments. Notably, treatment with 20% autologous serum tears, four times daily, led to a sustained resolution of the FK within 1 week. CONCLUSIONS: This case demonstrates the complexity of FK management and introduces autologous serum tears as a viable management option when conservative approaches to this condition fail.

Compliance and Subjective Patient Responses to Eyelid Hygiene.

OBJECTIVES: Lid hygiene is a commonly prescribed first-line therapy in patients with lid margin disease, yet compliance with therapy is not well characterized. The goals of this study were to assess patient compliance with lid hygiene and evaluate which factors predict a favorable symptomatic response to treatment. METHODS: This was a cross-sectional study of patients seen in the Miami Veterans Affairs eye clinic between August and December 2014. An evaluation was performed to assess dry eye symptoms and lid margin signs. All patients were then instructed to perform warm compresses and lid scrubs. A follow-up phone survey assessed compliance and subjective therapeutic response 6 weeks later. RESULTS: Two hundred seven of 211 (98%) patients (94% male, 60% white) completed the survey. Of the 207 patients, 188 (91%) completed the follow-up survey. Compliance with therapy was reported in 104 patients (55%); 66 reported complete improvement, 30 partial improvement, and 8 no improvement in symptoms. Patients who self-reported dry eye symptoms at first visit (n=86, 74%) were more likely to be compliant with lid hygiene than those who did not report symptoms (n=18, 25%) (P<0.0005). The only factor associated with poorer response to lid hygiene was longer time of self-reported dry eye symptoms. None of the other signs studied, including the presence of skin rosacea and lid margin telangiectasia, were associated with a differential response to lid hygiene. CONCLUSIONS: Patients with dry eye symptoms were moderately compliant with lid hygiene, and patients who performed the routine noted improvement in symptoms.

Surgical versus Medical Treatment of Ocular Surface Squamous Neoplasia: A Cost Comparison.

PURPOSE: The objective of this study was to compare the cost associated with surgical versus interferon-alpha 2b (IFNα2b) treatment for ocular surface squamous neoplasia (OSSN). DESIGN: A matched, case-control study. PARTICIPANTS: A total of 98 patients with OSSN, 49 of whom were treated surgically and 49 of whom were treated medically. METHODS: Patients with OSSN treated with IFNα2b were matched to patients treated with surgery on the basis of age and date of treatment initiation. Financial cost to the patient was calculated using 2 different methods (hospital billing and Medicare allowable charges) and compared between the 2 groups. These fees included physician fees (clinic, pathology, anesthesia, and surgery), facility fees (clinic, pathology, and operating room), and medication costs. Time invested by patients was calculated in terms of number of visits to the hospital and compared between the 2 groups. Parking costs, transportation, caregiver wages, and lost wages were not considered in our analysis. MAIN OUTCOME MEASURES: Number of clinic visits and cost of therapy as represented by both hospital charges and Medicare allowable charges. RESULTS: When considering cost in terms of time, the medical group had an average of 2 more visits over 1 year compared with the surgical group. Cost as represented by hospital charges was higher in the surgical group (mean, $17 598; standard deviation [SD], $7624) when compared with the IFNα2b group (mean, $4986; SD, $2040). However, cost between the 2 groups was comparable when calculated on the basis of Medicare allowable charges (surgical group: mean, $3528; SD, $1610; medical group: mean, $2831; SD, $1082; P = 1.00). The highest cost in the surgical group was the excisional biopsy (hospital billing $17 598; Medicare allowable $3528), and the highest cost in the medical group was interferon ($1172 for drops, average 8.0 bottles; $370 for injections, average 5.4 injections). CONCLUSIONS: Our data in this group of patients previously demonstrated equal efficacy of surgical versus medical treatment. In this article, we consider costs of therapy and found that medical treatment involved two more office visits, whereas surgical treatment could be more or equally costly depending on insurance coverage.

Epidemiology of Herpes Zoster Ophthalmicus: Recurrence and Chronicity.

PURPOSE: A hospital-based epidemiology study to describe herpes zoster ophthalmicus (HZO) prevalence and risk factors for recurrent and chronic disease. DESIGN: Retrospective, hospital-based cohort study. PARTICIPANTS: All patients evaluated in the Broward and Miami Veterans Administration Healthcare System (MIAVHS) during the study period. METHODS: Retrospective medical record review of patients seen in the MIAVHS from January 1, 2010, through December 31, 2014, with a HZO clinical diagnosis. Assessment of the patient's clinical course was defined by the following: an acute episode of HZO was defined as quiescence of disease within 90 days of initial presentation, HZO recurrence was defined as any recurrent eye disease or rash 90 days or more after quiescence of disease was noted off therapy, and chronic HZO was defined as active disease persisting more than 90 days from initial presentation. MAIN OUTCOME MEASURES: Main outcome measures included the frequency of HZO with and without eye involvement, HZO recurrence rates, and risk factors for recurrent or chronic HZO. RESULTS: Ninety patients with HZO were included in the study. The mean age at incident episode of HZO was 68±13.8 years (range, 27-95 years). Most patients were white (73%), immune competent (79%), and did not receive zoster vaccination at any point during the follow-up (82%). Patients were followed for a mean of 3.9±5.9 years (range, 0-33 years). The period prevalence of HZ in any dermatome was 1.1%, the frequency of HZ involving V1 (HZO) was 0.07%, and the frequency of HZO with eye involvement was 0.05%. The overall 1-, 3-, and 5-year recurrence rates for either recurrent eye disease or rash were 8%, 17%, and 25%, respectively. Ocular hypertension (hazard ratio [HR], 4.6; 95% confidence interval [CI], 1.3-16.5; odds ratio [OR], 6.7; 95% CI, 1.5-31.2) and uveitis (HR, 5.7; 95% CI, 1.7-19.0; OR, 6.7; 95% CI, 1.5-31.2) increased the risk of recurrent and chronic disease. CONCLUSIONS: This study supports newer data indicating that a significant proportion of patients experience recurrent and chronic HZO. Further study is needed to guide preventative and therapeutic approaches to recurrent and chronic HZO.

Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia.

PURPOSE: To determine the efficacy of topical 5-fluorouracil 1% (5-FU) as a primary treatment of ocular surface squamous neoplasia (OSSN). DESIGN: Retrospective study. PARTICIPANTS: Topical 5-FU was used as primary therapy in 44 patients with OSSN. METHODS: 5-Fluorouracil 1% administered topically 4 times daily for 1 week followed by a drug holiday of 3 weeks. Patients were identified through a pharmacy database. Patients were excluded if 5-FU was used as adjuvant therapy, if they did not complete therapy, or if they were still actively receiving treatment for OSSN at the time of last follow-up. MAIN OUTCOME MEASURES: The primary outcome measures were the frequency of complete resolution with topical 5-FU treatment and the rate of OSSN recurrence. RESULTS: Of the 44 patients identified, 32 were men and 12 were women. The mean age was 68 years. Complete resolution of OSSN was noted in 82% of patients (36/44); 18% (8/44) were considered treatment nonresponders. Patients were treated with a median of 4 cycles (range, 2-9 cycles). Nasal location was the only risk factor identified for nonresponse to therapy (P = 0.04). The median follow-up after resolution was 10 months (range, 2-77 months). In the 36 patients who showed complete resolution, 4 experienced tumor recurrence. Recurrence rates at 1 and 2 years were 6% and 15%, respectively, using Kaplan-Meier survival analysis. At least 1 side effect from the medication was reported by 61% of patients (21/44), but only 1 patient discontinued the medication because of intolerance. The most common side effect was pain (n = 17; 39%), followed by tearing (n = 10; 23%), photophobia (n = 6; 14%), itching (n = 4; 9%), swelling (n = 2; 5%), and infection (n = 1; 2%). No long-term complications were reported. CONCLUSIONS: 5-Fluorouracil is effective and well tolerated as a primary treatment for OSSN, with 82% of tumors responding completely to therapy.

Human Papilloma Virus Infection Does Not Predict Response to Interferon Therapy in Ocular Surface Squamous Neoplasia.

PURPOSE: To identify the frequency of human papilloma virus (HPV) in ocular surface squamous neoplasia (OSSN) and to evaluate differences in clinical features and treatment response of tumors with positive versus negative HPV results. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-seven patients with OSSN. METHODS: Ocular surface squamous neoplasia specimens were analyzed for the presence of HPV. Clinical features and response to interferon were determined retrospectively and linked to the presence (versus absence) of HPV. MAIN OUTCOME MEASURES: Clinical characteristics of OSSN by HPV status. RESULTS: Twenty-one of 27 tumors (78%) demonstrated positive HPV results. The HPV genotypes identified included HPV-16 in 10 tumors (48%), HPV-31 in 5 tumors, HPV-33 in 1 tumor, HPV-35 in 2 tumors, HPV-51 in 2 tumors, and a novel HPV in 3 tumors (total of 23 tumors because 1 tumor had 3 identified genotypes). Tumors found in the superior limbus were more likely to show positive HPV results (48% vs. 0%; P=0.06, Fisher exact test). Tumors with positive HPV-16 results were larger (68 vs. 34 mm2; P=0.08, Mann-Whitney U test) and were more likely to have papillomatous morphologic features (50% vs. 12%; P=0.07, Fisher exact test) compared with tumors showing negative results for HPV-16. Human papilloma virus status was not found to be associated with response to interferon therapy (P=1.0, Fisher exact test). Metrics found to be associated with a nonfavorable response to interferon were male gender and tumors located in the superior conjunctivae. CONCLUSIONS: The presence of HPV in OSSN seems to be more common in lesions located in the nonexposed, superior limbus. Human papilloma virus presence does not seem to be required for a favorable response to interferon therapy.

Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications.

PURPOSE: Treatment for ocular surface squamous neoplasia (OSSN) has historically been surgery, but nonsurgical interventions are increasingly used. Treatment with interferon is efficacious, but evidence is needed regarding recurrence and complication rates in comparison with surgery. The objective of this study is to compare the recurrence and complication rates of surgical treatment and interferon treatment for OSSN. DESIGN: A matched, case-control study. PARTICIPANTS: Ninety-eight patients with OSSN, 49 of whom were treated with interferon (IFN) α2b therapy and 49 of whom were treated with surgical intervention. METHODS: Patients with OSSN were treated with surgery versus IFNα2b therapy, either in topical or injection form. Median follow-up after lesion resolution was 21 months (range, 0-173 months) for the IFNα2b group and 24 months (range, 0.9-108 months) for the surgery group. MAIN OUTCOME MEASURES: The primary outcome measure for the study was the rate of recurrence of OSSN in each of the treatment groups. Recurrence rates were evaluated using Kaplan-Meier survival analysis. RESULTS: Mean patient age and sex were similar between the groups. There was a trend toward higher clinical American Joint Committee on Cancer tumor grade in the IFNα2b group. Despite this, the number of recurrences was equal at 3 per group. The 1-year recurrence rate was 5% in the surgery group versus 3% in the IFNα2b group (P = 0.80). There was no statistically significant difference in the recurrence rate between the surgically and medically treated groups. Nonlimbal location was a risk factor for recurrence (hazard ratio, 8.96) in the entire study population. In patients who were treated successfully, the side effects of the 2 treatments were similar, with mild discomfort seen in the majority of patients in both groups. There was no limbal stem cell deficiency, symblepharon, or diplopia noted in either group. Two patients were excluded from the IFNα2b group because of intolerance to the medication. CONCLUSIONS: No difference in the recurrence rate of OSSN was found between surgical versus IFNα2b therapy.

Punctal and Canalicular Stenosis Following Topical 1% 5-Fluorouracil Eye Drop Therapy for Ocular Surface Squamous Neoplasia.

PURPOSE: To present the first known cases of punctal and canalicular stenosis following topical 5-fluorouracil (5-FU) eye drops for ocular surface squamous neoplasia (OSSN). METHODS: A retrospective chart review of patients with OSSN receiving topical 1% 5-FU eye drops as a primary or adjuvant treatment between 2013 and 2021 was performed. Individuals diagnosed with punctal or canalicular stenosis during or after topical 5-FU use were included in this study. Four individuals met these criteria; we report clinical findings and treatment course for each patient. RESULTS: We reviewed 303 patients (316 eyes) with OSSN. All patients were treated with topical 1% 5-FU eye drops in cycles, given 4 times daily for 1 week with 3 weeks off. Four patients (5 eyes) developed punctal stenosis, for a frequency of 1.3%. The mean age at 5-FU initiation in the 4 individuals was 61 years (range 53-69). Most individuals were male (75%), White (75%), and non-Hispanic (100%). The most common presenting symptom of stenosis was epiphora, noted 4.6 ± 3 months after initiating topical 5-FU (after 4.9 ± 2.0 cycles). This occurred in 4 eyes while on therapy (3, 2, 4, and 4 months since 5-FU initiation) and in 1 eye after stopping therapy (10.3 months since 5-FU initiation). In 1 eye, punctal stenosis and epiphora resolved spontaneously after stopping 5-FU. Punctal dilation led to symptom resolution in 2 eyes. Surgical intervention (punctoplasty and external dacryocystorhinostomy) was needed in 2 eyes for punctal and canalicular stenosis, respectively. CONCLUSIONS: Punctal or canalicular stenosis is a rare and previously unreported adverse effect of topical 5-FU that may require surgical treatment.

Ocular Surface Squamous Neoplasia: Changes in the Standard of Care 2003 to 2022.

PURPOSE: The aim of this review was to elucidate treatment preferences for ocular surface squamous neoplasia and to examine the changes in treatment modalities over the past 2 decades. METHODS: An electronic survey was distributed to members of The Cornea Society, Ocular Microbiology and Immunology Group, and 4 international corneal specialist listservs. Questions examined medical and surgical treatment preferences, and results were compared with surveys administered in 2003 and 2012. RESULTS: A total of 285 individuals responded to the survey; 90% of respondents were self-classified as corneal specialists. Seventy-three percent reported using primary topical monotherapy to treat ocular surface squamous neoplasia as compared with 58% in 2012 ( P = 0.008). Compared with 2003, the percentage use of topical interferon significantly increased ( P < 0.0001) from 14% to 55%, 5-fluorouracil increased ( P < 0.0001) from 5% to 23%, and mitomycin C decreased ( P < 0.0001) from 76% to 19% as a primary monotherapy. The frequency of performing excision without the use of postoperative adjunctive medical therapy decreased significantly ( P < 0.0001), from 66% to 26% for lesions <2 mm, 64% to 12% for lesions between 2 and 8 mm, and 47% to 5% for lesions >8 mm from 2003 to 2022. More clinicians initiated topical immuno/chemotherapy without performing a biopsy as compared to 2003 (31% vs. 11%, P < 0.0001). CONCLUSIONS: These results demonstrate a paradigm shift in the management of ocular surface squamous neoplasia. The use of primary medical therapy as a first approach has significantly increased, with a reduction in the frequency of performing surgical excision alone.

Chronic inflammation as a proposed risk factor for ocular surface squamous neoplasia.

PURPOSE: Chronic inflammation is a predisposing factor for metaplastic changes and ultimately dysplasia. We describe cases of OSSN occurring in the setting of chronic ocular surface inflammation. METHODS: Sixteen eyes from 14 individuals were included from one ocular oncology clinic between 2010 and 2023. Patients presented with ocular surface squamous neoplasia (OSSN) in the setting of chronic inflammation. The diagnosis of OSSN was made using anterior segment high-resolution optical coherence tomography (HR-OCT) and confirmed by histopathological analysis in all cases. RESULTS: Median age on presentation was 61 [IQR 47.5-69.2] years. Eleven (86%) individuals were male and five (36%) identified as White Hispanic. Ten eyes were referred with ocular surface diagnoses including pannus (n = 4), scarring (n = 3), pterygium (n = 2), and herpetic keratitis (n = 1). Only six eyes were referred as possible neoplasia. All individuals had a history of ocular surface inflammation. The most common inflammatory conditions were ocular rosacea (seven individuals) and atopic keratoconjunctivitis (AKC) (five individuals). Two individuals were found to have bilateral OSSN, one in the setting of ocular rosacea and the other in the setting of AKC. All 16 eyes from 14 individuals were suspected to have OSSN based on HR-OCT findings which guided the location of the incisional biopsies that subsequently confirmed histopathological diagnosis in all cases. CONCLUSION: OSSN may arise in the setting of chronic inflammation on the ocular surface. Identification of the tumor can be challenging in these cases, and HR-OCT can be a key diagnostic tool in detecting OSSN.

Role of Topical 5-Fluorouracil in Demodex -Associated Blepharitis.

PURPOSE: The aim of this study was to report clinical observations suggesting the efficacy of topical 1% 5-fluorouracil (5-FU) in treating Demodex -associated blepharitis. METHODS: An observational retrospective review of 13 eyes from 13 individuals with conjunctival neoplastic lesions and concomitant Demodex lash infestation that received topical 1% 5-FU eye drops. Patients underwent slit-lamp examination at each follow-up visit. Clinical photographs of the lash line were obtained after treatment initiation. In a subset of patients, lashes were epilated bilaterally and microscopically analyzed for presence of Demodex mites before and after treatment initiation. RESULTS: The mean age of the population was 68 ± 14 years (range: 30-84 years) and 92% were male. In all 13 patients, a marked reduction in cylindrical dandruff was noted in the treated eye by slit-lamp examination after 2 cycles of 5-FU. There was complete resolution of cylindrical dandruff in 10 of 13 treated eyes compared with 0 resolution of cylindrical dandruff in untreated eyes ( P = 0.0001). In the 6 patients who received epilation, the lashes from the treated eye showed no Demodex , whereas lashes from the fellow untreated eye revealed persistent Demodex . CONCLUSIONS: Topical 1% 5-FU shows efficacy in treating Demodex -associated blepharitis. Further studies are indicated to reproduce our findings and evaluate the potential use of 5-FU as a treatment ingredient.

Intrinsic disorder in the human vitreous proteome.

The vitreous is a vital component of the eye, occupying a substantial portion of its volume and maintaining its structure. This study delves into the presence and significance of intrinsically disordered proteins (IDPs) within the vitreous, utilizing a dataset of 1240 vitreous proteins previously discovered in the vitreous proteome by Murthy et al.in five healthy subjects. The results indicate that 26.9 % of vitreous proteins are highly disordered, 68.8 % possess moderate disorder, and only 4.3 % are highly ordered. A complex interaction network among these proteins suggests their biological importance, and approximately 25 % may undergo liquid-liquid phase separation (LLPS). These findings offer new perspectives on the vitreous' molecular composition and behavior, potentially impacting our understanding of eye-related diseases, physiological changes such as vitreous syneresis. Further research is needed to translate these insights into clinical applications, although the intrinsic protein disorder and its association with LLPS appears to play a role in vitreous proteome function.