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Purpose: To report the demographic profile, clinical presentation, and management outcomes of ocular surface squamous neoplasia (OSSN) treated with primary topical chemotherapy in a limited resource secondary eye care facility in rural parts of South India., Methods: Retrospective interventional study of 38 eyes of 37 patients with OSSN treated with topical 1% 5-Fluorouracil (5FU), over a period of two years., Results: The median age at presentation with OSSN was 44 years (mean, 46 years; range 13 to 74 years). Majority (76%) were males. The most common morphological variant was placoid OSSN (18, 47%). Limbus was the most common epicenter (31, 82%). Corneal OSSN was the most initially misdiagnosed variant (n = 3). Of the 38 eyes receiving one week on and 3-weeks off cycles of 5FU regimen, complete tumor resolution was achieved in 36 (95%) eyes. The median number of topical 5FU cycles for tumor resolution was 2 (mean, 2; range, 1 to 4). Over a median follow-up period of 5 months (mean, 6 months; range, 1 to 27 months), tumor recurrence was noted in 3 eyes (8%), of which one case had xeroderma pigmentosum with bilateral multifocal recurrence. Complication rate was 5% (n = 2), which included transient conjunctival hyperemia (n = 1), and bacterial keratitis (n = 1) which resolved with fortified antibiotics., Conclusion: Primary chemotherapy with topical 1% 5FU is a safe and effective management modality for OSSN at limited resource settings in rural India., (© 2024. The Author(s).)

Objective: To comprehensively analyze reported cases of nasolacrimal squamous cell carcinoma (NLSCC), focusing on risk factors, treatment modalities, and outcomes. Additionally, investigate the impact of human Papillomavirus (HPV) status and histopathological subtypes' impact on prognosis., Data Sources: Pubmed, Embase., Review Methods: We conducted a systematic literature review to identify relevant studies reporting cases of NLSCC. The review methods adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final update was performed on May 31, 2023., Results: The 72 studies included a total of 313 participants (mean age: 55; 60% male). Longer symptom duration (44.1 ± 59.2 months) correlated with recurrence (p = 0.004), and males exhibited higher mortality rates (19.6% vs. 2.4% in females, p = 0.01). The overall survival (OS) rate among all patients was 87.1%. Basaloid NLSCC had a worse death outcome (p ≤ 0.001). HPV-positive cases showed comparable OS, recurrence, and metastasis rates to the general population (p = 0.917, 0.851, 0.07, respectively). Comparing treatment approaches (surgery, surgery with adjuvant radiation, chemoradiotherapy [CRT] followed by surgery), no significant differences in 5 and 10-year OS rates or recurrence were observed (p = 0.4, 0.24, respectively), but 5-year metastasis events were significant (p = 0.024). Eye exenteration rates were 31.1%, 20%, and 0% for the respective treatments (p = 0.089). Induction chemotherapy saved four cases from potential exenteration with favorable prognosis., Conclusion: Early detection and diagnosis are of utmost importance in the management of NLSCC. Regardless of the treatment approach, HPV-related NLSCC demonstrated similar outcomes to the general population. Basaloid histology represents the worst subtype in terms of prognosis. Limited adjuvant CRT cases showed improved outcomes and induction chemotherapy's importance was emphasized in recent literature and our shared experience. Laryngoscope, 134:3892-3902, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To report an unusual case of ocular surface squamous neoplasia (OSSN) associated with human papilloma virus (HPV)-16 infection with an atypical morphology in a young otherwise healthy patient., Case Description: A 17 year-old healthy male was referred to our department for evaluation of a corneal infiltrate with anterior stromal neovascularization in the right eye. One year before, the patient underwent an excision of a corneo-conjunctival lesion that was located inferiorly in the same eye. Histopathological analysis had shown moderate and severe dysplasia of the conjunctival epithelium and resulted positive for HPV-16. We performed a diagnostic incisional biopsy of the limbal conjunctiva and of the corneal epithelium for histological examination and molecular testing for HPV and Chlamydia by using polymerase chain reaction (PCR). Histopathologic evaluation demonstrated low-grade dysplasia of conjunctiva. PCR testing of the corneal epithelium was positive for HPV-16, similarly to the first biopsy performed by another centre. The patient was successfully treated with topical interferon alfa-2b (1,000,000 IU/ml) for a total of six months. After the treatment, the corneal infiltrate improved dramatically with regression of neovascularization and improvement of corneal transparency and vision., Discussion: The present report described an atypical presentation of HPV-related OSSN due to its unusual morphology, young age of onset and absence of associated comorbidity., Conclusion: Conservative treatment with topical interferon-alpha 2b could be used to treat successfully HPV-16 positive OSSN, with no corneal irregularity or potential loss of vision compared to surgical excision., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A patient presented with corneoscleral thinning five months after the treatment of suspected ocular squamous surface neoplasia with mitomycin-C and interferon. For tectonic and aesthetic purposes, we decided to perform lamellar corneoscleral transplantation. The approach used established new tectonic support and corneal homeostasis. This technique might be an option in similar cases.

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., Competing Interests: C. L. Karp and A. Galor have a pending PCT/US2022/029842 with the University of Miami. C. L. Karp is on the medical advisory board for Interfeen Biologics, after the writing of this manuscript. J. Chodosh is a consultant for the US FDA. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We describe the first reported case of granulomatosis polyangiitis (GPA)-associated sclerokeratitis in a patient with treated ocular adnexal lymphoma (OAL). The patient presented with pain and decreased vision in the left eye over several weeks. Past medical history was significant for recent bilateral relapsing OAL that was treated successfully with radiotherapy. Examination of the eyes revealed sectoral scleritis and peripheral ulcerative keratitis. Magnetic resonance imaging (MRI) of the orbits excluded recurrence of OAL and serum antineutrophil cytoplasmic autoantibody (ANCA) titres confirmed the diagnosis of GPA. Disease was poorly responsive to systemic steroids, azathioprine and rituximab. Ultimately, resolution was achieved with successive subconjunctival dexamethasone and subconjunctival triamcinolone injections. This case highlights the need to consider ocular inflammation in patients with a history of malignant hemopathies.

Objective: To assess the efficacy and safety of topical 0.5% 5-Fluorouracil (5-FU) as a primary therapy of ocular surface squamous neoplasia (OSSN)., Design: Retrospective study., Participants: Patients with clinically suspected OSSN referred to a Brazilian tertiary health center between October 2015 and December 2022., Methods: After diagnostic confirmation of OSSN with exfoliative cytology, 0.5% 5-FU was administered topically 4 times daily for 2 weeks followed by a pause of 2 weeks., Results: A total of 54 patients were included in this study, 32 males (59.3%), mean age of 62.9 years old. Complete resolution of OSSN was achieved in 70.4%. The median number of cycles was 2 (range 1-5). Side effects were reported in 35.2%, which included eyelid erythema, conjunctival hyperemia, and punctal stenosis. None of the patients stopped treatment due to adverse effects. Patients who had partial response to 0.5% 5-FU had complementary treatment with surgery, Mitomycin-C and/or Interferon ⍺2b. Overall recurrence was 14.8%. Median follow-up was 14 months (range 2-92 months). In a multivariate Cox regression analysis, the risk of relapse was 84% lower in patients who had complete response to 0.5% 5-FU (p = 0.018)., Conclusion: Topical 0.5% 5-FU may be considered a safe and effective primary therapy for OSSN, with a low rate of side effects., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Objective: To study the efficacy and side-effect profile of topical 5-Fluorouracil (5-FU) in the treatment of ocular surface squamous neoplasia (OSSN)., Methods: Retrospective study of 101 eyes of 100 patients treated with 5-FU with one week on and 3 weeks off regimen., Results: Of the 100 patients (101 eyes), the mean age at diagnosis of OSSN was 49 (median, 52 years; range, 11-87 years). History of prior intervention was noted in 6 (6%) eyes. Tumor epicenter included bulbar conjunctiva (n = 54; 53%), limbus (n = 27; 27%), and cornea (n = 20;20%). Mean number of cycles of topical 5-FU administered was 3 (median, 3; range, 1-8). Complete tumor regression was achieved with topical 5-FU in 89 (88%) eyes with a mean number of 2 cycles (median, 2; range, 1-6) of 5-FU. The remaining 12 (12%) lesions underwent additional treatment including excisional biopsy (n = 7), extended enucleation (n = 3), and topical Interferon alpha 2b (n = 2) for complete tumor control. Over a mean follow-up period of 6 months (median, 5 months; range, 1-36 months) following treatment, tumor recurrence was noted in 2 (2%) patients, and side-effects were noted in 7 (7%) eyes including conjunctival hyperemia (n = 1), punctal stenosis (n = 1), sterile keratitis (n = 4), and limbal stem cell deficiency (n = 1)., Conclusion: Topical 5-FU is an effective non-invasive therapy for OSSN with a minimal side-effect profile., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A 17-year-old Appaloosa mare was referred for evaluation of presumed refractory keratitis of the left eye. Gross examination revealed ocular discomfort and corneal neovascularization with a nasal focal opacification affecting approximately 40% of the corneal surface. On ophthalmic examination, extensive subepithelial to mid-stromal vascular branching accompanied by a homogeneous white, dense opacification, which affected up to 80% of the total corneal thickness, were apparent. Signs of concurrent uveitis were absent. Deep-stromal lamellar keratectomy with a conjunctival pedicle graft was performed under general anesthesia. Histopathology confirmed a poorly differentiated corneal stromal invasive squamous cell carcinoma (SI-SCC) with neoplastic cell extension to the surgical margins. Postoperatively, 4 topical mitomycin C 0.04% chemotherapy cycles combined with oral firocoxib therapy were initiated. Seven months after surgery, regrowth of the SI-SCC was clinically suspected. A total volume of 1 ml bevacizumab 2.5% was administered in the standing sedated horse via 3 mid-stromal corneal injections. Four weeks later, intrastromal bevacizumab injections (ISBIs) were repeated, however, this time the solution was injected directly into the main corneal vessel branches.Seven weeks after the second ISBIs, the left eye was comfortable and significant remission of corneal vascularization and opacity was recognized. No recurrence has been noted for a follow-up period of more than 53 months.Equine SI-SCC usually has a very poor prognosis for globe maintenance. To the authors' knowledge this is the first report of well-tolerated intrastromal antivascular endothelial growth factor adjunctive therapy with bevazicumab 2.5% and SI-SCC resolution after a multimodal treatment approach., Competing Interests: The authors did not receive any commercial company funding and have no conflicts of interest. Open Access fee was paid by the University of Veterinary Medicine Vienna., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Lacrimal gland adenoid cystic carcinoma (LGACC) has historically been associated with a poor prognosis even with localized disease, with a survival of 56% at 5 years. In 1988, we treated the first patient with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC). Since then, we have used this protocol as the standard approach. We aim to analyze the outcomes of patients with LGACC treated with the protocol and compare them to a population-based cohort to assess if IACC can improve survival., Methods: We prospectively assessed all non-metastatic patients with LGACC treated with IACC at a single institution between 1988 and 2021. For a comparison group, we identified all non-metastatic patients with LGACC treated with excision from the Surveillance, Epidemiology, and End Results (SEER) registry. We calculated disease-specific survival using the Kaplan-Meier and Cox proportional-hazards modeling methods., Results: Thirty-five non-metastatic patients with LGACC treated with IACC were identified at a single institution, and 64 patients with non-metastatic LGACC treated with excision were identified in the SEER database. The 5- and 10-year disease-specific survival rates for patients treated with IACC were 84% (95%CI 71-97) and 76% (95%CI 60-92), respectively. While the 5- and 10-year disease-specific survival rates for the population-based cohort were 72% (95%CI 62-82) and 46% (95%CI 32-60). The survival analysis favored IACC, with a 60% lower risk of death (HR: 0.4; 95%CI 0.2-0.9)., Conclusion: IACC improves disease-specific survival in comparison to a population-based cohort treated with excision. Additional patients treated with IACC at multiple institutions are required to provide further external validity., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Lacrimal gland adenoid cystic carcinoma (LGACC) is a rare orbital malignancy with devastating lethality. Neoadjuvant intra-arterial chemotherapy (IACC) has demonstrated cytoreductive effects on LGACC macroscopically, but limited studies have examined cellular and molecular determinants of the cytoreductive effect. This post hoc study assessed apoptotic marker expression on excised tumor specimens after neoadjuvant IACC and globe-sparing resection, emphasizing the examination of tumor margins., Methods: This retrospective study identified LGACC specimens resected in a globe-sparing technique after neoadjuvant IACC by reviewing the Florida Lions Ocular Pathology database at Bascom Palmer Eye Institute. Histopathology slides of the specimens were re-examined to confirm the diagnosis and identify the tumor margin. Immunofluorescent staining was performed for apoptotic markers, including P53, cleaved caspase-3, cleaved PARP-1, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Positive expression was determined by comparison to the negative control., Results: Tumor specimens from 5 patients met inclusion criteria. All 5 cases were positive at the center and the margin for TUNEL, p53, and cleaved caspase-3. One case did not show positive expression of cleaved PARP-1 at the margin but was positive for the other apoptotic markers., Conclusions: This post hoc study demonstrated positive staining for multiple apoptotic markers in post-IACC tumor specimens at the tumor center and margin. Apoptotic marker expression along the margins of post-treatment specimens is important, as it may offer surrogate information to speculate on the state of residual cancer cells adjacent to the excision margin inadvertently remaining in the orbit., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

There have been rapid advancements in the field of ocular oncology for the diagnosis and management of intraocular, adnexal, and orbital tumors. Targeted therapy is in the forefront of medical research in all fields including ocular oncology. Targeted therapy include drugs that target specific genetic mutations, pathways or proteins involved in the development of cancer. In contrast to traditionally used chemotherapy, drugs used in targeted therapy are highly specific for tumor cells and preserve the function of normal cells. This review aims to familiarize ophthalmologists with the drugs that are currently approved or undergoing clinical trials for use in ocular oncology. Targeted therapy is particularly useful for locally advanced or metastatic tumors, including but not limited to eyelid and periocular basal cell carcinoma, periocular cutaneous and conjunctival squamous cell carcinoma, ocular adnexal lymphoma, conjunctival melanoma, and uveal melanoma. The results are promising with improved survival outcomes and better tolerability than chemotherapeutic drugs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effectiveness and safety of intravitreal melphalan (IVM) injection therapy in vitreoretinal lymphoma., Methods: Eight eyes of five biopsy-proven vitreoretinal lymphoma patients who were treated with IVM injection as a second-line therapy after intravitreal methotrexate and rituximab injections were retrospectively evaluated between January 2011 and March 2023., Results: The medical records of five vitreoretinal lymphoma patients (mean age of 62 years at the diagnosis) including 4 (80%) female patients and 1 (20%) male patient were retrospectively analyzed. Three patients (60%) either had a history of central nervous lymphoma or developed it during the follow-up. Patients were previously treated with a mean of five cycles of monthly intravitreal methotrexate and rituximab injections. All eyes showed complete response by the disappearance of vitreal and/or subretinal neoplastic cells within 6 weeks after IVM injections (range, 1-4 injections per eye). Of 12 IVM injections, 3 (25%) injections were associated with macular edema diagnosed on optical coherence tomography at 1-month follow-up and resolved spontaneously within 5 months. The IVM administration induced new retinal pigment epithelium changes in three eyes (37%)., Conclusion: Intravitreal melphalan injection may be effective in the management of vitreoretinal lymphoma as a second-line local therapy. Randomized clinical trials with larger numbers of patients are needed to establish the efficacy, treatment protocol, and safety of IVM injection.

Periocular and ocular surface nonmelanoma malignancies, including basal cell carcinoma (BCC), squamous cell carcinomas (SCC), and ocular surface squamous neoplasia (OSSN), are rare, but their management requires special considerations. The most common periocular malignancy is BCC, which constitutes 80% to 96% of tumors, followed by SCC, which represents 5% to 10% of tumors. OSSN represents a spectrum of diseases that encompass dysplastic alteration to the squamous epithelium of the eye. OSSN ranges from squamous dysplasia to conjunctival intraepithelial neoplasia/carcinoma in situ to invasive SCC, which is the most common ocular malignancy. These tumors can be staged using the eighth edition of the American Joint Committee on Cancer categorization system. The standard of care for periocular malignancies is Mohs micrographic surgery, while medical management with 5-fluorouracil (5-FU), interferon alfa-2b (INF), and mitomycin C (MMC) or "no touch" surgical excision are options for OSSN. Systemic therapies, including sonic hedgehog inhibitors for BCC and epidermal growth factor inhibitors and immune-checkpoint inhibitors for SCC, can be utilized for advanced disease. Recurrence rates are higher for periorbital and ocular malignancies than their respective cutaneous counterparts. These carcinomas and their respective treatments have unique side effects and considerations in an effort to preserve visual function., Competing Interests: Declaration of competing interest Hao Feng is a consultant for Cytrellis Biosystems Inc and Soliton Inc. Jette Hooper, Kimberly Shao, Paula Feng, and Madina Falcone declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Intravitreal methotrexate injection (400 µg/0.1 mL) is the current mainstay for managing vitreoretinal lymphoma. Various complications associated with intravitreal methotrexate are cataract, keratopathy, maculopathy, sterile endophthalmitis, optic atrophy, vitreous haemorrhage, etc. The most common adverse effect of intravitreal methotrexate is keratopathy occurring in more than half of cases. The severity may range from diffuse punctate keratopathy to severe epitheliopathy leading to photophobia, pain, visual blurring, epiphora, etc. This may become a reason for reduced compliance with treatment. The management of these complications includes oral folic acid, topical folinic acid supplementations and reduced frequency or cessation of methotrexate intravitreal injections. Here, we report a simple method of eyewash in a large amount of balanced salt solution after the intravitreal injection procedure to reduce the severity of keratopathy, which helped the patient tolerate the treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Since there is a lack of clear information regarding the benefit to combine supportive therapies (such as artificial tears) to mitomycin C (MMC) in the treatment of ocular surface neoplasia, the primary purpose of the study was to evaluate hyaluronic acid eye drops and hyaluronic acid-conjugated lactobionic acid (LACTOyal FREE) eye drops as supportive therapy., Methods: Retrospective evaluation of patients with ocular surface squamous neoplasia or conjunctival melanocytic tumor treated with MMC, who had used also artificial tears as supportive treatment. A 6-month follow-up with evaluation of subjective and objective tests for ocular surface integrity was conducted., Results: A total of 35 patients were analyzed, most of them with squamous disease (71.4%). The break-up time (BUT), Ocular Surface Disease Index (OSDI) and Schirmer test values showed a significant difference at any time point with overall population. No statistical difference was found among subgroups (Lactoyal vs No Lactoyal)., Conclusion: The use of an ancillary therapy based on hyaluronic acid allows to improve both subjective and objective ocular parameters, reducing MMC induced adverse effects. Meantime, hyaluronic acid-conjugated lactobionic acid eye drops highlighted the same advantages with a more positive trend in OSDI results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To explore the trend of ocular manifestations and interleukin (IL) during the treatment of vitreoretinal lymphoma (VRL) and to evaluate the potential effects of different intravitreal administration schedules on the therapeutic response., Design: Interventional comparative nonrandomized clinical study., Methods: Patients diagnosed with VRL between January 2011 and January 2022 were included. Intravitreal methotrexate (MTX) injections consisting of induction, consolidation, and maintenance were scheduled. At baseline and each visit, ocular manifestations and IL in aqueous humor were recorded. Effects of the variations (eg, frequency and number) in the injection schedule on the therapeutic response were analyzed., Results: Fifty-eight eyes of 33 patients were treated with intravitreal MTX chemotherapy. A mean ± standard deviation of 9 ± 3 injections were given; 52 eyes achieved complete remission (CR). IL-10, keratic precipitates, and subretinal lesions correlated well with the course of treatment (all P < .001). Initial injection given twice weekly was correlated with a higher rate of CR (36/36) than given once weekly or less frequently (16/22; P = .011). Ocular progression occurred in 13 eyes of 8 patients. The completion of schedule was correlated with PFS (induction + consolidation + maintenance: 547 [335-874] days; induction + consolidation: 355 [322-831] days; induction only: 147 [116-187.5] days; P < .001). IL-10 >50 pg/mL was a feasible threshold for the detection of ocular relapse (sensitivity 100.0%, specificity 95.1%)., Conclusion: Keratic precipitates, subretinal lesions, and IL-10 could serve as indicators for therapeutic response. Intensive initial administration and adequate injection numbers would help to improve the response and prognosis. IL-10 >50 pg/mL could help detect ocular relapse., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The authors describe two cases of corneal ocular surface squamous neoplasia (OSSN), presenting at our rural eyecare centre, which were initially misdiagnosed as viral epithelial keratitis and corneal pannus with focal limbal stem cell deficiency. Both the cases were refractory to initial treatment and corneal OSSN was suspected. Anterior segment-optical coherence tomography (AS-OCT) revealed a thickened, hyper-reflective epithelium with abrupt transition and an underlying cleavage plane, features typical of OSSN. Topical 1% 5-fluorouracil (5-FU) therapy was initiated and in two cycles (first case) to three cycles (second case), complete resolution was noted both clinically and on AS-OCT, with no significant side effects. Both patients are currently free of tumour at the 2-month follow-up period. The authors report the rare, atypical presentations of corneal OSSN, discuss the masquerades and highlight the role of primary topical 5-FU in managing corneal OSSN in limited resource settings., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: To evaluate the safety and efficacy of ruthenium-106 (Ru-106) plaque brachytherapy in managing invasive ocular surface squamous neoplasia (OSSN)., Methods: This is a retrospective, non-comparative, interventional case series of 42 eyes with OSSN with histopathologically-proven corneal stromal and/or scleral invasion that underwent Ru-106 plaque brachytherapy. Main outcome measures were tumour regression, eye salvage, final visual acuity, treatment complications and metastasis., Results: At presentation, the mean tumour basal diameter was 9.3 mm (range 5-26 mm) and thickness 3.1 mm (range 1.5-11 mm). Prior treatment included excision biopsy in two patients (5%), incision biopsy and topical interferon in one each (2%). Following excision with 4 mm clinically clear margins, corneal stromal and/or scleral invasion of OSSN was confirmed in all 42 cases, with the excised base showing invasive squamous cell carcinoma. A total dose of 5000 cGy over a mean duration of 19.7 hours (range 7-41 hours) was provided to an axial depth of 2 mm using Ru-106 surface plaque. Over a mean follow-up of 36.9 months (range 22.3-72 months), complete tumour regression was achieved in all eyes (100%). Two eyes (5%) showed conjunctival tumour growth remote from the site of prior treatment. Visual acuity was maintained at ≥20/200 in 35 eyes (83%), with a loss of >2 Snellen lines in 1 eye (2%). There was no evidence of regional lymph node or systemic metastasis., Conclusion: Histopathology-guided use of Ru-106 surface plaque brachytherapy is a safe and an effective adjuvant therapy in the management of corneal stromal and/or scleral invasion of OSSN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To assess the efficacy of topical interferon α-2β(IFN) eye drops as a primary treatment for ocular surface squamous neoplasia(OSSN) and evaluate factors that impact response to treatment and recurrence of OSSN., Method: A retrospective study of 143 OSSN patients treated with topical IFN(1MIU/ml) from January 1998 to June 2021. The diagnosis was based on clinical examination and anterior segment optical coherence tomography, with histologic confirmation was present in 46.2% of patients. Data on demographic, tumor characteristics, treatment outcome, and side effects were collected. The primary outcomes were tumor resolution frequency and recurrence rate. Secondary outcomes were predictive factors for resolution and recurrence and side effects of treatment., Result: Participants were mostly older (mean age, 69 years, SD 12.9, range 29-97), white(89%) males (74%). Complete tumor resolution was achieved in 80.4% of individuals with a mean time to resolution of 4.2 months (SD 2, range 0.5-12.3 months). On multivariable analysis, history of skin cancer (HR: 0.66, p = 0.05, 95%CI: 0.44-0.99) and immune system abnormalities (HR: 0.37, p = 0.009, 95%CI: 0.18-0.79) reduced the risk of tumor resolution, while a prior history of OSSN (HR: 3.49, p < 0.001, 95%CI: 1.76-6.93) increased the risk of resolution. With a mean follow-up time of 44.3 months (SD 50.9, 0-290 months), the recurrence rate was 0%, 2.3% and 3.1% at 1, 2, and 5 years respectively. Mild hyperemia(18.9%) and pain(10.6%) were the two most common side effects., Conclusion: Topical IFN eye drops are a safe and effective primary treatment modality for OSSN with a reasonable side effect profile., Competing Interests: Declaration of competing interest Drs. Karp and Galor: pending PCT/US2022/029,842 with the University of Miami. Dr. Karp began on the medical advisor board for Interfeen Biologics after the submission of this manuscript. The other authors have no financial disclosures to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: Various treatment modalities are available for treatment of ocular tumors, which include chemotherapy, laser, and radiotherapy (external beam radiation therapy or brachytherapy). Brachytherapy using plaque applicator is preferred over external beam radiation therapy when the tumor is well localized, as this therapy delivers radiation dose to the tumor with lower doses to normal tissues in the vicinity. However, plaque therapy is expensive and beyond the reach of many poor patients in India. The Bhabha Atomic Research Center (BARC) recently introduced an indigenous Ruthenium-106 plaque to make brachytherapy treatment available and affordable to all needy patients in India. In the present case series, we report our experience using the indigenous Ru-106 plaque for the treatment of a spectrum of ocular tumors., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Purpose: To determine the efficacy and safety of topical 1% 5-fluorouracil (5FU) eye drops as primary treatment of ocular surface squamous neoplasia (OSSN)., Methods: Patients were diagnosed with OSSN based on slit-lamp examination and anterior segment optical coherence tomography (AS-OCT). In ambiguous cases an incisional biopsy was performed. All were treated with 5FU eye drops as primary therapy and retrospectively reviewed. Data on demographics, tumor characteristics, treatment outcome, and side effects were collected. The primary outcome measures were resolution frequency and recurrence rate of OSSN. Secondary outcomes were risk factors for resolution and recurrence, and side effects of treatment., Results: The mean age of 251 subjects (258 eyes) was 67.5 ± 11.7 years, 182 were male. Patients were followed up on average for 752 ± 580 days. Overall, 87% of patients experienced complete tumor resolution. Multivariable analysis revealed that superior tumor location (HR: 0.62, 95% CI: 0.41-0.93, p = 0.02) and leukoplakia (HR: 0.65, 95% CI: 0.41-0.93, p = 0.02), decreased the likelihood of tumor resolution. The recurrence rate was 4% at six months, 8% at one year, and 19% at two years. Larger tumor area increased chances of tumor recurrence (HR: 1.01, 95% CI: 1.00-1.02 p = 0.03). The most common side effects of 5-FU were mild hyperemia and pain, which occurred in 26% and 23% of patients, respectively. Among the sight-threatening side effects, limbal stem cell deficiency occurred in only 3% of patients., Conclusions: Topical 1% 5FU eye drops are a safe and effective medication for OSSN. Superior tumor location and leukoplakia decreased the chance of tumor resolution., Competing Interests: Declaration of competing interest Adam Wylegala received consultant fees from Optopol Technology and speaker honorary from Zeiss Meditec, Bayer, Verco, and AbbVie independent from this work. Pending PCT/US2022/029842 (Drs. Karp and Galor) and unrelated to OSSN treatment. Dr. Karp began on the medical advisor board for Interfeen Biologics after the submission of this manuscript. All other authors declare that they have no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The purpose of this study was to report a unique case of ocular surface squamous neoplasia that masqueraded as a nonresolving toxic epithelial keratitis., Methods: This was a case report and review of the literature., Results: A 79-year-old man presented with decreased vision, redness, and a foreign body sensation in his right eye that was refractory to treatment with lubrication and topical nonsteroidal antiinflammatory drops. Before presentation, the referring provider believed that he had medicamentosa-related keratitis and placed him on oral methazolamide. Slitlamp biomicroscopy of the right eye revealed diffuse epitheliopathy with punctate fluorescein staining and subtle underlying corneal epithelial opalescence. A mildly thickened and inflamed pinguecula was noted from 2 to 5 o'clock at the limbus of the right eye. An anterior segment high-resolution optical coherence tomography revealed thickened, hyperreflective epithelium with an abrupt transition. An incisional biopsy confirmed conjunctival and corneal intraepithelial neoplasia. The patient improved after 4 cycles of topical chemotherapy with 1% 5-fluorouracil eye drops with complete resolution of the corneal and conjunctival pathology., Conclusions: Ocular surface squamous neoplasia can rarely masquerade as a recalcitrant medicamentosa and epithelial keratitis. In subtle cases or in cases with combined ocular surface morbidities, anterior segment high-resolution optical coherence tomography can be helpful to diagnose and direct therapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ocular surface squamous neoplasia (OSSN) has different treatment modalities. Although surgical excision has been the gold standard therapeutic option, topical pharmacotherapy agents such as 5-fluorouracil (5-FU), interferon alfa-2b (IFN) and mitomycin-C (MMC) are also commonly used. The protocol was registered (CRD42021224961). Comprehensive literature research was carried out to compare topical pharmacotherapy (5-FU or IFN or MMC) to surgical excision regarding clinical success (tumor resolution), recurrence and complications in patients undergoing treatment for OSSN. From 7859 records, 7 articles were included in the qualitative and 4 in the quantitative synthesis. The outcomes of surgical excision and topical pharmacotherapy were comparable in the included articles. There were no significant differences between surgical excision and topical pharmacotherapy regarding the clinical success [odds ratio (OR): 0.785; confidence interval (CI): 0.130-4.736, P = 0.792)] and tumor recurrence (OR: 0.746; CI: 0.213-2.609; P = 0.646). The most common side effect of the different therapeutic options was dry eye. The highest rate of dry eye symptoms was reported after surgical excision (in 59%). Topical pharmacotherapy with all the 3 agents is as effective and well-tolerable as surgical excision in terms of tumor resolution, recurrence rate and side effects in all OSSN patients suggesting similar long-term clinical benefits., (© 2022. The Author(s).)

Purpose: To report the therapeutic efficacy of integrating neoadjuvant chemotherapy with conventional bimodal therapies for lacrimal gland adenoid cystic carcinoma by providing an additional 8 years of follow-up data on the same cohort of patients whose cumulative 10-year disease-free survival outcomes were reported in 2013., Design: Non-randomized, retrospective, interventional case series., Methods: Nineteen consecutive patients treated with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC), orbital exenteration, chemoradiotherapy, and adjuvant intravenous chemotherapy at a single institution were included. Analyses were undertaken of locoregional recurrences and distant metastases, disease-free survival time, TNM tumor stage at presentation, response to IACC, and prognostic impact of positive resection margins. The main outcome measures were overall survival, disease-free survival, disease relapse, positive tumor resection margins, and tumor stage at presentation., Results: Eight patients with an intact lacrimal artery (group 1), 7 with AJCC stage T4a-c, had significantly better overall survival (87.5% versus 14.3% at 15 years), disease-specific mortality, and recurrences (all < .001, log-rank test) than prior conventionally treated patients from the Bascom Palmer Eye Institute. Group 1 was superior to group 2, patients lacking an intact lacrimal artery, concerning overall survival (P = .042) and recurrence (P = .017), but with no significant difference in disease-specific mortality (P = .23). Group 2 was associated with a significantly lower cause-specific mortality than the institutional comparator group (P = .039). Prior tumor resection with lateral wall osteotomy and failure to adhere to all protocol elements were adverse prognostic factors for suboptimal outcomes. Positive tumor margins increased the risk of all-cause mortality 4.1 times (P = .036, stratified Cox proportional hazards regression) and disease-specific mortality 8.0 times (P = .043, stratified Cox proportional hazards regression) than a patient with negative margins., Conclusions: Extended follow-up supplemented with AJCC staging data supports neoadjuvant IACC as an integral component of a trimodal treatment strategy in patients with an intact lacrimal artery. Protocol elements implemented as designed appear to have improved overall survival and decreased disease relapse in this cohort. This extended long-term IACC dataset suggests that a critical bar of at least 15 years of follow-up is appropriate for assessing the efficacy of current conventional and future globe-sparing bimodal therapies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Approximately 50% of limited-stage ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) patients with adverse prognostic factors relapse after radiotherapy. Chemoimmunotherapy has been proposed as an alternative frontline therapy. However, only a few studies have reported its long-term treatment outcome., Methods: In 2011, we commenced a phase 2 trial to investigate the efficacy of rituximab, cyclophosphamide, doxorubicin, and prednisolone (R-CVP) in bilateral and non-conjunctival limited-stage OAML patients. Results of the clinical trial showed a response rate of 100% and a 4-year progression-free survival of 90.3% without significant toxicity. We extended the study period to December 2020 to determine the long-term efficacy of R-CVP chemoimmunotherapy., Results: At a median observation period of 66.0 months, eight of 33 study patients had relapsed. The cumulative incidence of relapse was 18.9% at 5 years and 44.7% at 8 years. The majority of relapses developed more than 4 years after treatment. Local relapse was more prevalent than distant relapse. The relapse risk of orbital and lacrimal diseases was likely to be higher than that of conjunctival and eyelid diseases (HR: 2.5, 95% CI: 0.498-12.500, p = 0.25)., Conclusion: Although the response rate was remarkable for chemoimmunotherapy, the risk of late relapse was considerable. Based on our findings, clinical trials for limited-stage OAML patients should have a long-term observation period. To minimize radiation toxicity and reduce the risk of delayed relapse (local relapse and distant relapse), a future study with sequential or combination treatment of local low-dose radiation and systemic chemoimmunotherapy can be considered., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Optical coherence tomography angiography (OCTA) was utilized to examine changes in ocular surface squamous neoplasia (OSSN) vascular patterns over time in individuals treated with topical medical therapy., Methods: Ten individuals with OSSN diagnosed by clinical examination and high resolution (HR)-optical coherence tomography (OCT) were recruited. All individuals received topical immuno- or chemotherapy. OCTA images were obtained and analyzed at three points: presentation, mid-treatment and tumor resolution. Tumor metrics including tumor area (TA), tumor volume (TV), tumor depth (TD), and total tumor density (TTD) were calculated. Vessel area density (VAD) was also quantified within the OSSN, the subepithelium under and adjacent to the OSSN and the subepithelium of the uninvolved, contralateral eye. Vascular network changes were also subjectively evaluated., Results: TA, TV, TD and TTD all significantly decreased with time (p < 0.001). The mean VAD within the OSSN significantly decreased (p < 0.001) between visits (presentation: 26.52 ± 6.8%, mid-treatment: 7.19 ± 5.88%, tumor resolution: 0.11 ± 0.34%). The mean subepithelial VAD under the OSSN also decreased with time (23.22 ± 11.03%, 20.99 ± 5.99% and 19.58 ± 7.08%), and after resolution the sub-tumor VAD (19.58 ± 7.08%) was comparable to the subepithelial VAD in the contralateral eye (15.47 ± 4.37%, p > 0.05). The mean VAD in the subepithelium adjacent to the OSSN increased with treatment, then decreased significantly between mid-treatment and resolution (23.26 ± 4.54, 28.30 ± 7.43% and 21.68 ± 6.10%, p = 0.009). Qualitatively, the tumor subepithelial vascular network was complex and dense but with tumor resolution appeared less tortuous and similar to the uninvolved eye., Conclusion: OCTA provided insight into the pathophysiology of tumor angiogenesis, showing decreased vascular density and normalization of vascular networks associated with tumor resolution., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts., Methods: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined., Results: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively., Conclusions: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GL has received travel support for congress participation: Sun Pharma. PJ declares no conflicts of interest. IM declares no conflicts of interest. AS declares no conflicts of interest. JCH receives a scientific grant from BMS, payments ad consultant from Pierre Fabre, MSD, Sunpharma and speaker honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi, GSK, Amgen, Almirall. AF Advisory board: Pierre-Fabre, Roche, Novartis, BMS, MSD, travel support for congress participation: Pierre-Fabre, Roche, Novartis, BMS, honoraria for talks: Roche, Novartis, BMS, MSD, CeGaT, research funding: Stiftung Immunonkologie BMS. All outside the submitted work. JE declars no conflicts of interest. FM has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. LR declares no conflicts of interest. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. MZ has served as consultant or/and has received honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, Novartis, Sanofi Genzyme and SUN Pharma. MS Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma, Immunocore. FR declares no conflicts of interest. AS declares no conflicts of interest. KS declares no conflicts of interest. FM served as consultant and/or has received honoraria from Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sunpharma and Bristol-Myers Squibb, outside the submitted work. RG Honoraria for lectures (personally): Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Honoraria for advice (personally): BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants (to institution): Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Almirall Hermal. Support for meeting participation: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. PT declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, Almirall, and 4SC; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work.BS is on the advisory board or has received honoraria from Almirall, Pfizer, Sanofi, Incyte, Novartis, Roche, Bristol-Myers Squibb (BMS) and MSD Sharp & Dohme, research funding from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb and MSD Sharp & Dohme and travel support from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme and Amgen, outside the submitted work. MS declares no conflict of interest. MH has been a member of advisory boards of Almirall Hermal, Sanofi-Aventis, MSD, 622 BMS, Novartis, and received speaker's honoraria from Galderma and Biofrontera. UL speaker fees: Roche, Novartis, Sanofi, MSD; consultancy: Roche, Sanofi, MSD, Novartis. AZ received travel support from Novartis, Sanofi Grenzyme, Sun Pharma, and Bristol-Myers Squibb, outside the submitted work. CM declares no conflicts of interest. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. EH declares no conflicts of interest. NB declares no conflicts of interest. DS D.S. Served as consultant, advisory board and/or speaker and has received honoraria from Amgen, Array, Bristol-Myers Squibb, Helsinn, Immunocore, InflarX, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, OncoSec, Pfizer, Philogen, Regeneron, Replimune, Sandoz, Sanofi, Sunpharma, 4SC and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, Pierre Fabre, Sandoz, Sanofi, and 4SC, outside the submitted work. HW declares no conflicts of interest. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. KG declares no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We present a very rare case of squamous cell carcinoma (SCC) ex pleomorphic adenoma of the lacrimal gland. Our patient presented with a 12 month history of painful proptosis of his left eye associated with severe headache. Imaging showed a left lacrimal gland lesion with extensive orbital disease extending into lateral and superior rectus muscles, cavernous sinus and the greater wing of the sphenoid. A lacrimal gland biopsy showed a combination of small bland glandular structures and sclerotic, elastin-containing stroma showing that the SCC had arisen on a background of a probable pleomorphic adenoma. Treatment with cisplatin and 5-Fluorouracil proved efficacious with a significant reduction of orbital and post-orbital disease on interval scanning.

Adenoid cystic carcinoma of the lacrimal gland is an aggressive, malignant epithelial neoplasm. We report the case of a 30-year-old male with lacrimal gland adenoid cystic carcinoma treated with neoadjuvant intra-arterial chemotherapy through the internal carotid artery, followed by orbital exenteration and chemoradiation. Treatment response was evaluated using a novel combination of pre- and posttreatment genome sequencing coupled with immunohistochemical evaluation, which showed diffuse tumor apoptosis. A posttreatment decrease in variant allele frequency of the NOTCH1 mutation, and robust tumor cytoreduction on imaging, supports exploration of NOTCH1 analysis as a potential marker of cisplatin sensitivity. The use of genome sequencing and immunohistochemical evaluation could provide a more targeted therapeutic assessment of neoadjuvant intra-arterial chemotherapy in the management of lacrimal gland adenoid cystic carcinoma., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

A 56-year-old woman presented with floaters and diminution of vision in the right eye for 1 week. On examination, visual acuity was 20/400 in the right eye and 20/60 in the left eye. Indirect ophthalmoscopy revealed vitritis in the right eye and subretinal deposits in both eyes. Vitreous biopsy of the right eye revealed large B-cell-type primary intraocular lymphoma and the patient underwent multiple intravitreal methotrexate injections (400 μg/0.1 mL) in the right eye and systemic chemotherapy for bilateral disease. Following biweekly injections of methotrexate, her visual acuity improved considerably from 20/400 to 20/60 with resolution of vitritis. However, following eighth dose of intravitreal methotrexate, she experienced visual decline to 20/120 along with photophobia, redness and watering. Whorl-shaped opacities, limbitis and corneal haze were noted on slit-lamp examination. Intravitreal methotrexate was stopped, and the patient was started on frequent topical lubricants, loteprednol, topical folinic acid and oral folic acid. Complete resolution of corneal toxicity was observed at 3 weeks and the injections were suspended as there was no recurrence at 6 months follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The quininib series is a novel collection of small-molecule drugs with antiangiogenic, antivascular permeability, anti-inflammatory, and antiproliferative activity. Quininib was initially identified as a drug hit during a random chemical library screen for determinants of developmental ocular angiogenesis in zebrafish. To enhance drug efficacy, novel quininib analogs were designed by applying medicinal chemistry approaches. The resulting quininib drug series has efficacy in in vitro and ex vivo models of angiogenesis utilizing human cell lines and tissues. In vivo , quininib drugs reduce pathological angiogenesis and retinal vascular permeability in rodent models. Quininib acts as a cysteinyl leukotriene (CysLT) receptor antagonist, revealing new roles of these G-protein-coupled receptors in developmental angiogenesis of the eye and unexpectedly in uveal melanoma (UM). The quininib series highlighted the potential of CysLT receptors as therapeutic targets for retinal vasculopathies (e.g., neovascular age-related macular degeneration, diabetic retinopathy, and diabetic macular edema) and ocular cancers (e.g., UM).

Purpose: To identify the frequency of intraepithelial (Pagetoid) spread beyond the ocular surface-namely beyond conjunctiva and cornea-in patients undergoing orbital exenteration for advanced periocular Sebaceous carcinoma (SC)., Design: A retrospective, noncomparative observational case series., Subjects: Patients undergoing orbital exenteration for biopsy-proven SC, at Moorfields Eye Hospital between 1997 and 2013., Methods: Review of clinical records and histological specimens, with particularly reference to involvement of conjunctiva and the extent of Pagetoid infiltration beyond the examinable ocular surface-here termed "hidden" disease., Main Outcome Measures: Histological evidence of intraepithelial SC within the lacrimal sac or lacrimal gland., Results: Twenty-nine patients had clinical data and histological specimens adequate for review. Seventeen (59%) did not have a discrete mass (clinically or histologically) and, on clinical examination, were thought to only have extensive intraepithelial carcinoma; foci of microscopic invasion were, however, detected histologically in 11/17 (65%) of these specimens. Moreover, the in situ carcinoma was found to have invaded far in lacrimal gland ductules in 1/17 patients, in the lacrimal sac (in 2 patients; 12%) or in both the gland and sac (in 2 patients); these 5/17 (29%) cases all showed extensive poorly differentiated intraepithelial SC. Of the 12 other patients who had both Pagetoid spread and a clinically evident nodule, 3 had histological evidence of "hidden" disease., Conclusion: Although-due to their being operated in the era prior to the accepted usage of topical therapy for this condition-some of these exenterations might have had particularly advanced in situ SC, over a quarter of patients with periocular SC warranting orbital exenteration show "hidden" intraepithelial tumor within the lacrimal gland and sac. This important finding might significantly reduce the efficacy (particularly in the lacrimal gland) of the various topical therapies used for in situ SC of the ocular surface, and it also emphasizes the importance of excising both the lacrimal gland and sac in all orbital exenterations for this particular tumor., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Neoadjuvant intra-arterial cytoreductive chemotherapy is used for the treatment of lacrimal gland adenoid cystic carcinomas (ACC) to improve outcomes in this condition with an otherwise dismal prognosis. We share our experience in the management of an advanced case of ACC using a novel, highly targeted intra-arterial cytoreductive chemotherapy delivery technique involving both the internal and external carotid circulation, with an attempt to correlate the effect histologically. Refinement of the chemotherapy delivery using the tumor's vascular anatomy and appropriate blood vessel selection may lead to future globe sparing procedures without compromising survival., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: To investigate the clinical features, diagnostic approaches, and outcomes of young patients with vitreoretinal lymphoma., Methods: Fifty-one vitreoretinal lymphoma patients (97 eyes) referred to the Eye and ENT Hospital of the Fudan University from 2011 to 2020 were grouped based on their onset age (age ≤50 years and age >50 years). Complete eye examinations, evaluation of systemic conditions, and biological analysis of intraocular fluids were performed., Results: Young patients accounted for 31.4% (n = 16) of the cohort. More eyes had retinal/subretinal pigment epithelial infiltration (20 [64.5%] vs. 23 [34.8%]; P = 0.018) in young patients than in elderly ones. The mutation rate of Myeloid Differentiation Factor 88 gene (MYD88) was significantly lower in young patients than in elderly ones (5 [50%] vs. 21 [91.3%]; P = 0.016). The median time to new onset of central nervous system lymphoma was significantly shorter in young patients (11.7 vs. 36.2 months; P = 0.012). However, mean overall survival did not differ between the 2 groups (64.9 vs. 57.5 months; P = 0.871)., Conclusion: Early diagnosis and central nervous system evaluation are crucial for young vitreoretinal lymphoma patients with rapid central nervous system involvement. Meanwhile, young vitreoretinal lymphoma patients have some unique features, including more retinal/subretinal pigment epithelial infiltrations and lower MYD88 mutation rates.

Purpose: To explore clinical features and outcomes of ocular surface squamous neoplasia (OSSN) treated with primary interferon (IFN)-α2b, based on patient cigarette smoking status., Methods: Retrospective nonrandomized, interventional cohort study on 212 consecutive tumors in 194 patients, all of whom were treated with topical and/or injection IFNα2b., Results: There were 88 tumors in 76 patients with current or past smoking history (smokers) and 124 tumors in 118 nonsmoking patients (nonsmokers). A comparison (smokers vs. nonsmokers) revealed smokers with more frequent bilateral disease (16% vs. 3%, P = 0.003), more frequent involvement of inferior forniceal (34% vs. 21%, P = 0.03) and inferior tarsal conjunctiva (38% vs. 24%, P = 0.04), greater mean number of clock hour involvement (4.1 vs. 3.5 clock hours, P = 0.04), and greater dome growth pattern (30% vs. 15%, P = 0.01). There was no difference regarding method of IFNα2b administration as topical (61% vs. 71%, P = 0.14), injection (10% vs. 6%, P = 0.32), or combination topical/injection (28% vs. 23%, P = 0.33). A comparison revealed smokers with more frequent recurrence after initial response (23% vs. 13%, P = 0.04). There was no difference regarding initial tumor response or time to response, treatment side effects, or systemic outcomes., Conclusions: Regarding ocular surface squamous neoplasia, smokers more often display bilateral, dome-shaped tumors with inferior forniceal or tarsal involvement, and greater extent than nonsmokers. After treatment with topical and/or injection IFNα2b, control is equivalent, but smokers show greater recurrence., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Sebaceous carcinoma (SC) is a malignant eyelid tumor of the ocular adnexa that is primarily treated via surgical excision. Few therapies exist in advanced cases, and medical therapy is limited because of our incomplete understanding of SC biology. Herein, we describe a technique to culture human ocular adnexal SC for use as an in vitro model., Methods: Human ocular adnexal SC tumor cells were isolated from a patient undergoing orbital exenteration surgery and named Bascom Palmer 50 (BP50). They were cultured in Dulbecco's modified Eagle medium/nutrient mixture F-12 supplemented with 10% fetal bovine serum and antibiotics and were maintained at 37°C in humidified 5% CO2. The cells were characterized by immunohistochemistry, exome sequencing, and short tandem repeats analysis. In vitro drug screening against mitomycin-C (MMC) was performed using a cell viability assay., Results: BP50 grew past 40 passages with a doubling time of 52.3 hours. Immunocytochemical staining revealed expression of SC-associated markers adipophilin, epithelial membrane antigen, p53, and androgen receptor. Whole exome sequencing showed a significant carryover in somatic mutations between the tumor tissue and corresponding cell line, revealing genetic markers consistent with SC. MMC affected cell viability in a dose-dependent manner., Conclusions: BP50 displays characteristics of ocular adnexal SC and therefore may facilitate improved understanding of SC biology and the high throughput assessment of novel therapeutic compounds and new drug combinatorial approaches targeted for this disease., Translational Relevance: Drug screening with MMC against these cells shows in vitro evidence to support its continued clinical use in SC.

Purpose: To assess whether exenteration specimens obtained after neoadjuvant intra-arterial cytoreductive chemotherapy (IACC) for adenoid cystic carcinoma of the lacrimal gland demonstrate significant ocular histopathologic alterations that might preclude future pursuit of globe-preserving therapy., Methods: Retrospective histopathologic analysis of globes in IACC-treated exenteration specimens among the same cohort of patients whose survival outcomes have been reported., Results: Twenty patients had specimens available. Nineteen globes revealed no abnormalities of the iris, ciliary body, lens, retinal pigment epithelium, choroid, or chorioretinal vasculature. Eighteen globes showed no optic nerve abnormalities. One globe from a patient who refused exenteration until adenoid cystic carcinoma recurrence supervened demonstrated optic nerve edema with a peripapillary hemorrhage and cotton wool spot, as well as hemorrhage and necrosis within an extraocular muscle. Eighteen globes showed no retinal abnormalities attributable to intra-arterial chemotherapy. Three globes showed incidental retinal findings: 2 globes contained 1 to 2 small peripheral retinal hemorrhages and 1 had a pigmented retinal hole. Seven demonstrated mild, chronic extraocular muscle inflammation, and 13 had unremarkable musculature. The single patient who received IACC via the internal carotid rather than the external carotid artery developed ophthalmic artery occlusion with orbital apex syndrome prior to exenteration, and diffuse necrosis and hemorrhage were evident histopathologically., Conclusions: Neoadjuvant IACC does not cause significant histopathologic damage to key ocular structures or compromise visual function in patients receiving intra-arterial chemotherapy through the external carotid artery. However, delivering chemotherapy through the internal carotid artery may result in visually significant thrombotic vascular events. The generally benign histopathological findings in these exenteration specimens support the concept of IACC delivery through the external carotid system as the cornerstone of a future globe-preserving strategy for lacrimal gland adenoid cystic carcinoma., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped)., Methods: Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed., Results: The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death., Conclusion: Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration., Competing Interests: None

A man with a history of blind eye due to trauma 22 years earlier consulted at 53 years of age with a large conjunctival neoplastic lesion, compromising almost the entire temporal limbus, and reaching a size of approximately 16 mm on its larger diameter, in the conjunctiva. Management was started with topical and subconjunctival chemotherapy (interferon alpha-2b) in order to perform immunoreduction, but a dramatic response with total disappearance of the lesion was observed. In the follow-up time period of more than 7 years, there were no signs of recurrence., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To study the efficacy of interferon alfa-2b (IFN-a2b) on pigmented ocular surface squamous neoplasia (p-OSSN) and assess the resolution of the pigment to the treatment., Methods: A retrospective case series of 8 tumors in 7 patients., Results: The mean age at diagnosis of p-OSSN was 65 years (median, 61 years; range, 51-84 years), and all patients were men. The mean duration of symptoms was 2 months (median, 1 month; range, 1-4 months). One patient had 2 distinct lesions in the same eye. Tumor epicenter was located at the limbus (n = 5) or bulbar conjunctiva (n = 2). Complexion-associated melanosis was noted in all eyes. The mean basal dimension of the tumor was 8 mm (median, 7 mm; range, 5-12 mm). The mean % of tumor pigmentation was 47% (median, 30%; range, 10%-100%). The treatment details included topical IFN-a2b (n = 1) or a combination of topical and subconjunctival injection of IFN-a2b (n = 7). All patients with p-OSSN showed excellent response to IFN-a2b with complete tumor regression and resolution of tumor-associated pigment with a mean number of 2 subconjunctival IFN-a2b injections (median, 2; range, 0-3) and topical IFN-a2b for an average of 2 months (median, 2 months; range, 1-3 months). There was no change in the complexion-associated melanosis with IFN-a2b., Conclusions: IFN-a2b is very effective in the management of p-OSSN. There is a complete resolution of the pigment along with the tumor., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Local chemotherapy is increasingly used, either in combination with surgery or as monotherapy, for management of ocular tumors. Yet many of the local chemotherapeutic agents used for ocular tumors are cytotoxic drugs that are frequently associated with toxicities in normal ocular tissues. Understanding and managing these side effects are important because they affect treatment tolerability, outcome and quality of vision. Herein, we review local anticancer drugs administered for the treatment of ocular tumors, with an emphasis on their toxicities to the ocular surface, adnexa and lacrimal drainage system. We provide the underlying mechanisms and management strategies for the ocular side effects. Recent innovations in anticancer immunotherapy and ocular drug delivery systems also are discussed as new potential therapeutic modalities for alleviation of side effects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To investigate the effectiveness and safety of subconjunctival/perilesional 5-fluorouracil injections on ocular surface squamous neoplasia (OSSN) during a 3-year follow-up period., Patients and Methods: We followed up six patients with intraepithelial OSSN (in one eye each) that had regressed after subconjunctival/perilesional 5-fluorouracil injections. Conjunctival fluorescein angiography (FA) and indocyanine green angiography (ICGA), as well as anterior segment optical coherence tomography (AS-OCT), were performed to evaluate the OSSN status 3 years after initiation of treatment., Results: The mean age of patients (five males, one female) at baseline was 62.3±11.6 years. The mean number of 5-fluorouracil injections was 17.0±8.6, with a mean treatment duration of 13.0±7.4 weeks. At the final visit, both intratumoral and conjunctival feeding vessels had disappeared on ICGA and FA, with no neovascularization-related leakage, in accordance with the results of AS-OCT. The period from complete tumor regression to final visit according to AS-OCT was 32.5±4.2 months, which was longer than that according to ICGA (31.3±3.2 months, p=0.034). The final best-corrected visual acuity was similar to that at baseline (p=0.128). No side effects were observed in any of the eyes., Conclusion: Subconjunctival/perilesional 5-fluorouracil injections are an effective and safe treatment for OSSN. Future studies with a larger sample size are warranted for confirmation of our findings, as well as investigation into the reasons for residual areas of non-perfusion in the conjunctiva., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Sun and Hua.)

Bovine ocular squamous cell carcinoma (BOSCC) also called cancer eye, represents the most economically important neoplasm in large animals. Hereditary factors, environmental factors, lack of eyelid pigmentation, age and dietary habits have all been reported to play a role in the etiopathogenesis of bovine ocular squamous cell carcinoma. In group I, six animals with small, localized eye cancer where vision was not affected were included and subjected to intralesional injection of Bacillus Calmette- Guerin (BCG) vaccine at 0, 14, 35, and 56 days interval. In group II (six animals), surgical excision and Mitomycin C 0.04% topically on alternate weeks for two months as adjunctive therapy. All the animals recovered completely with no recurrence for a follow up period of one year., (Copyright © 2020 Elsevier Ltd. All rights reserved.)