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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.Non-randomized, retrospective, interventional case series.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.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.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.

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.

To examine the clinical and histopathologic characteristics of lacrimal gland biopsies at a tertiary academic center.A retrospective chart review of patients undergoing lacrimal gland biopsy or excision between 1962 and 2017 was performed via the ocular pathology specimen log. All cases were reviewed for demographics, clinical presentation, and histopathologic diagnoses.Four hundred and two eyes in 356 patients were included in the analysis. Median age was 49 (range 5-91) with a female predominance (255, 72%, p .001). Most had unilateral involvement (308, 86.5%) and visual acuity of 20/50 or better (332 eyes, 83%). Limitation in extraocular motility was present in 71 eyes (18%), relative afferent pupillary defect in 10 eyes (2.5%), and intraocular pressure 20 mmHg or above in 80 eyes (20%). The pre-operative radiology report commented on the enlargement of the lacrimal gland in 236 eyes (58.7%), and lack thereof in 73 eyes (18.2%). The most common histopathologic diagnoses were nonspecific inflammation or orbital pseudotumor (170, 42%), lymphoma (65, 16%), pleomorphic adenoma (22, 5.5%), adenoid cystic carcinoma (19, 4.7%), granulomatous inflammation (19, 4.7%), and normal lacrimal gland (16, 4%). Three hundred and seven cases were benign (76%) and 95 malignant (24%). The biopsy specimen was diagnostic in 343 (85%), and non-diagnostic in 59 (15%).This is a comprehensive review of one of the largest ocular pathology databases of lacrimal gland lesions. This study confirms the wide range of inflammatory and neoplastic conditions affecting the lacrimal gland and highlights the nuances of histopathologic diagnoses and diagnostic yield of biopsies in clinical practice.

A 19-year-old with blunt trauma and repeated nose blowing presented with orbital emphysema and orbital compartment syndrome. Orbital emphysema is the abnormal presence of air within the orbit, typically secondary to trauma. Most cases will resolve with observation alone, however orbital compartment syndrome is a feared complication that necessitates urgent decompression. A superior fornix, trans-conjunctival approach was safely utilized to decompress the orbit while avoiding unwanted complications. Various decompression techniques have previously been described, most of which describe trans-palpebral approaches. The key safety benefit to the trans-conjunctival approach is direct visualization of the needle tip adjacent to the superior fornix, therefore posterior to the equator of the globe. With the needle positioned parallel to the curvature of the globe at the equator, the posterior sclera surface curves away from the tip, rendering it difficult to pierce the globe. In addition, the needle needs to be advanced only 3-4 millimeters and traverses only the conjunctiva and Tenon's to enter the central surgical space - the most direct route to the air pocket. The trans-conjunctival approach lowers the risk of damage to eyelid neurovascular structures and is less painful.

Zweck: Eine Proof-of-Concept-Workflow-Studie zur Herstellung von maßgefertigten Orbitalprothesen nach Exenteration durch automatisierten kontaktlosen Scan, 3D-Druck und Silikonguss. Ausführung: Nicht vergleichende, interventionelle Fallreihe. · Setting: Monozentrische institutionelle Studie. · Studienpopulation: Drei Patienten, die das Tragen der vom Okularisten hergestellten Exenterationsprothese aufgrund veränderter Passform, Verfärbung oder Materialdegradation eingestellt haben. · Interventionsverfahren: Mithilfe kontaktlosen Gesichtstopographiemappings wurde ein digitales Abbild der exenterierten Augenhöhle und der kontralateralen periokularen Region erfasst. Die digitale Konstruktion der vorderen Prothesenoberfläche basierte auf dem gespiegelten Bild der kontralateralen Seite und die hintere Oberflächenkontur auf der Geometrie der Augenhöhle. Die Details der vorderen und hinteren Oberfläche wurden digital zusammengeführt. Im 3D-Drucker wurde eine zweiteilige Form entworfen und hergestellt. Mithilfe der Kolorimetrie wurde eine individuelle Pigmentmischung für das Shore 40-Silikonelastomer erstellt, um eine Prothese zu erzeugen, die dem Hautton des Patienten nahekommt. · Wichtigste Zielparameter: Prothesensymmetrie, Übereinstimmung mit Hautton, Tragekomfort und Kosmese. Ergebnisse: Das erste Exemplar jeder 3D-gedruckten Orbitalprothese, die in diesem Produktionsworkflow hergestellt wurde, wies eine gute Symmetrie, Farbübereinstimmung und Passgenauigkeit der Prothese auf. In einem Fall wurde das neu konturierte zweite Exemplar mit verbesserter Prothesenkante an der Haut in Abwesenheit des Patienten angefertigt. Fazit: Ein kontaktloser 3D-Scan, computergestütztes Design, 3D-Druck und Silikonguss zur Herstellung von Orbitalprothesen wurden entwickelt und validiert. Dieser Produktionsworkflow hat das Potenzial, effiziente, standardisierte und reproduzierbare Exenterationsprothesen zu liefern und die Haupthindernisse für erschwingliche maßgefertigte Prothesen weltweit zu überwinden: Zugänglichkeit und Kosten.

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.

Purpose A proof-of-concept workflow study for the fabrication of custom orbital exenteration prostheses via automated noncontact scanning, 3D printing, and silicone casting. Design Noncomparative, interventional case series. Methods S etting : Single-center institutional study. S tudy P opulation : Three patients who have discontinued wearing of the ocularist-made exenteration prosthesis due to altered fit, discoloration, or material degradation. I ntervention P rocedure : A digital representation of the exenteration socket and contralateral periocular region was captured through noncontact facial topography mapping. Digital construction of the anterior prosthesis surface was based on the mirrored image of the contralateral side, and the posterior surface contour was based on orbital cavity geometry. The anterior and posterior surface details were digitally merged. A 2-piece mold was designed and produced in a 3D printer. Colorimetry was used to create a custom blend of pigments for incorporation into the Shore 40 silicone elastomer to generate a prosthesis that approximates the patient's skin tone. M ain O utcome M easures : Prosthesis symmetry, skin tone match, comfort of wear, and appearance. Results The first copy of every 3D-printed orbital prosthesis using this fabrication workflow produced good symmetry, color match, and prosthesis fit. In one case, the recontoured second copy with improved prosthesis edge-to-skin interface was made without the patient present. Conclusion A noncontact 3D scanning, computer-aided design, 3D printing, and silicone casting for fabrication of orbital prosthesis was developed and validated. This production workflow has the potential to provide an efficient, standardized, reproducible exenteration prosthesis and to overcome the principal barriers to an affordable custom prosthesis worldwide: access and cost.

Zygomatic implants (ZIs) are used to support dental prostheses in patients with inadequate maxillary bone volume. Although the ZI success rates have been high, cases of inadvertent orbital entry during zygoma drilling have been reported, with varying severity of clinical sequelae. We report the second case treated at our institution of inadvertent orbital entry during zygoma drilling. The patient experienced partial lateral rectus muscle transection resulting in diplopia, and ultimately underwent strabismus surgery. Postoperatively, his diplopia resolved, and only a small angle esophoria persisted. A review of the literature revealed 3 other cases of extraocular muscle injury secondary to orbital entry during zygoma drilling, all of which required strabismus surgery to restore alignment. We propose placement of a metal shoehorn in the inferior fornix during zygoma drilling to protect the globe and intraorbital structures from injury in the event of orbital entry.

A 45-year-old man presented with a progressively enlarging left lower lateral eyelid lesion. The initial biopsy was inconclusive; however, a repeat biopsy 5 years later revealed infiltrative morpheaform basal cell carcinoma with sclerosis. Two years later, the patient presented with ophthalmoplegia of the left eye. Computed tomography illustrated a heterogeneous enhancing soft tissue mass in the inferolateral orbit with erosion into the globe. Despite treatment with vismodegib for 1 year, the lesion progressed to involve the entire left lower eyelid and corneal-scleral junction with adjacent maxillary sinus invasion. The patient tested positive for human immunodeficiency virus and underwent a left orbital exenteration followed by adjuvant radiotherapy. The patient remained stable with no evidence of recurrent disease or distant metastasis 2 years after exenteration. This rare case highlights a neglected basal cell carcinoma in those immunocompromised with histopathological correlation of the aggressive disease on to the globe.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant ‘ACC phenotype’. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.

A 12-year-old boy presented with persistent proptosis and periorbital swelling after a school altercation. MRI revealed a mass in the right superonasal orbit extending along the orbital roof to the frontal bone and right frontal sinus, and intracranially to the dura of the right frontal lobe. Immunohistochemistry revealed CD20- and CD43-positive B cells consistent with a low-grade B-cell lymphoma. The patient was diagnosed with stage I ocular adnexal MALT lymphoma and treated with radiation therapy, followed by systemic chemotherapy. However, an enhancing orbital and intracranial mass remained on follow-up imaging, leading to a repeat biopsy, which was consistent with a diagnosis of Rosai-Dorfman disease. This is the first reported pediatric case of ocular adnexal MALT lymphoma with subsequent development of Rosai-Dorfman disease.

To investigate the effects of mitomycin-C (MMC) and 5-fluorouracil (5-FU) on the viability, proliferation, and migratory capacity of cultured ocular adnexal sebaceous carcinoma (SC) cells.Laboratory investigation.Human SC cell lines (Bascom Palmer 50 and 52 [BP50 and BP52]) and human limbal stem cells (LSCs) were treated with various concentrations of MMC and 5-FU. Cytotoxicity was assessed with the tetrazolium MTT colorimetric viability assay on normal corneal vs tumor cells. Growth curves and scratch assays were performed to characterize the effects of these chemotherapeutic agents on SC proliferation and migration, respectively.MMC decreased BP52 cell viability in a dose-dependent manner with a half-maximal effective dose (ECOur in vitro data corroborate clinical observations that MMC is efficacious for treating ocular adnexal SC, albeit at the expense of LSC viability. Our findings also demonstrate that topical 5-FU exhibits antiproliferative effects that supersede its cancer-killing and antimigratory effects on cultured SC cells.

Metastases of solid tumors to the eye and ocular adnexa are rare. Herein, the authors describe the clinical, histologic, and immunohistochemical findings of a patient with a history of adenocarcinoma of the colon and a uterine carcinosarcoma (malignant mixed Mullerian tumor) who presented with proptosis and decreased vision. Positive staining with PAX-8, p16 and negative reaction for CK20 and CDX2 helped to establish the uterine origin of the metastasis. This rare case demonstrates the utility of immunohistochemical probes, especially in patients with a complex oncological history, where multiple primary sources of the metastasis are in the differential diagnosis.

Sebaceous carcinoma (SC) is a malignant neoplasm that predominantly arises from the sebaceous glands of the ocular adnexa. It is the second most common malignant eyelid neoplasm in the United States. No standardized treatment exists, but surgical excision is the mainstay of therapy. Therapeutic advances have been stagnant largely due to a limited understanding of SC tumor biology. We performed single-cell RNA sequencing to profile primary ocular adnexal SC and gain insights into its tumor microenvironment. Ocular adnexal SC has extensive intra-tumoral heterogeneity at the transcriptional level. Dimensionality reduction via principal component analysis was performed to identify major cell types. 8 clusters were detected, including clusters for cancer epithelial cells and various immune cells. Transcriptional programs were related to pathways in cancer, immune response, and antigen processing and processing, among others. We identified unique subpopulations of tumor-infiltrating immune cells, including plasma B cells, GNLY+ natural killer cells, CD8+ T cells, memory T cells, and CD20+ B cells. This complex ecosystem of tumor and immune cells provides new insights into SC biology. Additional patient samples we be analyzed in the immediate future. Follow-up mechanistic studies are needed to clarify the roles of the identified immune cells and how they can be exploited for immunotherapeutic approaches. Citation Format: Ryan Alexander Gallo, Michelle G. Zhang, David T. Tse, Daniel Pelaez, Andrew J. Rong. Single-cell RNA sequencing reveals insights into the intra-tumoral heterogeneity and tumor microenvironment of ocular adnexal sebaceous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1717.

Lacrimal gland adenoid cystic carcinoma (LGACC) is a rare but highly lethal indolent cancer originating in the cells of secretory glands, primarily of the head and neck. With the 10-year survival rate of 20%, the only life extending technique is to remove the eye and surrounding socket contents followed by extensive chemoradiation. Despite radical treatment, LGACC has a poorer prognosis than head and neck adenoid cystic carcinoma in part due to its propensity for perineural invasion (PNI) and intracranial spread. Analysis of LGACC tumors has revealed signatures enriched for pathways known to be involved in normal LG development, suggesting LGACC tumor cells re-engage or hijack developmental programs during its progression. This project sought to evaluate if developmental pathways involved in embryologic LG innervation were similarly recapitulated by LGACC tumors, and whether any of those markers could be correlated to perineural invasion phenotypes. We performed microarray analysis of embryonic and adult murine lacrimal glands and generated a differential expression signature associated with normal LG developmental pathways. Among other pathways, Notch and FGF signaling are significantly upregulated during LG organogenesis and our group and others have shown that activating mutations in these pathways are correlated with poor prognosis in LGACC. Interestingly, among the highest differentially expressed genes in the embryonic LG was the low-affinity nerve growth factor receptor (p75NTR). We thus subsequently evaluated the expression of p75NTR in LGACC tumors and its correlation to PNI. Our immunofluorescent imaging of histologically confirmed tumors with PNI demonstrated that p75NTR is highly correlated to cancer cells that have invaded the nerve. This correlation of p75NTR expression in nerve infiltrating LGACC cells can inform our investigation into the mechanisms for LGACC PNI and elucidate possible therapeutic targets to limit this aggressive manifestation in LGACC. Citation Format: Acadia H. Moeyersoms, Ryan A. Gallo, Madison Weiss, Michelle M. Maeng, David T. Tse, Daniel Pelaez. Expression of the low affinity neurotrophin receptor (p75NTR) correlates with perineural invasion in adenoid cystic carcinoma of the lacrimal gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2405.

PURPOSE: To assess whether exenteration specimens obtained after neoadjuvant intra-arterial cytoreductive chemotherapy (IACC) for adenoid cystic carcinoma of the lacrimal gland (ACC) 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 ACC 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: two globes contained one to two small peripheral retinal hemorrhages and one had a pigmented retinal hole. Seven demonstrated mild, chronic extraocular muscle inflammation, and thirteen 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 supports the concept of IACC delivery through the external carotid system as the cornerstone of a future globe-preserving strategy for lacrimal gland ACC. PRECIS: After delivery of neoadjuvant intra-arterial chemotherapy for lacrimal gland adenoid cystic carcinoma through the external carotid system, none of the studied eyes showed histopathologic changes that would portend loss of ocular function.

A 68-year-old man with a history of type 2 diabetes mellitus and kidney transplantation on chronic immunosuppression presented with right-sided proptosis and vision loss. He was hospitalized 4 months prior for invasive sinus aspergillosis. MRI revealed abnormal enhancement in the right orbital apex, inferior medial right orbit, anterior cranial fossa floor, and anterior aspect of the falx cerebri. The patient was successfully managed with extensive sinus surgery, bifrontal craniotomy with resection of dura, cribriform plate resection, and a right orbital apex exenteration. The globe and anterior orbital structures were preserved to cover the large surgical sinodural-orbital defect and avoid complex reconstructive surgery. Orbital perfusion was maintained by exploiting the robust anastomoses between branches of external carotid and ophthalmic artery.

The lacrimal gland is the epicenter of a broad spectrum of neoplastic and inflammatory diseases (Table 58.1). Space occupying lesions of the lacrimal gland and its fossa constitute approximately 5–13% of orbital masses upon biopsy [1–3]. Based primarily on Reese’s [4] 1956 clinicopathologic survey of 112 consecutive expanding lesions of the lacrimal gland, most authorities generally report that approximately 50% of the lesions originate from epithelial elements of the lacrimal gland and 50% are of non-epithelial origin [5–7]. Of non-epithelial lesions, 50% are lymphoid tumors and 50% are comprised of various infections and inflammatory pseudotumors. Among the epithelial tumors of the lacrimal gland, approximately 50% are pleomorphic adenomas (benign mixed tumors), 25% adenoid cystic carcinoma, and the remainders are other types of carcinoma. Recent reports, however, suggest that inflammatory lesions and lymphoid tumors are more common, and that epithelial malignancies of the lacrimal gland are considerably less frequent than commonly cited, ranging from 22% to 47% [1, 3, 7–10]. Proper differentiation between these two groups is of paramount importance since several of the lesions are life threatening.

Traumatic optic neuropathy (TON) can occur following blunt trauma to the orbit and can lead to permanent vision loss. In this study, we investigated the effectiveness of elamipretide (MTP-131), a small mitochondrially-targeted tetrapeptide, in conjunction with etanercept, a tumor necrosis factor (TNF) inhibitor, as neuroprotective agents of retinal ganglion cells (RGCs) after optic nerve trauma with sonication-induced TON (SI-TON) in mice. Treatment with intravitreal MTP-131 and subcutaneous etanercept and MTP-131 showed a 21% increase (p 0.01) in RGC survival rate compared to PBS-treated control eyes. Subcutaneous etanercept and MTP-131 had an 11% increase (p 0.05) in RGC survival compared to controls. Subcutaneous etanercept only group showed 20% increase (p 0.01) in RGC survival compared to controls, while subcutaneous MTP-131 alone showed a 17% increase (p 0.01). Surprisingly, we did not observe a synergistic effect between the two drugs in the group receiving both etanercept and MTP-131. One possible explanation for the absence of a synergistic effect is that MTP-131 and etanercept may be acting on different portions of the same pathway.

Purpose To evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify small molecules that revert pathologic gene signature and alter disease phenotype in orbital adipose stem cells (OASCs) derived from patients with thyroid-associated orbitopathy (TAO). Methods Differentially expressed genes identified via RNA sequencing were inputted into LINCS L1000 Characteristic Direction Signature Search Engine (L1000CDS2) to predict candidate small molecules to reverse pathologic gene expression. TAO OASC cell lines were treated in vitro with six identified small molecules (Torin-2, PX12, withaferin A, isoliquiritigenin, mitoxantrone, and MLN8054), and expression of key adipogenic and differentially expressed genes was measured with quantitative polymerase chain reaction after 7 days of treatment. OASCs were differentiated into adipocytes, treated for 15 days, and stained with Oil Red O (OD 490 nm) to evaluate adipogenic changes. Results The expression of key differentially expressed genes (IRX1, HOXB2, S100B, and KCNA4) and adipogenic genes (peroxisome proliferator activated receptor-γ, FABP4) was significantly decreased in TAO OASCs after treatment (P < .05). In treated TAO adipocytes (n = 3), all six tested small molecules yielded significant decrease (P < .05) in Oil Red O staining. In treated non-TAO adipocytes (n = 3), only three of the drugs yielded a significant decrease in Oil Red O staining. Conclusions Combining disease expression signatures with LINCS small molecule prediction software can identify promising preclinical drug candidates for TAO. Translational Relevance These findings may offer insight into future potential therapeutic options for TAO and demonstrate a streamlined model to predict drug candidates for other diseases.

Purpose To determine the effectiveness of etanercept, a tumor necrosis factor (TNF) inhibitor, in conferring neuroprotection to retinal ganglion cells (RGCs) and improving visual outcomes after optic nerve trauma with either optic nerve crush (ONC) or sonication-induced traumatic optic neuropathy (SI-TON) in mice. Methods Mouse optic nerves were unilaterally subjected to ONC (n = 20) or SI-TON (n = 20). TNF expression was evaluated by using immunohistochemistry and quantitative RT-PCR (qRT-PCR) in optic nerves harvested 6 and 24 hours post ONC (n = 10) and SI-TON (n = 10). Mice in each injury group received daily subcutaneous injections of either etanercept (10 mg/kg of body weight; five mice) or vehicle (five mice) for 7 days. Pattern electroretinograms were performed on all mice at 1 and 2 weeks after injury. ONC mice were killed at 2 weeks after injury, while SI-TON mice were euthanized at 4 weeks after injury. Whole retina flat-mounts were used for RGC quantification. Results Immunohistochemistry and qRT-PCR showed upregulation of TNF protein and gene expression within 24 hours after injury. In both models, etanercept use immediately following optic nerve injury led to higher RGC survival when compared to controls, which was comparable between the two models (24.23% in ONC versus 20.42% in SI-TON). In both models, 1 and 2 weeks post injury, mice treated with etanercept had significantly higher a-wave amplitudes than untreated injured controls. Conclusions Treatment with etanercept significantly reduced retinal damage and improved visual function in both animal models of TON. These findings suggest that reducing TNF activity in injured optic nerves constitutes an effective therapeutic approach in an acute setting.

Background: Sebaceous carcinoma (SC) is a highly malignant and potentially lethal neoplasm that most commonly arises from the ocular adnexa. Surgical management is the current mainstay of treatment; however, globe sparing tumor control is often complicated by pagetoid (or intraepithelial) invasion. Topical mitomycin-c (MMC) or 5-fluorouracil (5-FU) have been used as adjunctive medical therapy on the basis of their success in treating other ocular neoplasms. Yet, little is known of their effects on SC tumorgenicity. Here, we characterized effects of MMC and 5-FU in SC in vitro. Methods: Periocular SC tissue samples were collected from two patients with histologically confirmed disease. This study was approved by the University of Miami Institutional Review Board and was conducted in a Health Insurance Portability and Accountability Act of 1996—compliant manner. Molecular characterization of the SC cells was done by immunocytochemistry and whole exome sequencing. SC cells were treated with MMC and 5-FU. The cytotoxic effects were evaluated using a viability assay and the kinetics of these effects were investigated by measuring cell proliferation over time. Migration capability of SC cells after drug treatment was examined by wound healing assays. Results: Two SC cell lines, called Bascom Palmer 50 and 52 (BP50 and BP52), were established. Both cell lines retain the immunophenotypic and molecular features of SC. MMC reduced cell viability in both cell lines in a dose-dependent manner. MMC decreased SC cell proliferation and reduced overall cell number significantly compared to the untreated controls in a dose-dependent manner. MMC also inhibited SC migration capacity significantly. Conversely, 5-FU treatment did not affect cell viability or migration capacity in a dose-dependent fashion. While treatment with high-dose 5-FU inhibited SC proliferation, it did not reduce cell number below baseline. Conclusions: We successfully generated SC cell lines and characterized the effects of MMC and 5-FU on these lines. Clinical medical management of periocular SC has been based of empirical data. Our findings suggest that MMC possess superior cytotoxic and cytostatic activity against SC compared to 5-FU in vitro. Taken together, these preliminary findings indicate that MMC may be more efficacious than 5-FU in the treatment of periocular SC. Currently, investigations are underway to identify novel therapeutic targets and test their efficacy in our cell lines. Citation Format: Steven H. Lang, Ryan A. Gallo, Michelle G. Zhang, David T. Tse, Daniel Pelaez, Andrew J. Rong. Comparison of the anticancer effects of Mitomycin-C and 5-Fluorouracil on novel periocular sebaceous carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2987.

A 20-year-old woman presented with loss of vision in her right eye and a "black nose" after receiving hyaluronic acid filler injections in her right glabella 1 month prior. Her vision was no light perception, and external examination revealed resolving skin necrosis at the nasal tip. A dilated fundus exam showed a fibrotic membrane emanating from a pale optic nerve and a diffusely atrophic retina with sclerotic vessels. An MRI demonstrated scattered right-sided parietal lobe infarcts. These findings were consistent with inadvertent cannulation of the supraorbital artery, followed by injection of filler into the internal carotid circulation. The product traveled in a retrograde fashion, occluding the right ophthalmic artery, right dorsal nasal artery, and arterial segments to the Circle of Willis. This case highlights the importance of understanding the complex vascular architecture of the periorbita and the mechanism by which such occlusions occur.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Purpose To present a novel myocutaneous flap for anterior lamellar reconstruction. Methods Retrospective interventional case series of consecutive patients who underwent Mohs reconstruction using the flip-back flap. Operations were performed by a single surgeon (DTT) between January 2012 and May 2016. For lower eyelid defects, an extended subciliary incision was made and a skin-muscle flap developed and suspended in the manner of lower eyelid blepharoplasty. A back-cut was used to develop a pedicle from the overlapping tissue, which was then rotated 180 degrees into the defect. A similar method was employed in an inverted manner for upper eyelid defects. Postoperative eyelid function, cosmesis, complications, and need for further interventions were assessed. Results Ten patients-8 with lower and 2 with upper eyelid defects-were reconstructed using this method. Mean follow up was 18.3 ± 15.5 months with a minimum interval of 4 months. Despite the 180-degree rotation of a relatively narrow pedicle, none of the patients experienced flap necrosis. Postoperative function and cosmesis was satisfactory, with no tissue puckering, notching, or symptomatic retraction. No antimetabolite/steroid injection or surgical revision was required. Conclusions The flip-back flap expands the armamentarium of the periocular reconstructive surgeon. Its particular forte is in addressing broad and relatively shallow anterior lamellar defects where sufficient tissues are not available for transposition via a uni- or bipedicle flap. By leveraging the robust periocular vascular plexus and defying traditional guidelines governing pedicle formation and rotation, it permits creation of a local flap in cases where skin grafts or extensive Mustarde-style flaps might otherwise be required.The flip-back myocutaneous flap offers a novel alternative to skin grafting or more extensive cheek rotational flaps for reconstruction of challenging anterior lamellar defects involving the eyelids and adjacent periocular tissues.

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.

e18051 Background: Lacrimal gland adenoid cystic carcinoma (LGACC) has historically been associated with a poor prognosis even in localized disease, with the survival of 56% at 5 years and 49% at 10 years. In 1988, our group treated the first patient with neoadjuvant intra-arterial chemotherapy (IACC) followed by adjuvant chemoradiation. Since then, we use this protocol as the standard approach for localized LGACC. Herein, we aim to analyze the clinical characteristics and outcomes of LGACC patients at a single academic institution treated with the protocol to provide information on this approach's efficacy. Methods: We prospectively assessed all patients with pathologically confirmed LGACC treated at Bascom Palmer, Sylvester Comprehensive Cancer Center, or Jackson Memorial Hospital between 1988 and 2021. We calculated overall survival (OS) using the Kaplan-Meier and Cox proportional-hazards modeling methods with Log-Rank Test to estimate the 95% confidence interval. Results: 42 LGACC patients were identified, and 37 (88%) underwent IACC, with 2 (5%) being metastatic at the time of the protocol. In our cohort, the median follow-up was 10 years, 21 (56%) were men, and the median age at diagnosis was 42 (range 20-72). The average tumor size was 3cm (range 0.8-7.6). The dominant histological pattern was cribriform (n = 23, 54%), followed by basaloid (n = 6, 14%) and solid (n = 6, 14%). 16 patients underwent whole genome sequencing, and the most common mutations found were NOTCH1 (n = 7, 41%), ATM (n = 4, 25%), BPTF (n = 4, 25%), FGFR 2 (n = 3, 18%), Frem3 (n = 3, 18%), and NOTCH2 (n = 3, 18%), with additional biomarker data forthcoming. The 5, and 10-year survival rates were 85% (95% CI 73–97) and 71% (95% CI 53-89), respectively, giving and overall mean survival of 23 years (95% CI 19–28). The risk of death was higher with a tumor size larger than 3 cm and with bone invasion (HR: 6.5 and 7.5 respectively; P < 0.05). Conclusions: Despite the historically described poor prognosis, patients with LGACC treated with IACC have an excellent prognosis. Future research on tumor molecular characteristics might identify susceptibility to targeted therapies such as NOTCH or FGFR inhibitors that could be incorporated into the IACC protocol, further extending its benefits.

e15018 Background: Few effective systemic therapies are available for adenoid cystic carcinoma (ACC). Multitargeted Tyrosine Kinase inhibitors (TKIs) as Lenvatinib and Rivoceranib can provide disease control and limited radiographic response in unselected ACC patients. Next-generation sequencing in tissue (tNGS) has identified MYB gene fusions in [patients with ACC but currently, only Notch1 mutations have an available targeted agent. The fibroblast growth factor receptor (FGFR) pathway is a downstream target of MYB. Methods: We retrospectively reviewed adult patients with a diagnosis of recurrent ACC seen at the University of Miami Sylvester Comprehensive Cancer Center between January 1, 2019 and October 31, 2020. Commercially available cell free DNA panel of 73 genes was used for analyzing circulating tumor DNA (ctDNA). Patients included had radiographically measurable disease and both tNGS and ctDNA data available. Results: Twelve patients were included. Median age at diagnosis was 54 years (28 - 68), and 69% were males. 83% of the patients had genomic abnormalities reported by tNGS, with the same number by ctDNA sequencing. Seven patients (58%) had genomic abnormalities in ctDNA of potentially therapeutic significance which were not found on tNGS, including FGFR1 amplification as well as FGFR2, BRAF, KRAS and JAK2 mutations. Three patients with FGFR genomic abnormalities only seen by ctDNA had been previously treated with Lenvatinib. One patient with primary lacrimal gland ACC metastatic to the liver and tNGS positive for NOTCH 1 had disease progression despite treatment with Lenvatinib and a NOTCH γ-secretase inhibitor. The patient’s ctDNA reported a FGFR2 mutation. The patient was started on Erdafitinib, an oral selective FGFR inhibitor, achieving a partial response at the primary site and metastatic liver lesions and remained on therapy for 7 months. Follow-up ctDNA after 3 months of therapy noted resolution of both FGFR and NOTCH abnormalities. Conclusions: Patients treated with lenvantinib or other TKIs may develop acquired resistance mutations and other genomic abnormalities. ctDNA can reveal additional therapeutic targets not present on tNGS and can be repeated serially. FGFR genomic abnormalities can be a driver mutation in patients with refractory advanced ACC and the activity of Erdafinib should be evaluated in this subset of patients with few therapeutic options.

Human parasitization by oestrid flies is a rare occurrence. The authors report a case of ophthalmomyiasis externa caused by Dermatobia hominis infestation in a 10-year-old female. Misdiagnosis resulted in a delay in treatment, which can be potentially devastating in cases of orbital or ocular involvement. The treatment of choice is early surgical removal of the larvae to minimize the inflammatory response and the extent of surgery. Patients should also be screened for multiple sites of cutaneous infestation. When the organism is completely excised, the prognosis is good.

PURPOSE To highlight features of lateral canthal tendon disinsertion (LCTD), provide an algorithm for systematic assessment, and describe the anatomic genesis of signs and symptoms. METHODS Retrospective case series of consecutive patients with lateral canthal tendon disinsertion, who underwent lateral canthal tendon fixation by a single surgeon (DTT) between 2004 and 2011. RESULTS One hundred and seventeen eyes in 90 patients underwent lateral canthal tendon fixation. Average age was 69.3 ± 17.9 years. Twenty-three percentage of eyes had undergone lower eyelid blepharoplasty and 52% had undergone lateral canthal tightening; 35% had no previous periocular surgery. Patients with purely involutional lateral canthal tendon disinsertion were significantly older (76.1 ± 7.8 years of age; p < 0.03). Six key features associated with lateral canthal tendon disinsertion were identified. On static evaluation: 1) a blunted or vertically displaced lateral canthal angle; 2) a narrow horizontal fissure with reduced temporal scleral triangle; and 3) pseudo eyelid retraction. On dynamic evaluation with attempted closure: 4) medial and inferior movement of the lateral commissure; 5) incomplete apposition of the eyelid margins in the absence of anterior lamellar shortage; and 6) temporal eyelid imbrication. Improved blink dynamics with manual lateral canthal tendon complex repositioning ("the thumb test") predicted a favorable outcome with surgical tightening in 95.7% of cases. CONCLUSIONS Lateral canthal tendon disinsertion results in altered eyelid fissure symmetry, blink dynamics, and lacrimal pump function. The authors recommend the mnemonic-A.B.C.: for Aperture configuration, Blink dynamics, and eyelid Closure-to structure the examination of all symptomatic patients. Manual restoration of the disinserted lateral canthal tendon with the "thumb test" predicts favorable outcomes with surgical fixation.

Purpose To describe a surgical technique to correct lateral canthal tendon disinsertion with a strabismus surgery-inspired locking capture of the tendon complex and osseous integration via drill holes. Methods Retrospective interventional case series including all patients with lateral canthal tendon disinsertion who underwent locking Y lateral canthopexy with drill hole reinforcement by 1 surgeon (D.T.T.) between 2006 and 2011. Outcome measures included resolution of presenting ocular symptoms, improved blink dynamics and lid closure, correction of lagophthalmos and exposure keratopathy, and need for further surgery. Results A total of 53 lateral canthopexies with osseous integration were performed in 42 patients who fulfilled clinical criteria for lateral canthal tendon disinsertion. The population was biased toward treatment failures; 81% of eyes (43/53) had a history of prior lateral canthal tightening, and of these 30.2% (16/53) had undergone 3 or more procedures. Postoperatively, all eyes demonstrated improved eyelid position and blink mechanics, and 83% (44/53) had subjective resolution of epiphora and ocular irritation. Lagophthalmos was fully corrected in 95% (19/20) of cases, and corneal staining resolved in 88% (14/16). With a mean follow-up period of 24 months, 3.7% of eyes (2/53) required additional lateral canthal tightening. Conclusions The locking Y lateral canthopexy is an effective and durable method for repositioning the lateral canthal tendon complex to improve blink dynamics, eyelid closure, and cosmesis. Even in a population heavily biased toward treatment failure, clinical results are excellent and the reoperation rate is low.

A 49-year-old woman with debilitating nystagmus and oscillopsia failed conservative therapy. A titanium T-plate was anchored to the lateral orbital rim and cantilevered into the orbit where it was secured to the inferior rectus muscle tendon with a suture. After the procedure was performed on both eyes, the patient had significant decreases in the amplitudes of her nystagmus and oscillopsia, thereby improving her daily function. She had sustained duration of effect through 7 years of follow up. This novel surgical technique holds promise in the treatment of acquired nystagmus and debilitating oscillopsia for which conventional therapy may be ineffective. The case report is in compliance with the Health Insurance Portability and Accountability Act.

Identification of molecular targets is the first step in developing efficacious therapeutic strategies for tumors. A tumors' biological response to perturbagens yields important information on the molecular determinants for tumor growth. The aim of this study was to characterize the response of adenoid cystic carcinoma of the lacrimal gland (LGACC) to intra-arterial cytoreductive chemotherapy (IACC) in order to identify novel targets to enhance therapy. We performed high-throughput proteomic analysis on paired samples from pre-IACC diagnostic biopsies and post-IACC excised tumor samples from 6 LGACC patients. This proteomic analysis provides a comprehensive landscape of the cellular compartments contained within the excised tumors. Interestingly, we found a strong upregulation across the fibroblast growth factor (FGF) signaling pathway, with FGF receptor 1 (FGFR1) exhibiting a consistent and significant upregulation in all post-IACC samples. We thus evaluated the therapeutic efficacy of a novel FGFR1 selective inhibitor, AZD4547, in combination with cisplatin on LGACC cells in-vitro. The combination index (CI) value (

Purpose: To describe a novel technique of using a hard palate-dermis fat composite graft (HPDFG) for reconstruction of a contracted anophthalmic socket. Methods: Retrospective, noncomparative, interventional case series of four patients who underwent HPDFG placement by one surgeon between 2010 and 2017. Results: Six harvested HPDFGs were placed in four patients with contracted anophthalmic sockets. A harvested hard palate graft (HPG) and a dermis fat graft (DFG) were adjoined with sutures to form a composite graft. All adhesions and symblephara between the eyelid and the anterior surface of the anophthalmic socket were lysed. The HPG component was attached to the tarsal margin to vertically lengthen the eyelid. The free edge of the DFG was sutured to the cut edge of the bulbar conjunctiva to simultaneously expand the anterior conjunctival surface area and fornix volume. The line of union between the two grafts formed the apex of the new fornix. Four HPDFG were used to reconstruct both the upper and lower lid fornices in two severely contracted sockets. Three patients received post-operative 5-fluorouracil (5-FU) injections. Three patients underwent additional revisions with buccal mucous membrane graft, amniotic membrane graft, full-thickness skin graft, pedicle flap, and dermal fillers. All four patients achieved excellent cosmesis and comfortable prosthesis fit. Conclusions: Composite HPDFG is an effective method of reconstructing a contracted anophthalmic socket by restoring volume, lengthening the posterior lamella, and expanding the fornix to allow for successful prosthesis retention. Adjunctive use of 5-FU injections can delay post-operative cicatrization.

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, describes a disease of poorly understood pathophysiology with a specific set of signs and symptoms including potentially irreversible and blinding visual loss. Optic nerve sheath fenestration (ONSF) is a well-described surgical treatment for patients with IIH and progressive visual loss despite maximally tolerated medical therapy. A number of optic nerve access procedures have been described including medial transconjunctival, superomedial lid crease, and lateral orbitotomy with and without bone takedown. The purpose of this report is to describe a revised lateral approach for temporal optic nerve access that obviates the need to traverse through the intraconal fat of the central surgical space in the previously described lateral approach techniques.

Ectropion is a commonly encountered eyelid malposition characterized by eversion of the eyelid margin away from the globe. Although the upper or lower eyelid may be affected, this condition more commonly involves the lower eyelid. Chronic exposure of the globe and palpebral conjunctiva results in dry eye symptoms with reflex tearing. The exposed palpebral conjunctiva becomes inflamed and may develop metaplastic changes of epidermalization. An exposed punctum can become stenotic, contributing to tear outflow impairment. Additionally, corneal exposure may lead to epithelial breakdown, with increased risk of infectious keratitis. Upper eyelid ectropion often results from cicatricial changes of the anterior lamella related to previous injury, such as laceration or burn. Iatrogenic upper eyelid ectropion may occasionally occur after ptosis repair or blepharoplasty.

Sebaceous carcinoma (SC) is a malignant neoplasm that frequently affects the eyelids. It is an aggressive malignancy with metastasis rates as high as 25%. Historical studies have shown that mortality rates could be as high as 83%, but with the advent of increased detection, diagnosis, and treatment options, mortality rates have dropped substantially. A major issue with obtaining a proper diagnosis of SC is that it can mimic many other benign and malignant pathologies. Consequently, a delay in the diagnosis of SC can result in a poor prognosis and outcome for patients. The standard of care for SC is surgical excision, however, there is a reoccurrence rate of approximately 4% after excision. In these cases, it is necessary to treat patients with further excision and possibly radiation. Not all patients can have their tumors treated with surgery. In cases where there is diffuse intraepithelial seeding of the tumor cells, metastasis, or orbital invasion, other methods such as chemotherapy, radiation, and exenteration must be performed. It is essential that we elucidate the cellular mechanisms regarding the etiology of SC to develop better methods of diagnosis and treatment for the future. In this chapter, we will focus on the clinically relevant topics regarding SC, signaling pathways involved in the pathogenesis, and how miRNAs interact with these cascades. Both Wnt and TGF-β signaling have been implicated in the developing sebaceous glands and SC. Several miRNAs have been studied in this disease and downstream targets include: NF-κB, PTEN, c-Myc, and AKT2. These miRNAs may be used as biomarkers for SC or they may be potential therapeutic targets for patients who do not benefit from current interventions.

Carcinogenesis has a multifactorial etiology, and the underlying molecular pathogenesis is still not entirely understood, especially for eye cancers. Primary malignant intraocular neoplasms are relatively rare, but delayed detection and inappropriate management contribute to poor outcomes. Conventional treatment, such as orbital exenteration, chemotherapy, or radiotherapy, alone results in high mortality for many of these malignancies. Recent sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve management. Transcription factors are proteins that regulate gene expression by modulating the synthesis of mRNA. Since transcription is a dominant control point in the production of many proteins, transcription factors represent key regulators for numerous cellular functions, including proliferation, differentiation, and apoptosis, making them compelling targets for drug development. Natural compounds have been studied for their potential to be potent yet safe chemotherapeutic drugs. Since the ancient times, plant-derived bioactive molecules have been used to treat dreadful diseases like cancer, and several refined pharmaceutics have been developed from these compounds. Understanding targeting mechanisms of oncogenic transcription factors by natural products can add to our oncologic management toolbox. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in various types of eye cancer.