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Localized orbital amyloidosis is a rare clinical entity. Periocular and orbital amyloid deposits are mainly located at the lacrimal apparatus, eyelid, conjunctiva, ocular adnexa, extraocular muscles, and levator palpebrae muscle. In this article, the authors report an unusual case of optic nerve amyloid deposition in an 82-year-old African American woman who presented with vertical diplopia. MRI revealed an enhancing mass from the optic nerve sheath, and CT showed foci of calcifications suggestive of optic nerve meningioma. However, an incisional biopsy demonstrated lymphoproliferative disease with focal optic nerve sheath amyloid deposition confirmed by histologic Congo red staining and immunohistochemistry., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Adenoid cystic carcinoma (ACC) is a rare and lethal malignancy that originates in secretory glands of the head and neck. A prominent molecular feature of ACC is the overexpression of the proto-oncogene MYB. ACC has a poor long-term survival due to its high propensity for recurrence and protracted metastasis. Currently, clinical technologies lack the efficiency to distinguish patient prognosis prior to its redevelopment. We hypothesize that metastatic ACC can be detected by monitoring tumor-specific MYB expression in patients' blood. We developed a quantitative polymerase chain reaction (qPCR) assay for MYB transcripts and screened blood samples from four patient cohorts: no history or evidence of ACC (n=23), past history of ACC and no evidence of disease (NED) for greater than three years (n=15), local ACC (n=6), and metastatic ACC (n=5). Our assay detected significantly elevated levels of MYB transcripts in the metastatic ACC cohort (p < 0.01). Receiver operating characteristic (ROC) curves comparing metastatic to NED and metastatic to local disease were significant, with p values < 0.0001 and 0.0008, respectively. Single-cell RNA sequencing (scRNA-seq) of blood from metastatic ACC identified a cluster of circulating tumor cells (CTCs) expressing MYB. Here, we report a sensitive, cost-effective, and minimally invasive diagnostic test that leverages tumor-specific signatures to screen for metastatic ACC disease, potentially enhancing detection earlier than the current clinical standard., Competing Interests: Competing interests The authors declare that there are no competing interests.

Since three-dimensional (3D) bioprinting has emerged, it has continuously to evolved as a revolutionary technology in surgery, offering new paradigms for reconstructive and regenerative medical applications. This review highlights the integration of 3D printing, specifically bioprinting, across several surgical disciplines over the last five years. The methods employed encompass a review of recent literature focusing on innovations and applications of 3D-bioprinted tissues and/or organs. The findings reveal significant advances in the creation of complex, customized, multi-tissue constructs that mimic natural tissue characteristics, which are crucial for surgical interventions and patient-specific treatments. Despite the technological advances, the paper introduces and discusses several challenges that remain, such as the vascularization of bioprinted tissues, integration with the host tissue, and the long-term viability of bioprinted organs. The review concludes that while 3D bioprinting holds substantial promise for transforming surgical practices and enhancing patient outcomes, ongoing research, development, and a clear regulatory framework are essential to fully realize potential future clinical applications.

Competing Interests: The authors have no financial or conflicts of interest to disclose.

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.)

Purpose: Conjunctival melanoma is a rare neoplasm with high rates of recurrence and metastasis. Traditional management includes surgical excision and cryotherapy, followed by adjuvant therapy as needed. Immune checkpoint inhibitors, including nivolumab, are a targeted treatment option with improved survival rates. However, various immune-related adverse effects have been reported with these drugs. While systemic granulomatous inflammation is a documented systemic side effect, it has rarely been reported in the conjunctiva and ocular adnexa., Observation: A patient with a history of recurrent metastatic conjunctival melanoma presented with both a left sub-conjunctival and upper eyelid lesion after the commencement of treatment with nivolumab. The lesions were excised with a clinical suspicion for metastasis and consisted of noncaseating granulomatous inflammation with no evidence of malignancy on histopathologic examination. Infectious and primary autoimmune etiologies were ruled out., Conclusion and Importance: This is a biopsy-proven case of periocular immune checkpoint inhibitor-associated granulomatous inflammation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

Purpose: To evaluate the incidence of nasocutaneous fistula (NCF) development, following en bloc resection of lacrimal outflow system malignancies (LOSM), and describe the methods of surgical repair., Methods: Retrospective review of all patients who underwent resection of LOSM with reconstruction and post-treatment protocol at the University of Miami between 1997 and 2021., Results: Of the 23 included patients, 10 (43%) developed postoperative NCF. All NCFs developed within one year of surgical resection or completion of radiation therapy. NCF was seen more frequently in patients who underwent adjuvant radiation therapy and those who had reconstruction of the orbital wall with titanium implants. All patients underwent at least one revisional surgery to close the NCF, including local flap transposition (9/10), paramedian forehead flap (5/10), pericranial flap (1/10), nasoseptal flap (2/10), and microvascular free flap (1/10). Local tissue transfer, pericranial, paramedian, and nasoseptal forehead flaps failed in most cases. Two patients had long-term closure; one patient who underwent a paramedian flap and a second who underwent a radial forearm free flap, suggesting that well-vascularized flaps may be the most viable option for repair., Conclusions: NCF is a known complication, following en bloc resection of lacrimal outflow system malignancies. Risk factors for formation may include adjuvant radiation therapy and use of titanium implants for reconstruction. Surgeons should consider utilizing robust vascular-pedicled flaps or microvascular free flaps for repair of NCF in this clinical scenario.

Purpose: To present four female-to-male (FTM) transgender patients on testosterone therapy diagnosed with idiopathic intracranial hypertension (IIH)., Methods: The authors report 4 consecutive FTM transgender patients on exogenous testosterone diagnosed with IIH at a single institution., Results: Patient 1 presented with progressive blurred vision and a central scotoma 10 weeks after starting testosterone cypionate injections for hormonal gender transition. Bilateral grade 5 papilledema was present; the patient underwent bilateral optic nerve sheath fenestration with improved vision and resolution of edema. Patient 2 presented with transient vision loss, pulsatile tinnitus, and blurred vision 13 months after starting testosterone cypionate injections. The patient had grade 4 and 3 disc edema of the right and left eyes, respectively. Patient 3 presented with headaches and pulsatile tinnitus and was on testosterone injections at an unknown dose. The examination revealed grade 1 and 2 disc edema of the right and left eyes, respectively. Patient 4 presented with decreased vision, transient visual obscurations, and daily migraines while using topical testosterone gel every other day. Color vision was reduced, and lumbar puncture revealed elevated intracranial pressure. All patients had neuroimaging findings consistent with increased intracranial pressure., Conclusions: Testosterone therapy plays an essential role in FTM hormonal transitioning and may play a role in IIH. Patients undergoing testosterone therapy for gender transition should be informed of the possibility of developing IIH while on treatment, with obesity possibly increasing this risk. Comprehensive eye examinations should be considered in these patients before initiating hormone therapy., Competing Interests: The authors have no financial or conflicts of interest to disclose. The authors are responsible for the content and writing of the paper., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

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.

Purpose: To assess the sensitivity and specificity of superior visual field tests administered in virtual reality (VR) with eye tracking (VR-ET) and without eye tracking (VR 0 ) for the fulfillment of insurance coverage criteria for functional upper eyelid surgery as compared with standard automated perimetry (SAP)., Methods: This prospective cross-sectional study included 78 eyes from 41 patients with ptosis, brow ptosis, and dermatochalasis undergoing functional upper eyelid surgery evaluation. Participants underwent serial superior visual field tests using SAP and VR 0 or VR-ET in randomized order. Fulfillment of insurance coverage criteria for blepharoplasty was defined as a 30% increase in the grid seen from the untaped to the taped state. The main outcome measure was the sensitivity and specificity of VR 0 , VR-ET, and overall VR in meeting insurance coverage criteria as compared with SAP., Results: VR had a sensitivity of 84.1% and specificity of 67.6%, with no significant difference between VR 0 and VR-ET. SAP agreed on insurance coverage criteria fulfillment with VR 0 in 28 (71.8%) eyes and with VR-ET in 32 (82.1%) eyes. Insurance coverage criteria fulfillment rates varied significantly by diagnosis on SAP ( p = 0.012) but not VR ( p = 0.059)., Conclusions: VR may be an alternative to SAP for functional upper eyelid surgery evaluation. Future studies are needed to determine differences in patient satisfaction, testing and waiting time, and test-retest reliability between VR and SAP., Competing Interests: W.W. Lee reports consultant fees from Allergan, Galderma, Revance, Evolus, Mallinckrodt, Horizon, RVL, Solta, RoC, and Tarsus. M. Ziff has patents pending for intellectual property in Virtual Vision. A.L. Grajewski has patents pending for intellectual property in Virtual Vision. S.T. Wester reports advisory board fees from Horizon Therapeutics and advisory board and consulting fees from Immunovant. Other authors have no financial or conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Adenoid cystic carcinoma of the lacrimal gland (LGACC) is a slow-growing but aggressive orbital malignancy. Due to the rarity of LGACC, it is poorly understood, which makes diagnosing, treating, and monitoring disease progression difficult. The aim is to understand the molecular drivers of LGACC further to identify potential targets for treating this cancer. Mass spectrometry was performed on LGACC and normal lacrimal gland samples to examine the differentially expressed proteins to understand this cancer's proteomic characteristics. Downstream gene ontology and pathway analysis revealed the extracellular matrix is the most upregulated process in LGACC. This data serves as a resource for further understanding LGACC and identifying potential treatment targets. This dataset is publicly available., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed by chemoradiation. Even with this radical treatment, the 10-year survival rate for LGACC is 20% given the propensity for recurrence and metastasis. Due to the rarity of LGACC, its pathobiology is not well-understood, leading to difficulties in diagnosis, treatment, and effective management. Here, we integrate bulk RNA sequencing (RNA-seq) and spatial transcriptomics to identify a specific LGACC gene signature that can inform novel targeted therapies. Of the 3499 differentially expressed genes identified by bulk RNA-seq, the results of our spatial transcriptomic analysis reveal 15 upregulated and 12 downregulated genes that specifically arise from LGACC cells, whereas fibroblasts, reactive fibrotic tissue, and nervous and skeletal muscle account for the remaining bulk RNA-seq signature. In light of the analysis, we identified a transitional state cell or stem cell cluster. The results of the pathway analysis identified the upregulation of PI3K-Akt signaling, IL-17 signaling, and multiple other cancer pathways. This study provides insights into the molecular and cellular landscape of LGACC, which can inform new, targeted therapies to improve patient outcomes.

Purpose: To examine the clinical and histopathologic characteristics of lacrimal gland biopsies at a tertiary academic center., Methods: 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., Results: 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%)., Conclusions: 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.

Infectious scleritis is a potentially devastating condition that can result in severe vision loss. When traditional management fails, a subpalpebral antibiotic lavage system (SAL) can be considered to bathe the infected area with a high volume and concentration of antibiotics. Several reports show that this method can be curative for infectious scleritis, otherwise refractory to care. However, surgical approaches for this technique are either not well described, advocate for transecting the levator aponeurosis, or do not expose the entire width of the superior fornix, which can lead to postoperative ptosis. The authors describe a case where a novel approach was utilized, using a fenestrated angiocather in the superior lateral fornix, to maximize outcomes and minimize postoperative complications. In the setting of infectious scleritis refractory to traditional management, a SAL can be safely and effectively placed with the technique detailed in this report., Competing Interests: The authors report no conflict of interests., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

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.

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., (© 2022 Wiley Periodicals LLC.)

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.)

Purpose: 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., Design: Laboratory investigation., Methods: 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., Results: MMC decreased BP52 cell viability in a dose-dependent manner with a half-maximal effective dose (EC 50 ) of 11.8 μM after 72 hours. SC viability decreased >50% at 80 mM 5-FU after 72 hours. MMC reduced LSC viability in a dose-dependent manner with an EC 50 value of 3.24 μM, and 5-FU decreased LSC viability >50% at 160 μM. MMC decreased SC cell proliferation and migration in a dose-dependent manner. 5-FU displayed antiproliferative effects but did not affect cell migration at concentrations below 1000 μM., Conclusions: Our 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

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 Müllerian 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., 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.)

A 34-year-old Caucasian male who underwent a ventricular shunt at age 21 presented with bilateral enophthalmos, poor eyelid-globe apposition and exposure keratopathy characteristic of silent brain syndrome. Progressive enophthalmos and corneal decompensation were documented in serial photographs and radiographic studies over 36 years. Over this period, no sequelae of shunt over-drainage were observed. A lumbar puncture at the last follow-up measured CSF opening pressure to be within the normal range. Additional systemic findings included pneumosinus dilatans, loss of adipose tissue in the temporalis fossa and atrophy of the dorsal interossei of the hand. Surgical interventions to preserve ocular function included insertion of orbital floor wedge and sheet implants, sheet orbital roof implants, and retroplacement of canthal tendons. This report chronicles the long-term clinical course of a patient with silent brain syndrome. The systemic changes suggest factors beyond low intracranial pressure may contribute to the pathogenesis of the condition in our patient.

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., 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: 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.)

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., 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.)

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.

Competing Interests: None declared.

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: Setting: Single-center institutional study. StudyPopulation: Three patients who have discontinued wearing of the ocularist-made exenteration prosthesis due to altered fit, discoloration, or material degradation. InterventionProcedure: 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. MainOutcomeMeasures: 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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 (L1000CDS 2 ) 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., Competing Interests: Disclosure: J.Y. Lee, None; R.A. Gallo, None; P.J. Ledon, None; W. Tao, None; D.T. Tse, None; D. Pelaez, None; S.T. Wester, Horizon Therapeutics (C), (Copyright 2020 The Authors.)

The lacrimal gland (LG) is an exocrine organ responsible for the secretion of aqueous tear film. Regenerative and stem cell therapies that target LG repair are coming to the fore, although our understanding of LG cell lineage hierarchy is still incomplete. We utilize the analysis of label-retaining cells (LRCs) and genetic lineage tracing to define LG cell lineage hierarchy. Our study suggests that embryonic LG contains unique long-lived multipotent stem cells that give rise to all postnatal epithelial cell types. Following birth, lineages become established and the fate of progenitor cell descendants becomes restricted. However, some cell lineages retain plasticity after maturation and can trans-differentiate into other cell types upon injury. The demonstration that the LG contains progenitor cells with different levels of plasticity has profound implications for our understanding of LG gland function in homeostasis and disease and will be helpful for developing stem cell-based therapies in the future., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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.

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.

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 (<0.895) demonstrated synergistic effect of AZD4547 and cisplatin in inhibiting cell growth and viability (p<0.02), with a differential response seen in post-IACC cultures when compared to pre-IACC cultures. The combination approach showed synergy of the drugs in the migration assay. Western blot analysis indicated a significant upregulation of cleaved caspase-3 and downregulation the expression of FGFR1 (p<0.05) with the combination treatment as compared to either agent independently. Our findings demonstrate that FGFR1 inhibition potentiates the cytoreductive effects of cisplatin and suggest a potential therapeutic benefit of using AZD4547 in the management of LGACC., Competing Interests: CONFLICTS OF INTEREST The authors declared no conflicts of interest.

Fibromas are benign, well-circumscribed tumors that are characterized as spindle-cell lesions with interlacing fibrous stroma. Here, we describe the clinical presentation, management, and outcome of a patient with an orbital fibroma. To our knowledge, this is the second case report of a biopsy-proven subperiosteal orbital fibroma to date.

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.

Importance: Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies., Objective: To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups., Design, Setting, and Participants: In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017., Main Outcomes and Measures: The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis., Results: Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores., Conclusions and Relevance: Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.

Traumatic optic neuropathy (TON) is a devastating cause of permanent visual loss following blunt injury to the head. Animal models for TON exist, but most fail to recapitulate the clinical scenario of closed head indirect trauma to the nerve and subsequent neurodegeneration. Thus, we developed a clinically-relevant animal model for TON using a novel ultrasonic pulse injury modality (sonication-induced TON; SI-TON). To trigger TON, a microtip probe sonifier was placed on the supraorbital ridge directly above the entrance of the optic nerve into the bony canal. An ultrasonic pulse was then delivered to the optic nerve. After injury, the number of RGCs in the retina as well as visual function measured by PERG steadily decreased over a two-week period. In the optic nerve, pro-inflammatory markers were upregulated within 6 hours following injury. Immunohistochemistry showed activation of microglia and infiltration of CD45-positive leukocytes in the optic nerve and initiation of a gliotic response. The SI-TON model is capable of delivering a non-contact concussive injury to the optic nerve and induce TON in mice. Thus, our data indicate that the SI-TON model reliably recapitulates the pathophysiology and progressive neurodegeneration seen in the human manifestation.

Purpose: To identify genomic mutations in lacrimal gland adenoid cystic carcinoma (LGACC) samples from patients., Methods: Genomic DNA was extracted from LGACC specimens. Whole exome sequencing (exome-seq) was conducted to screen for mutations. Capillary sequencing was performed to verify mutations in genes shared by multiple samples. Luciferase assays were used to evaluate functional consequences of NOTCH1 mutations., Results: The mutation profile of LGACC was complicated. The most frequently mutated gene observed (28.6%) was bromodomain PHD finger transcription factor (BPTF). No mutation was identified in common cancer genes such as TP53, KRAS, and BRAF. However, mutations predicted to be functionally severe were accumulated in the Notch signaling pathway including NOTCH1 and NOTCH2, of which mutations have been reported in head/neck adenoid cystic carcinoma (ACC). Of 14 LGACC samples, five samples carry mutations in Notch pathway genes. Capillary sequencing verified all the mutations in the two NOTCH genes identified by exome-seq. Compared to the wild-type NOTCH1, three frame shifting mutations and two missense mutations (C387W and L1600Q) increased luciferase activity approximately 10- to 25-fold., Conclusions: Major genomic mutation profiles in LGACC were uncovered by exome-seq. Although preliminary in nature, the Notch pathway could be a potential therapeutic target for LGACC.

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.

Background and Aims: The objective of the study was to determine the incidence of failed extubations in our Intensive Care Unit (ICU) and identify associated clinical factors., Materials and Methods: A prospective observational study of mechanically ventilated patients who underwent extubation attempts in our (predominantly surgical) ICU was undertaken from July 2012 to August 2013. The primary endpoint was the need for nonelective reintubation within 72 h of extubation. Clinical data of the reintubated patients were compared with those who were successfully extubated to identify factors associated with reintubation., Results: Five hundred and eight extubation attempts were documented, 38 (7.5%) of which were unsuccessful. On multivariate analysis, the following clinical factors were found to be associated with an increased risk of failed extubation: unplanned extubations (adjusted odds ratio [OR] 5.8), the use of noninvasive ventilation (NIV) postextubation (adjusted OR 3.2), and sepsis (adjusted OR 2.9). Patient demographic factors, other premorbid and comorbid medical conditions, and differences of laboratory parameters did not appear to significantly influence reintubation rates in our study., Conclusions: Our study has demonstrated a relatively low reintubation rate, likely due to inclusion of elective admissions/intubations in our patient population. Unplanned extubations, the use of NIV postextubation, and sepsis were associated with increased reintubation risk, reinforcing the need for increased vigilance in this subgroup of patients after extubation., Competing Interests: There are no conflicts of interest.

Purpose: Although normal function of the lacrimal gland is essential for vision (and thus for human well-being), the lacrimal gland remains rather poorly understood at a molecular level. The purpose of this study was to identify new genes and signaling cascades involved in lacrimal gland development., Methods: To identify these genes, we used microarray analysis to compare the gene expression profiles of developing (embryonic) and adult lacrimal glands. Differential data were validated by quantitative RT-PCR, and several corresponding proteins were confirmed by immunohistochemistry and Western blot analysis. To evaluate the role of NOTCH signaling in lacrimal gland (LG) development, we used the NOTCH inhibitor DAPT and conditional Notch1 knockouts., Results: Our microarray data and an in silico reconstruction of cellular networks revealed significant changes in the expression patterns of genes from the NOTCH, WNT, TGFβ, and Hedgehog pathways, all of which are involved in the regulation of epithelial-to-mesenchymal transition (EMT). Our study also revealed new putative lacrimal gland stem cell/progenitor markers. We found that inhibiting Notch signaling both increases the average number of lacrimal gland lobules and reduces the size of each lobule., Conclusions: Our findings suggest that NOTCH-, WNT-, TGFβ-, and Hedgehog-regulated EMT transition are critical mechanisms in lacrimal gland development and morphogenesis. Our data also supports the hypothesis that NOTCH signaling regulates branching morphogenesis in the developing lacrimal gland by suppressing cleft formation.