Publications by authors named "Victor Elner"

140 Publications

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

Oncologist 2021 May 14. Epub 2021 May 14.

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

Background: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC).

Materials And Methods: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists.

Results: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins.

Conclusion: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408.

Implications For Practice: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13820DOI Listing
May 2021

Long-term follow up of systemic rituximab therapy as first-line and salvage therapy for idiopathic orbital inflammation and review of the literature.

Orbit 2021 Jan 21:1-8. Epub 2021 Jan 21.

Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.

: To report long-term outcomes of systemic rituximab therapy for idiopathic orbital inflammation (IOI) as both primary and salvage therapy and to review the English literature.: A retrospective review of four consecutive biopsy-proven IOI cases managed with systemic rituximab including demographics, management, and outcomes, and review of English literature, were performed. Primary outcome measures included resolution of symptoms, recurrence, and length of follow up.: Of four cases, systemic rituximab was the first-line therapy in two cases and salvage therapy in two cases. The mean age of the patients was 62 years (range, 50-68 years). The orbit was involved in three cases and extraocular muscle in one case. Systemic rituximab (1 g weekly for 4 weeks) was given for one session in three patients and for 12 sessions in 1 patient. All four patients responded with the resolution of all symptoms without recurrence after at least 5 years of follow up. Review of the literature showed systemic rituximab had provided clinical improvement at shorter follow up in 14 of 15 cases when used as a salvage therapy.: Systemic rituximab therapy seems to be an effective therapy for IOI as salvage or first-line therapy with long-term clinical durability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01676830.2021.1874424DOI Listing
January 2021

Change in Postoperative Opioid Prescribing Patterns for Oculoplastic and Orbital Procedures Associated With State Opioid Legislation.

JAMA Ophthalmol 2021 02;139(2):157-162

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor.

Importance: Understanding whether statewide legislation, such as the Michigan Opioid Laws, is associated with reduction in postoperative opioid prescriptions is informative in guiding future legislation.

Objective: To identify changes in opioid prescribing patterns for oculoplastic and orbital procedures associated with the enactment of the Michigan Opioid Laws in 2017 and 2018.

Design, Setting, And Participants: This cross-sectional study included 3781 patients who underwent any of 10 common oculoplastic and orbital procedures between June 1, 2016, and November 30, 2019, at a tertiary care institution.

Exposures: From 2017 to 2018, Michigan enacted a series of laws to address the state's worsening opioid epidemic. Two major components of this legislation enacted on June 1, 2018, required prescribers to review a report of patients' opioid use history and obtain signed consent after educating patients on the use and disposal of opioids prior to prescribing.

Main Outcomes And Measures: Demographic information, type of surgery, type and amount of opioid prescriptions, and morphine milligram equivalent (MME) were analyzed. MME was calculated as the product of dose, quantity, and opioid-specific conversion factor for each prescription. Linear interpolation spline regression was used to evaluate the association of prescription MME with time.

Results: Of 3781 patients, 1614 (42.7%) were male. The mean (SD) age at the time of surgery was 63.3 (16.6) years. Of 2026 patients undergoing surgery before June 1, 2018, 1782 (88.0%) were prescribed postoperative opioids; of 1755 patients undergoing surgery after June 1, 2018, 878 (50.0%) were prescribed postoperative opioids (P < .001). There was no difference in age, sex, race/ethnicity, surgery type, or opioids prescribed between these 2 cohorts. Linear interpolation spline regression showed a decrease of 26.025 MMEs (equivalent to a 36.2% reduction of mean MME) between June 1, 2017, and September 30, 2018 (β, -1.735; 95% CI, -0.088 to -0.024; P < .001), stabilizing at a persistently reduced rate of MME prescribed through the end of the study period (October 1, 2018, to November 30, 2019; β, -0.005; 95% CI, -0.039 to 0.016; P = .42). Changes in MME in the 12 months before or 12 months after the period of legislation enactment were not identified.

Conclusions And Relevance: In this cross-sectional study, reduction in opioid prescriptions for oculoplastic and orbital procedures was observed during the enactment period of the Michigan Opioid Laws and appeared to be sustained through the end of the study period. Similar statewide or national legislations aimed at increasing prescriber awareness and patient education on opioid use may help curtail the prescription opioid epidemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.5446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729578PMC
February 2021

Immunotherapy for Conjunctival Squamous Cell Carcinoma with Orbital Extension.

Ophthalmology 2021 May 25;128(5):801-804. Epub 2020 Sep 25.

Roger Cancer Center, University of Michigan, Ann Arbor, Michigan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2020.09.027DOI Listing
May 2021

Intralesional Rituximab Injection for Low-Grade Conjunctival Lymphoma Management.

Ophthalmology 2020 09 18;127(9):1270-1273. Epub 2020 Mar 18.

Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2020.03.014DOI Listing
September 2020

Atypical Presentation of Conjunctival Vascular Malformation.

JAMA Ophthalmol 2020 03 12;138(3):e190895. Epub 2020 Mar 12.

Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, Ann Arbor.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.0895DOI Listing
March 2020

Ciliary Body Mass as a Feature of Ocular Sarcoidosis.

JAMA Ophthalmol 2020 03;138(3):300-304

Department of Ophthalmology and Visual Science, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor.

Importance: Ocular sarcoidosis may be the primary and only clinical manifestation of sarcoidosis, and irreversible loss of visual acuity may occur from delayed treatment. Thus, early diagnosis is imperative to preserve visual acuity. Establishing the diagnosis of sarcoidosis in cases manifesting only in the eye may require a diagnostic biopsy, which may prove challenging in the absence of available ocular surface, lacrimal gland, and systemic tissue for biopsy.

Objective: To describe diffuse or segmental ciliary body mass as a clinical sign and tissue source for biopsy in the diagnosis of ocular sarcoidosis.

Design, Setting, And Participants: This case series captures 3 cases from a university-based ocular oncology and uveitis practice. All 3 patients presented with uveitis and a diffuse or segmental ciliary body mass, which was identified via ultrasonographic biomicroscopy.

Main Outcomes And Measures: Clinical, ancillary, and histopathological ocular findings in the 3 patients.

Results: The patients were a 52-year-old white woman, a 42-year-old African American man, and an 81-year-old white man. Two individuals had unilateral involvement, and 1 had bilateral involvement. All 3 individuals presented with uveitis. Diffuse, circumferential ciliary body masses were observed in 2 patients. A localized, nodular ciliary body mass on the temporal quadrant with superior and inferior extensions was observed in 1 patient. Moderate to high internal reflectivity was observed on ultrasonographic biomicroscopy in all 3 individuals. Biopsies of the ciliary body masses were diagnosed as sarcoidosis in all 3 patients.

Conclusions And Relevance: These findings support that diffuse or segmental ciliary body mass may serve as a clinical sign and tissue source for biopsy in the diagnosis of ocular sarcoidosis, although the frequency of this cannot be determined from 3 cases. To our knowledge, such cases all demonstrate a uveitic component; whether a ciliary body mass caused by sarcoidosis can occur in the absence of uveitis remains unknown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.5704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042929PMC
March 2020

Supernumerary Lacrimal Caruncle: A Case Series.

Ophthalmic Plast Reconstr Surg 2020 May/Jun;36(3):e70-e73

Department of Ophthalmology and Visual Sciences, W. K Kellogg Eye Center, Ann Arbor, Michigan, U.S.A.

A 12-year-old boy and 63-year-old woman were incidentally found to have a solitary, well-defined, raised, ovoid lesion involving the inferomedial palpebral conjunctiva. Both lesions were separate from the lacrimal caruncle with normal conjunctiva surrounding the lesions. Excisional biopsies were consistent with caruncular tissue. In the English literature, supernumerary lacrimal caruncle has only been previously described in adults despite the congenital nature of the lesion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000001584DOI Listing
March 2021

Integrative Exome and Transcriptome Analysis of Conjunctival Melanoma and Its Potential Application for Personalized Therapy.

JAMA Ophthalmol 2019 Dec;137(12):1444-1448

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.

Importance: Greater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management.

Objective: To evaluate molecular features of CM and application of this information into clinical care.

Design, Setting, And Participants: In a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018.

Interventions/exposures: Integrative exome and transcriptome analysis of CMs and clinical management of a patient's care by using this information.

Main Outcomes And Measures: Molecular characterization of CM and its potential clinical application.

Results: In the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision.

Conclusions And Relevance: The NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.4237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813594PMC
December 2019

Thyroid Glandular Epithelial Choristoma of the Iris.

JAMA Ophthalmol 2019 10 10;137(10):e186228. Epub 2019 Oct 10.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2018.6228DOI Listing
October 2019

Systemic anti-CD20 (rituximab) as primary treatment for symptomatic primary uveal lymphoma.

Am J Ophthalmol Case Rep 2019 Sep 5;15:100484. Epub 2019 Jun 5.

Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, USA.

Purpose: Uveal lymphomas are indolent, frequently choroid-involving neoplasms that are mainly CD20-positive B-cell extranodal marginal zone lymphoma. Irreversible visual loss may occur from retinal detachment and/or glaucoma among untreated symptomatic patients, or from radiation-induced changes secondary to external beam radiotherapy. To avoid radiation-induced complications, we used systemic rituximab monotherapy as primary treatment, and present two cases to show its long-term effectiveness for symptomatic primary uveal lymphoma.

Observations: Two elderly men who presented with painless blurred vision were clinically diagnosed with symptomatic primary uveal lymphoma, which were biopsy-confirmed to be marginal zone lymphoma. Both patients with symptomatic, primary marginal zone uveal lymphoma that appeared as multiple yellow, nummular choroidal infiltrates, had complete ocular remission after three and one cycles of systemic rituximab monotherapy (375mg/m2 infused intravenously once weekly for four consecutive weeks), with disappearance of the lesions and improvement of visual acuity. Both patients tolerated systemic monotherapy well without any adverse systemic or ocular effects. There was no local ocular recurrence at 29 and 39 months after the last treatment.

Conclusions: and Importance: Systemic rituximab monotherapy induced complete ocular remission and improved visual acuity, without adverse effects, and without local ocular recurrence of uveal lymphoma 29-39 months following the last treatment. To our knowledge, this is the first manuscript to show long-term effectiveness of systemic rituximab monotherapy as the primary treatment for symptomatic primary uveal lymphoma. Long-term follow-up of this indolent neoplasm is still imperative to monitor its ocular and systemic course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajoc.2019.100484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586989PMC
September 2019

Bilateral Annular Isolated Choroidal Melanocytosis.

Ophthalmic Surg Lasers Imaging Retina 2019 03;50(3):e74-e76

The authors present a unique case of bilateral isolated choroidal melanocytosis in an annular pattern that, to our knowledge, has not previously been described. A 44-year-old asymptomatic American Indian woman presented with bilateral choroidal hyperpigmentation in an annular pattern for 12 clock hours around the peripheral retina. No other uveal, scleral, or cutaneous hyperpigmentation was observed. Optical coherence tomography did not demonstrate choroidal thickening or subretinal fluid. The diagnosis of bilateral isolated choroidal melanocytosis was made. Long-term follow-up of this patient and other cases described in the literature is necessary to determine the malignant potential of these lesions. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e74-e76.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/23258160-20190301-15DOI Listing
March 2019

Technique and Results of Permanent Medial Tarsorrhaphy for Complex Eyelid Malposition.

Ophthalmic Plast Reconstr Surg 2019 Mar/Apr;35(2):197-201

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, U.S.A.

Purpose: To evaluate the results of permanent medial tarsorrhaphy and to describe the surgical technique.

Methods: Medial tarsorrhaphy was performed on 30 eyelids with symptomatic exposure keratopathy secondary to eyelid malposition. Observational, retrospective review of preoperative and postoperative examination findings was performed.

Results: Average age of the cohort was 66 years (31-91). Medial tarsorrhaphy was performed to correct eyelid retraction (100%), exposure keratopathy (80%), lagophthalmos (57%), and ectropion (17%) in patients with cranial nerve VII palsy (47%), Graves eye disease (13%), eczema (7%), floppy eyelid syndrome (7%), after Mohs reconstruction (7%), orbital myositis (3%), and neurofibromatosis (3%). Seventy-three percent (73%) of patients had an average of 3 surgeries (N = 22, standard deviation = 1.12, range = 2-7) before undergoing medial tarsorrhaphy. Medial tarsorrhaphy was performed in combination with another procedure in 53% of cases. Palpebral fissure decreased postoperatively an average of 1.1 mm (N = 20; p = 0.005), inferior scleral show decreased 0.72 mm (N = 22; p = 0.03), lagophthalmos decreased 0.4 mm (N = 15; p = 0.27), and superficial punctate keratopathy improved by 61% (N = 27; p = 0.009). Ectropion completely resolved in 4 of 10 patients (40%). Seven patients (23%) required additional surgery following tarsorrhaphy an average of 8 months later (range = 2-16). In 1 patient (3%), a tarsorrhaphy opened prematurely, and 1 patient (3%) requested partial opening of the tarsorrhaphy. Average duration of follow up was 13 months (N = 30, standard deviation = 14.97, range = 0.2-45.7).

Conclusions: Medial tarsorrhaphy is a safe and effective primary or salvage technique to address complex causes of eyelid retraction, lagophthalmos, ectropion, and exposure keratopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000001282DOI Listing
December 2019

Socket Reconstruction With Bleomycin, Gentamicin, and Gelatin Sponges Following Eyelid-Sparing Orbital Exenteration for a Colobomatous Macrocyst in an Infant.

Ophthalmic Plast Reconstr Surg 2018 Nov/Dec;34(6):e201-e203

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, U.S.A.

Microphthalmia is defined by a globe axial length greater than or equal to 2 standard deviations below the age-adjusted mean and can occur as part of a broader syndrome. The presence of a colobomatous cyst with microphthalmia signifies failure of the embryonic neuroectodermal fissure to close appropriately during development of the globe, creating a protuberant globular appendage that inhibits normal growth and development of the eye itself. Cystic reaccumulation of fluid is common after aspiration or surgical removal. Here, the authors describe a case of a young boy with a colobomatous cyst who underwent eyelid-sparing orbital exenteration followed by reconstruction with absorbable gelatin sponge (Gelfoam, Pfizer, Inc.) and the chemotherapeutic agent bleomycin to promote scarring, achieving the equivalent of a biointegrated implant and facilitating satisfactory placement of an ocular prosthesis. A 2-year follow-up MRI revealed adequate volume in the posterior orbit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000001246DOI Listing
May 2019

Flavoprotein Fluorescence Correlation with Visual Acuity Response in Patients Receiving Anti-VEGF Injection for Diabetic Macular Edema.

Oxid Med Cell Longev 2018 9;2018:3567306. Epub 2018 Aug 9.

New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA.

Anti-VEGF treatment of diabetic macular edema (DME) complicating diabetic retinopathy (DR) has greatly improved structural and visual outcomes for patients with diabetes mellitus. However, up to 50% of patients are either nonresponsive or refractory to anti-VEGF treatment (no improvement in BCVA or central macular thickness (CMT)). It is believed that factors such as mitochondrial structural and functional damage, due to oxidative stress, are partially responsible for this lack of improvement. Flavoprotein fluorescence (FPF) has been shown to be a sensitive marker of mitochondrial function and has been found to correlate with the degree of diabetic retinopathy. FPF may also provide additional information regarding therapeutic response of patients receiving anti-VEGF treatment for DME. Eight patients with DR and DME with clinically significant DME (CSDME) who underwent anti-VEGF (bevacizumab) treatment were imaged before injection and at follow-up visit using FPF in addition to standard color fundus photography and OCT CMT. A strong correlation = 0.98 ( = 0.000015) between the FPF decrease and the BCVA improvement was observed; BCVA improved as FPF values decreased. Notably, in the same patients, the correlation between OCT CMT decrease and BCVA improvement ( = 0.688) was not found to be significant ( = 0.13). These findings suggest that FPF can detect improvement in metabolic function preceding structural improvement and even with small changes in edema. Additionally, FPF may be supplementary to current diagnostic methods for earlier detection of therapeutic response to anti-VEGF treatment in patients with DME.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/3567306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109491PMC
December 2018

Expression and regulation of alarmin cytokine IL-1α in human retinal pigment epithelial cells.

Exp Eye Res 2018 07 15;172:10-20. Epub 2018 Mar 15.

Department of Ophthalmology, University of Michigan, Ann Arbor, MI, 48105, United States.

Human retinal pigment epithelial (hRPE) cells play important immune-regulatory roles in a variety of retinal pathologic processes, including the production of inflammatory cytokines that are essential mediators of the innate immune response within the ocular microenvironment. The pro-inflammatory "alarmin" cytokine IL-1α has been implicated in both infectious and non-infectious retinal diseases, but its regulation in the retina is poorly understood. The purpose of this study was to elucidate the expression and regulation of IL-1α within hRPE cells. To do this, IL-1α mRNA and protein in hRPE cells was assessed by RT-PCR, qPCR, ELISA, Western blot, and immunofluorescence following treatment with a variety of stimuli and inhibitors. ER stress, LPS, IL-1β, and TLR2 activation all significantly increased intracellular IL-1α protein. Increasing intracellular calcium synergized both LPS- and Pam3CSK4-induced IL-1α protein production. Accordingly, blocking calcium signaling and calpain activity strongly suppressed IL-1α protein expression. Significant but more moderate inhibition occurred following blockage of TLR4, caspase-4, or caspase-1. Neutralizing antibodies to IL-1β and TLR2 partially eliminated LPS- and TLR2 ligand Pam3CSK4-stimulated IL-1α protein production. IFN-β induced caspase-4 expression and activation, and also potentiated LPS-induced IL-1α expression, but IFN-β alone had no effect on IL-1α protein production. Interestingly, all inhibitors targeting the PI3K/Akt pathway, with the exception of Ly294002, strongly increased IL-1α protein expression. This study improves understanding of the complex mechanisms regulating IL-1α protein expression in hRPE cells by demonstrating that TLR4 and TLR2 stimulation and exposure to IL-1β, ER stress and intracellular calcium all induce hRPE cells to produce intracellular IL-1α, which is negatively regulated by the PI3K/Akt pathway. Additionally, the non-canonical inflammasome pathway was shown to be involved in LPS-induced hRPE IL-1α expression through caspase-4 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076434PMC
July 2018

Distinct CD40L receptors mediate inflammasome activation and secretion of IL-1β and MCP-1 in cultured human retinal pigment epithelial cells.

Exp Eye Res 2018 05 16;170:29-39. Epub 2018 Feb 16.

Department of Ophthalmology, University of Michigan, Ann Arbor, MI, 48105, USA.

CD40L signaling occurs in several diseases with inflammatory components, including ocular and retinal diseases. However, it has never been evaluated as a pathogenic mechanism in age-related macular degeneration (AMD) or as an inducer of inflammasome formation in any cell type. mRNA and protein levels of CD40, IL-1β, NALP1, NALP3, caspase-1, and caspase-5 were determined by RT-PCR, qPCR, and Western blot. CD40L receptor (CD40, α5β1, and CD11b) expression was determined by Western and immunofluorescent staining. IL-1β, IL-18, and MCP-1 secretions were determined by ELISA. NALP1 and NALP3 inflammasome formation were determined by Co-IP. Experiments were conducted on primary human retinal pigment epithelial (hRPE) cells from four different donors. Human umbilical vein endothelial (HUVEC) and monocytic leukemia (THP-1) cells demonstrated the general applicability of our findings. In hRPE cells, CD40L-induced NALP1 and NALP3 inflammasome activation, cleavage of caspase-1 and caspase-5, and IL-1β and IL-18 secretion. Interestingly, neutralizing CD11b and α5β1 antibodies, but not CD40, reduced CD40L-induced IL-1β secretion in hRPE cells. Similarly, CD40L treatment also induced HUVEC and THP-1 cells to secret IL-1β through CD11b and α5β1. Additionally, the CD40L-induced IL-1β secretion acted in an autocrine/paracrine manner to feed back and induce hRPE cells to secrete MCP-1. This study is the first to show that CD40L induces inflammasome activation in any cell type, including hRPE cells, and that this induction is through CD11b and α5β1 cell-surface receptors. These mechanisms likely play an important role in many retinal and non-retinal diseases and provide compelling drug targets that may help reduce pro-inflammatory processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2018.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924621PMC
May 2018

Massive Extraocular Extension of Choroidal Melanoma after Brachytherapy.

Ophthalmology 2017 10;124(10):1503

Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2017.03.031DOI Listing
October 2017

Eyelid Mass in 6-Week-Old Girl.

JAMA Ophthalmol 2017 10;135(10):1113-1114

Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2017.1201DOI Listing
October 2017

Preclinical Acute Ocular Safety Study of Combined Intravitreal Carboplatin and Etoposide Phosphate for Retinoblastoma.

Ophthalmic Surg Lasers Imaging Retina 2017 02;48(2):151-159

Background And Objective: To describe the ocular toxicity of intravitreal carboplatin and etoposide phosphate (VP16P) in Dutch-Belted rabbits.

Materials And Methods: Twenty-two adult male Dutch-Belted rabbits (Cohort 1) each received a single, bilateral intravitreal injection (0.05 mL). For Cohort 1, safety was assessed via electroretinograms (ERGs) and ocular examination. Of nine total groups in Cohort 1, the first five received the following single agents: Group 1: normal saline; Group 2: VP16P 75 µg; Group 3: VP16P 100 µg; Group 4: carboplatin 4 µg; and Group 5: carboplatin 8 µg. Groups 6 through 9 received the following combination of carboplatin/ VP16P, respectively: Group 6: 8 µg/75 µg, Group 7: 8 µg/50 µg, Group 8: 4 µg/50 µg, and Group 9: 2 µg/25 µg. Cohort 2 consisted of 15 Dutch-Belted rabbits in seven groups (Groups 10 through 16), each receiving a single, bilateral intravitreal injection. For Cohort 2, safety was assessed via histopathology.

Results: Groups 2 through 8 demonstrated a statistically significant decrease (relative to Group 1) in at least one ERG waveform amplitude obtained 4 weeks postinjection (P < .05). Group 9 (carbo 2 µg/VP16P 25 µg) did not manifest ERG toxicity. Fundoscopic toxicity consisted of slight-to-moderate attenuation of vessels in rabbits receiving doses above carbo 4 µg/VP16P 50 µg. Histopathologic retinal toxicity (Cohort 2) was dose-dependent, ranging from full-thickness atrophy in rabbits receiving the highest dose to normal in rabbits receiving carbo 2 µg/VP16P 25 µg.

Conclusions: Combined carboplatin and VP16P may be compatible for intravitreal injection therapy, and a single dose of 2 µg/25 µg appears to be safe in a rabbit model. These agents may be a safer alternative to intravitreal melphalan (Alkeran; GlaxoSmithKline, Brentford, United Kingdom) for the treatment of vitreous seeds in retinoblastoma. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:151-159.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/23258160-20170130-09DOI Listing
February 2017

Conjunctival Lymphoma in a Patient on Fingolimod for Relapsing-Remitting Multiple Sclerosis.

Ophthalmic Plast Reconstr Surg 2017 May/Jun;33(3):e73-e75

Department of Ophthalmology and Visual Science, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, U.S.A.

The authors describe a 39-year-old woman treated with fingolimod for relapsing-remitting multiple sclerosis for 2 years who then developed a bilateral conjunctival mucosa-associated lymphoid tissue lymphoma. Fingolimod treatment for multiple sclerosis has been associated with lymphoma in 3 previously reported cases. This is the first case of ocular adnexal lymphoma presumed to be due to fingolimod. Given that ophthalmologists regularly monitor many patients on fingolimod for fingolimod-associated macular edema and ophthalmic manifestations of multiple sclerosis, the authors hope to alert physicians of the possibility of ocular adnexal lymphoma in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000000774DOI Listing
September 2017

Intralesional Rituximab for the Treatment of Recurrent Ocular Adnexal Lymphoma.

Ophthalmic Plast Reconstr Surg 2017 May/Jun;33(3S Suppl 1):S70-S71

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, U.S.A.

A 41-year-old female with Sjogren syndrome presented with a 5-month history of bilateral upper eyelid swelling. Incisional biopsy of the left lacrimal gland revealed mucosa-associated lymphoid tissue lymphoma. Due to bilateral severe dry eyes, the patient declined external beam radiotherapy and systemic rituximab was initiated. The patient responded well to intravenous rituximab and the follow-up CT revealed decrease in size of both lacrimal glands. Eleven months after systemic rituximab, the patient developed bilateral lacrimal gland recurrence. The patient declined external beam radiotherapy. Intralesional rituximab (50 mg/1 ml) was injected into the left lacrimal gland, followed by injection in the right lacrimal gland 7 months later. Twenty-three months follow-up after the injection into the right lacrimal gland, there was significant decrease in size of bilateral lacrimal glands and subjective improvement of dry eye symptoms. This case highlights the intralesional rituximab as an alternative therapy for recurrent orbital mucosa-associated lymphoid tissue lymphoma in selected cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000000666DOI Listing
June 2017

Eyelid Swelling and Proptosis with Systemic Implications.

Am J Med 2016 Jul 8;129(7):e51-3. Epub 2016 Feb 8.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor; Department of Ophthalmology, Ann Arbor Veterans Administration Medical Center, Ann Arbor, Mich. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjmed.2016.01.027DOI Listing
July 2016

Severe Pediatric Thyroid Eye Disease: Surgical Case Series.

Ophthalmic Plast Reconstr Surg 2017 May/Jun;33(3S Suppl 1):S186-S188

Department of Ophthalmology and Visual Sciences, WK Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, U.S.A.

Thyroid eye disease (TED) usually has mild manifestations in pediatric patients, and orbital decompression is rarely necessarily. The authors present the clinical course of 3 pediatric patients age 16 or younger at the time of decompression surgery with severe orbitopathy. Case 1 is a 9-year-old prepubertal Asian-American female with Graves' disease and TED who underwent balanced decompression for compressive optic neuropathy. Case 2 is a 14-year-old white female with Graves' disease and TED who underwent balanced decompression for compressive optic neuropathy, stretch optic neuropathy, and globe subluxation. Case 3 is a 14-year-old African-American male with unilateral euthyroid TED who underwent staged right-sided lateral, medial, and floor decompressions for asymmetric proptosis. All cases also had disfiguring proptosis and exposure keratopathy, and in all cases, surgery successfully ameliorated the indications. Children, both pre- and post-pubertal, can rarely manifest visually threatening severe orbitopathy due to TED. This represents the first reports of thyroid-related optic neuropathy and globe subluxation in pediatric patients. Further studies examining the mechanism responsible for the disparities in pediatric and adult TED are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000000585DOI Listing
September 2017

Lymphangiogenic and Chemotactic Factors in Conjunctival Melanoma.

Ophthalmic Plast Reconstr Surg 2016 Nov/Dec;32(6):428-433

W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, U.S.A.

Purpose: The aim of this study was to evaluate expression patterns of known lymphangiogenic growth factors and chemokines in conjunctival melanoma, and to describe patterns of lymphatic vessel growth in these tumors.

Methods: This was a retrospective chart review comprising 5 participants (6 tumor specimens) and the main outcome measures were expression of growth factors, chemokines, and their receptors known to be important in tumor lymphangiogenesis as well as patterns of lymphatic vessel growth on immunohistochemical sections.

Results: Tumor cells in all specimens expressed lymphangiogenic growth factors VEGFC, VEGFD, and their receptor VEGFR3. Chemotactic factors CXCL12 and CCL21 and their receptors, CXCR4 and CCL21, were also expressed in tumor cells and lymphatic endothelial cells. Staining was most intense for these proteins at the invasive tumor edge, suggesting increased lymphangiogenic activity at this location. In addition, lymphatic vessels clustered near the invasive edge of the tumors.

Conclusions: VEGFC, VEGFD, and VEGR3 are diffusely expressed by conjunctival melanoma cells, most intensely at the invasive tumor edge. CXCL12, CXCR4, CCL21, and CCR7 were also most intensely expressed at the invasive edge, where the highest density of lymphatic vessels was also observed. These expression patterns suggest that these mediators of tumor-associated lymphangiogenesis warrant further investigation as potential therapeutic targets in conjunctival melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000000567DOI Listing
February 2017

Lower Eyelid Lesion.

JAMA Ophthalmol 2015 Aug;133(8):955-6

Department of Ophthalmology, University of Michigan, Ann Arbor.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2015.0711DOI Listing
August 2015

A Red and Swollen Eyelid. Breast carcinoma metastasis to left lacrimal gland.

JAMA Oncol 2015 Jul;1(4):537-8

Department of Ophthalmology, University of Michigan Medical School, Ann Arbor4University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2015.0461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521403PMC
July 2015

DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis.

Ann Rheum Dis 2016 06 2;75(6):1196-202. Epub 2015 Jun 2.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

Objective: To investigate the inflammatory response in giant cell arteritis (GCA) by characterising the DNA methylation pattern within the temporal artery microenvironment.

Methods: Twelve patients with non-equivocal histological evidence for GCA and 12 age-matched, sex-matched and ethnicity-matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in patients with GCA and from histologically confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies.

Results: We identified 1555 hypomethylated CG sites (853 genes) in affected temporal artery tissue from patients with GCA compared with normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/nuclear factor of activated T cells (NFAT) signalling pathway in GCA, confirmed by immunohistochemistry showing increased expression and nuclear localisation of NFAT1. NFAT signalling downstream targets such as interleukin (IL)-21/IL-21R and CD40L were overexpressed in GCA-affected arteries. Further, proinflammatory genes including TNF, LTA, LTB, CCR7, RUNX3, CD6, CD40LG, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R and IFNG were hypomethylated in the cellular milieu of GCA arteries.

Conclusions: We characterised the inflammatory response in GCA-affected arteries using 'epigenetic immunophenotyping' and identified molecules and pathways relevant to disease pathogenesis in GCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2014-207116DOI Listing
June 2016

Contemplating the Diagnostic Certainty of Primary Iris Mucosa-Associated Lymphoid Tissue Lymphoma—Reply.

JAMA Ophthalmol 2015 Aug;133(8):970

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2015.1167DOI Listing
August 2015

Solitary epibulbar neurofibroma in older adult patients.

Cornea 2015 Apr;34(4):475-8

*Department of Ophthalmology and Vision Sciences, WK Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI; and †Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.

Purpose: To report a solitary epibulbar neurofibroma in 2 elderly patients without systemic neurofibromatosis.

Methods: Case reports and literature review.

Results: A 67-year-old man presented with a 2-month history of left epibulbar mass. On slit-lamp examination, an 8- × 8-mm amelanotic, translucent, gelatinous, circumscribed lesion was present deep to the nasal bulbar conjunctiva. A 60-year-old otherwise healthy man presented with a 6-week history of a subconjunctival growth causing pain and photophobia in his right eye. On slit-lamp examination, an 8- × 8-mm amelanotic, translucent, gelatinous, circumscribed subconjunctival lesion, causing a delle was present near the nasal limbus. In each case, excisional biopsy was performed and histopathologic study revealed the diagnosis of neurofibroma. In both cases, after 12 months of follow-up, there was no evidence of recurrence or systemic disease.

Conclusions: Solitary epibulbar neurofibroma in older adult patients without systemic neurofibromatosis is rare but should be considered in the differential diagnosis of epibulbar tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ICO.0000000000000370DOI Listing
April 2015