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Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis

Verma, Rohan; Choi, Dongseok; Chen, Allison J; Harrington, Christina A; Wilson, David J; Grossniklaus, Hans E; Dailey, Roger A; Ng, John; Steele, Eric A; Planck, Stephen R; Korn, Bobby S; Kikkawa, Don; Czyz, Craig N; Foster, Jill A; Kazim, Michael; Harris, Gerald J; Edward, Deepak P; Al-Hussain, Haila; Maktabi, Azza M Y; Alabiad, Chris; Garcia, Armando; Rosenbaum, James T
BACKGROUND:Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy. AIMS/OBJECTIVE:To test the hypothesis that shared signalling pathways are activated in different forms of OID. METHODS:In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls. RESULTS:Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways. CONCLUSIONS:Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.
PMID: 33637620
ISSN: 1468-2079
CID: 4800892

GNA11 Mutation in an Intracranial Melanocytoma with Orbital Involvement and Nevus of Ota

Zhou, Henry W; Tran, Ann Q; North, Victoria S; Zagzag, David; Sen, Chandranath; Kazim, Michael
The prognostic value of mutations in G-protein genes GNAQ and GNA11 in patients with intracranial and orbital melanocytomas is unknown. The authors present a case of GNA11 mutation (GNA11Q209L) in a 32-year-old male suffering from a meningeal melanocytoma with orbital involvement and ipsilateral Nevus of Ota. The patient underwent gamma knife stereotactic radiosurgery without biopsy and later partial transcranial resection of the melanocytic tumor that was subject to immunohistochemical and molecular analysis. A 50-gene next-generation sequencing panel revealed a 626A>T mutation in the GNA11 gene. One year later, intracranial extension of the melanocytoma necessitated a ventriculoperitoneal shunt and immunotherapy. Future work is needed to determine how GNA11 mutations in melanocytomas influence prognosis and monitoring strategies.
PMID: 34750314
ISSN: 1537-2677
CID: 5050312

Teprotumumab and Hearing Loss: Case Series and Proposal for Audiologic Monitoring

Belinsky, Irina; Creighton, Francis X; Mahoney, Nicholas; Petris, Carisa K; Callahan, Alison B; Campbell, Ashley A; Kazim, Michael; Lee, H B Harold; Yoon, Michael K; Dagi Glass, Lora R
PURPOSE/OBJECTIVE:To present a protocol for audiologic monitoring in the setting of teprotumumab treatment of thyroid eye disease, motivated by 4 cases of significant hearing loss, and review the relevant literature. METHODS:Cases of hearing loss in the setting of teprotumumab were retrospectively elicited as part of a multi-institutional focus group, including oculoplastic surgeons, a neurotologist and an endocrinologist. A literature review was performed. RESULTS:An aggregate of 4 cases of teprotumumab-associated hearing loss documented by formal audiologic testing were identified among 3 clinicians who had treated 28 patients. CONCLUSIONS:Teprotumumab may cause a spectrum of potentially irreversible hearing loss ranging from mild to severe, likely resulting from the inhibition of the insulin-like growth factor-1 and the insulin-like growth factor-1 receptor pathway. Due to the novelty of teprotumumab and the lack of a comprehensive understanding of its effect on hearing, the authors endorse prospective investigations of hearing loss in the setting of teprotumumab treatment. Until the results of such studies are available, the authors think it prudent to adopt a surveillance protocol to include an audiogram and tympanometry before, during and after infusion, and when prompted by new symptoms of hearing dysfunction.
PMID: 34085994
ISSN: 1537-2677
CID: 4892082

Orbital Lipofibromatosis in a Pediatric Patient

Chang, Angela Y; North, Victoria S; Tran, Ann Q; Kazim, Michael
A 10-month-old boy presented with a 3-month history of progressive left lower eyelid swelling. Examination demonstrated left lower eyelid fullness and hyperglobus with a fatty appearing inferior fornix mass. Imaging showed a mass isointense to fat in the left lower eyelid extending posteriorly, surrounding the inferior oblique with complete fatty infiltration, obscuration of the inferior rectus, and adherence to the globe. The patient underwent orbitotomy with biopsy and debulking of the tumor. Surgical pathology showed multiple fragments of adipose tissue with foci of plump and spindle-shaped cells arranged in bundles and fascicles, consistent with lipofibromatosis. This case illustrates a rare presentation of orbital lipofibromatosis in a pediatric patient.
PMID: 34269771
ISSN: 1537-2677
CID: 4938992

Globe Subluxation After Proning in a Coronavirus Disease 2019 Patient

Karani, Rabia; Valenzuela, Ives A; Tran, Ann Q; North, Victoria S; Kazim, Michael
A 79-year-old male was hospitalized for respiratory failure secondary to coronavirus disease 2019 pneumonia. Approximately 6 hours after initiating proning, left globe subluxation with darkening of the superior sclera consistent with tache noir was noted. The left globe was thought to be hypotonus secondary to ciliary body shut down after a prolonged period of high intraocular pressure. The globe was reduced in the supine position with gentle traction of the eyelids. Over the next 24 hours, the left intraocular pressure improved to 10 mm Hg, and the tache-noir de la sclérotique resolved. The authors report the first known case of globe subluxation secondary to proning.
PMID: 34085993
ISSN: 1537-2677
CID: 4892072

Teprotumumab and Hyperglycemia Guidelines to Monitor for Hyperglycemia in Teprotumumab

Lee, H B Harold; Mariash, Cary N; Yoon, Michael K; Belinsky, Irina; Creighton, Francis X; Mahoney, Nicholas; Petris, Carisa K; Callahan, Alison B; Campbell, Ashley A; Kazim, Michael; Dagi Glass, Lora R
PMID: 34229337
ISSN: 1537-2677
CID: 4933142

Carcinoid Tumors of the Orbit and Ocular Adnexa

Mustak, Hamzah; Liu, Wenjing; Murta, Fabiola; Ozgur, Omar; Couch, Steven; Garrity, James; Shinder, Roman; Kazim, Michael; Callahan, Alison; Hayek, Brent; Kim, HeeJoon; Yu, Fei; Esmaeli, Bita; Rose, Geoffrey; Rootman, Daniel
PURPOSE/OBJECTIVE:Well-differentiated neuroendocrine or carcinoid tumors are found most commonly in the gastrointestinal tract. When metastatic to the orbit, they tend to have a propensity for the extraocular muscles. The purpose of this study was to better understand the diversity in presentation of orbital carcinoid disease and to determine predictors for survival. METHODS:In this observational cross-sectional cohort study, data from 8 tertiary orbital practices were compiled. Demographic, clinical, pathologic, American Joint Committee on Cancer stage and grade, imaging, and management data were extracted for all the patients. Descriptive statistics were calculated. Subgroups were compared utilizing analysis of variance analyses and Kaplan-Meier curves. Time to progression and disease-specific and overall mortality were calculated. Comparisons were performed for the following a priori pairs: unknown versus known primary tumor, single versus multiple extraocular muscle involvement, unilateral versus bilateral orbital disease, extraocular muscle versus other orbital involvement, and excisional versus incisional surgery. RESULTS:A total of 28 patients with carcinoid tumors of the orbit were identified. Of these, 57.1% of patients were female, the mean age at diagnosis of the primary tumor was 58.8 years and the mean age at diagnosis of orbital disease was 62.6 years. At primary presentation, all patients were American Joint Committee on Cancer stage III or IV and 21.4% demonstrated carcinoid syndrome. Muscle involvement was noted in 78.6% of patients, and of these, 72% were noted to have single muscle disease. Eight patients had no primary tumor identified; 3 of these 8 demonstrated disseminated disease at the time of diagnosis. The overall 5-year survival rate was 81.8% from diagnosis of primary tumor and 50% from diagnosis of orbital disease. Subgroup analysis revealed that patients with unilateral orbital disease when compared with bilateral orbital disease had a longer progression-free survival and time to death from all causes (p = 0.025). Patients with disease localized to the orbit at presentation had longer time to death than those with disseminated disease. Treatment with surgery, radiation, or octreotide did not appear to affect survival. Patients managed with systemic chemotherapy had a shorter time of survival than the rest of the group. All other subgroup comparisons were not found to be statistically significant. CONCLUSIONS:Neuroendocrine tumors of the orbit represent a wide spectrum of disease, with some cases being part of disseminated disease, while others being localized presentations. This heterogeneity may be responsible for the slightly higher overall survival in these patients than others with metastatic carcinoid tumors in other locations.
PMID: 32496392
ISSN: 1537-2677
CID: 4469222

Reliability of 3 Strategies of Orbital Tumor Volume Measurement Using Phantom Modeling

Tooley, Andrea A; Maher, Mary; Cooper, Cathleen; Godfrey, Kyle J; Tran, Ann Q; Kazim, Michael
PURPOSE/OBJECTIVE:The reliability of 3 volume measurement strategies was investigated using MRI and a simple method for creating phantom orbit tumors. METHODS:Water-based starch was molded into orbital "tumors" of 3 shapes (sphere, ovoid, diffuse); water displacement was used to calculate volume. "Tumors" were placed into 3D-printed orbit phantoms, MRIs were obtained and volume analysis was performed. Observers measured tumor volume using ellipsoid volume (EV), manual segmentation, and semi-automated segmentation strategies. Intraclass correlation coefficients were calculated comparing observer measurements to true volumes. The coefficient of repeatability determined the percentage of tumor volume change required for each method to detect tumor growth. RESULTS:Intraclass correlation coefficients comparing measured volumes to true volumes using EV, manual segmentation, and semi-automated segmentation were 0.61, 0.98, and 0.99 for spherical, 0.64, 0.97, and 0.98 for ovoid, and 0.18, 0.82, and 0.87 for diffuse tumors. Semi-automated segmentation followed by manual segmentation had the highest correlation between measured and true tumor volume for all 3 tumor geometries. EV had low correlation with true volume for all tumor geometries. Diffuse tumors had high variability and low correlation for all 3 measurement techniques. CONCLUSIONS:This study shows the reliability of 3 strategies to measure orbital tumor volume with MRI based on tumor geometry, using a simple phantom model. EV, the most commonly employed strategy in clinical practice, had low correlation and high variability across tumor shapes. Using manual segmentation and semi-automated segmentation, a measured change in volume greater than 25% may be considered true growth, while the EV strategy required a 40%-400% change in volume to reliably measure tumor growth.
PMID: 32732541
ISSN: 1537-2677
CID: 4540552

Prospective Correlation of Risk of Obstructive Sleep Apnea With Severe Clinical Features of Thyroid Eye Disease

Godfrey, Kyle J; Schmuter, Gabriella; Hu, Bo; Tooley, Andrea A; Dunbar, Kristen E; Basner, Robert C; Kazim, Michael
PURPOSE/OBJECTIVE:To evaluate the association between risk of obstructive sleep apnea (OSA) and severity of thyroid eye disease (TED) using a validated OSA screening tool. METHODS:A prospective, observational cohort study was performed. New adult TED patients were offered OSA screening with the Snoring Tired Observed Pressure (STOP)-Bang survey during their initial evaluation. Clinical examination and treatment for TED were standard of care and utilized the International Thyroid Eye Disease Society Vision Inflammation Strabismus Appearance system. At the conclusion of the study period, analysis was performed correlating maximum severity of TED signs and symptoms between high- and low-risk OSA groups. Multivariate logistic and linear regression analyses were also performed to analyze the association between the numerical STOP-Bang score and maximum severity of the potentially actionable clinical features of TED (compressive optic neuropathy, vertical prism deviation, horizontal prism deviation, exophthalmos, vertical fissure height). RESULTS:Eighty-five patients met inclusion criteria. Twenty-eight percent were at high risk of OSA (STOP-Bang score of 3 or higher). When comparing the low- and high-risk cohorts, increased risk of OSA was significantly associated with the development of TED compressive optic neuropathy (p = 0.014), conjunctival injection (p = 0.027), chemosis (p = 0.013), upper eyelid edema (p = 0.024), lower eyelid edema (p = 0.003), eyelid erythema (p = 0.037), and vertical strabismus (p = 0.047). In the multivariate regression analyses, higher STOP-Bang scores correlated with increased risk of TED compressive optic neuropathy (p = 0.006), vertical strabismus (p = 0.019), and higher subjective diplopia scores (p = 0.045). CONCLUSIONS:Increased risk of OSA, as determined by the STOP-Bang survey, is associated with increased severity of multiple clinical features of TED, including TED compressive optic neuropathy and strabismus.
PMID: 32852372
ISSN: 1537-2677
CID: 4575812

Atypical Cogan Syndrome Featuring Orbital Myositis and Dacryoadenitis

Zhou, Henry W; Tran, Ann Q; Tooley, Andrea A; Miyauchi, Jeremy T; Kazim, Michael
A 39-year-old male presented with bilateral hearing loss and progressive left eye vision loss over a 14-month period. The development of systemic symptoms including arthralgias, enlarged lymph nodes, and profound leg weakness, prompted a workup for lymphoproliferative disease, infection, and autoimmune inflammatory conditions which was unrevealing. Subsequently, the right visual acuity declined from 20/25 to 20/70 and the left to hand motions due to corneal interstitial keratitis. There was limitation of left infraduction. Neuroimaging revealed dural thickening of the internal auditory canals, cavernous sinuses, cerebellum, and along the optic nerves. There was fusiform enhancing enlargement of the left inferior and medial rectus muscles and pathologic enlargement of the left lacrimal gland. Biopsy of the left lacrimal gland and left inferior rectus revealed fibrosis and lymphocytic infiltration. The patient was diagnosed with atypical Cogan syndrome and treated with oral prednisone, with improvement in visual acuity of the right eye, motility of the left eye, and systemic weakness.
PMID: 32991499
ISSN: 1537-2677
CID: 4616732