Interrater reliability of photographic assessment of thyroid eye disease using the VISA classification.

PURPOSE: To determine the interrater reliability (IRR) of thyroid eye disease (TED) photographic assessment using the VISA classification. To assess whether a VISA grading atlas improves ophthalmology trainees' performance in photographic assessment of TED. METHODS: A prospective, partially randomized, international study conducted from September 2021 to May 2022. Online study invitation was emailed to a volunteer sample group of 68 ophthalmology college accredited consultants and trainees, and 6 were excluded from the study. Participants were asked to score 10 patient photographs of TED using only the inflammation and motility restriction components of the VISA classification. IRR was compared between groups of practitioners by their level of experience. A clinical activity grading atlas was randomized to 50% of the ophthalmology trainees. RESULTS: Overall rater ICC was 0.96 for inflammation and 0.99 for motility restriction. No statistically significant difference in IRR between rater groups was identified. Trainees with a grading atlas had the highest IRR for inflammation (ICC = 0.95). Each subcomponent of the inflammation and motility restriction components of VISA classification had an ICC considered good to excellent. The mean overall rater score was 4.6/9 for inflammation and 3.5/12 for motility restriction. For motility restriction there was a reduced mean score variance among all raters when scoring photographs with more severe motility restriction. CONCLUSION: IRR using the inflammation and motility restriction components of the VISA classification was excellent. A VISA grading atlas improved trainee performance in grading inflammation.

Dysthyroid optic neuropathy: a case series at a tertiary ophthalmic referral centre.

BACKGROUND/OBJECTIVES: To determine risk factors and treatment outcomes in dysthyroid optic neuropathy (DON) at a single tertiary ophthalmic centre. METHODS: Retrospective audit of DON patients who have received intravenous methylprednisolone (IVMP) therapy at Royal Victorian Eye and Ear Hospital, Melbourne, Australia from July 2015 to October 2021. RESULTS: Study included 24 patients (58% female) with an average age of 59.8 ± 14.7 years at DON diagnosis. Majority (92%) had Graves' hyperthyroidism and 77% had a smoking history. At diagnosis, average visual acuity (VA) of worse eye was LogMAR 0.46, and 48% had relative afferent pupillary defect. Proptosis (89%) and diplopia (73%) were most commonly present at diagnosis. 78% showed predominantly extra-ocular muscle enlargement, and apical crowding (52%) on radiology. 38% (n = 9/24) responded to IVMP alone, 58% (n = 14/24) progressed to surgical orbital decompression. The average total cumulative dose of IVMP during DON treatment was 6.8 ± 1.9 g. 29% required further treatment after IVMP and surgical decompression, 4 (17%) had additional radiotherapy, and three (13%) required immuno-modulatory therapy. Average final VA was LogMAR 0.207, with all patients having inactive TED at final follow-up (mean 1.7 years). In refractory DON cases, 71% retained VA ≥ 6/9 and 48% had DON reversal. CONCLUSIONS: DON patients typically present in late 50s, with a smoking history and predominant extra-ocular muscle enlargement. High-dose IVMP fully resolved DON in only 38%. A considerable proportion required urgent orbital decompression. Most patients retained good vision at final follow-up.

Orbital inflammation following COVID-19 vaccination: A case series and literature review.

PURPOSE: The purpose of the study was to report three cases of orbital inflammation following administration of the COVID-19 vaccination, manifesting as Tolosa-Hunt syndrome (THS) and orbital myositis. METHOD: A retrospective case series and literature review of patients who developed orbital inflammation following a COVID-19 vaccination. RESULTS: One patient presented with Tolosa-Hunt syndrome (THS) 14 days following her third (booster) COVID-19 vaccination, one patient developed orbital myositis 10 days following his first COVID-19 vaccination and one patient developed recurrent orbital myositis 1 and 7 days following her second and fourth COVID-19 vaccination. All patients received the Comirnaty vaccine (Pfizer-BioNTech). A thorough systemic autoimmune disease workup in both patients was unremarkable. Two patients had a prior history of orbital inflammation, with previous involvement of other different orbital structures. Characteristic MRI features for each pathology were observed, supporting the clinical presentation of THS and orbital myositis. There was complete resolution of THS following corticosteroids, with no recurrence at 2 months. Meanwhile, one case of orbital myositis self-resolved at 2 months without use of systemic corticosteroids, while the other patient with orbital myositis required treatment with intra-orbital steroid injections and oral corticosteroids. CONCLUSION: Orbital inflammation has been recognised as a rare adverse effect following COVID-19 vaccination. We present a case series of THS and orbital myositis as varied presentations of this entity.

Specific location of ocular adnexal lymphoma and mortality: an international multicentre retrospective study.

AIMS: To examine whether the specific location of ocular adnexal lymphoma (OAL) and the American Joint Committee on Cancer (AJCC) TNM tumour stage are prognostic factors for mortality in the main OAL subtypes. METHODS: Clinical and survival data were retrospectively collected from seven international eye cancer centres. All patients from 1980 to 2017 with histologically verified primary or secondary OAL were included. Cox regression was used to compare the ocular adnexal tumour locations on all-cause mortality and disease-specific mortality. RESULTS: OAL was identified in 1168 patients. The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n=688, 59%); follicular lymphoma (FL) (n=150, 13%); diffuse large B-cell lymphoma (DLBCL) (n=131, 11%); and mantle cell lymphoma (MCL) (n=89, 8%). AJCC/TNM tumour-stage (T-stage) was significantly associated with disease-specific mortality in primary ocular adnexal EMZL and increased through T-categories from T1 to T3 disease. No associations between AJCC/TNM T-stage and mortality were found in primary ocular adnexal FL, DLBCL, or MCL. EMZL located in the eyelid had a significantly increased disease-specific mortality compared with orbital and conjunctival EMZL, in both primary EMZL and the full EMZL cohort. In DLBCL, eyelid location had a significantly higher disease-specific mortality compared with an orbital or lacrimal gland location. CONCLUSION: Disease-specific mortality is associated with AJCC/TNM T-stage in primary ocular adnexal EMZL patients. Lymphoma of the eyelid has the highest disease-specific mortality in primary EMZL, and in the full cohort of EMZL and DLBCL patients.

Diagnostic accuracy of Immulite® TSI immunoassay for thyroid-associated orbitopathy in patients with recently diagnosed Graves' hyperthyroidism.

PURPOSE: The Immulite® thyroid stimulating immunoglobulin (TSI) immunoassay is a relatively new commercial assay that has shown good diagnostic accuracy in Graves' hyperthyroidism (GH). However, its clinical utility in thyroid-associated orbitopathy (TAO) is less clear. The purpose of this study was to assess the diagnostic accuracy of the Immulite® TSI immunoassay for TAO and investigate the associations between TSI and other clinical measures. METHODS: One hundred and forty patients that had been diagnosed with GH within the previous 12 months were recruited. Identification and grading of TAO were performed at enrolment and serum samples were analysed using the Immulite® TSI immunoassay. RESULTS: Of the 140 participants recruited, 75 (53.6%) had TAO. Age, sex and time since GH diagnosis were similar between those with and without TAO (p ≥ 0.300). TSI level tended to decrease with increasing time from GH diagnosis (Spearman's ρ - 0.28, 95% CI - 0.43, - 0.12). TSI levels were higher among those with than those without TAO (median 4.0 vs. 2.7 IU/L, respectively, p = 0.037). There was no correlation between TSI level and inflammatory index score (ρ = 0.14, 95% CI - 0.03, 0.30) or clinical severity (p = 0.527) among those with TAO. TSI level showed poor diagnostic accuracy for TAO (area under the receiver operating characteristic curve 0.60, 95% CI 0.51, 0.70). CONCLUSIONS: Although Immulite® TSI level was higher in the presence of TAO, it showed poor diagnostic accuracy and no correlation with clinical markers of TAO severity or activity.

Medical treatment in thyroid eye disease in 2020.

Thyroid eye disease (TED) affects 25% of patients with Graves' hyperthyroidism, where 1 in 20 patients has active, moderate-to-severe disease that will require medical treatment for reducing TED activity and severity. Intravenous corticosteroid has been the mainstay of treatment for active moderate-to-severe TED. With improved understanding of the pathophysiology of TED, immunotherapy targeting different molecular pathways including T cells, B cells, cytokines and cell surface receptors have been investigated in randomised clinical trials. This review provides an overview of the current advances in medical treatment including teprotumumab, tocilizumab, rituximab and mycophenolate and the indications for their use in the management of active, moderate-to-severe TED.

International multicentre retrospective cohort study of ocular adnexal marginal zone B-cell lymphoma.

BACKGROUNDS/AIMS: To date, this is the largest cohort study on extranodal marginal zone B-cell lymphoma (EMZL) of the ocular adnexa (OA). The aim of the study was to characterise the clinical features of OA-EMZL. METHODS: A retrospective multicentre study involving seven international eye cancer centres. Data were collected from 1 January 1980 through 31 December 2017. A total of 689 patients with OA-EMZL were included. RESULTS: The median follow-up time was 42 months. The median age was 62 years (range, 8-100 years), and 55 % (378/689 patients) of patients were women. The majority of patients (82%, 558/680 patients) were diagnosed with primary OA-EMZL with Ann Arbor stage IE (90%, 485/541 patients) and American Joint Committee on Cancer stage T2 (61%, 340/557 patients) at the time of diagnosis. The orbit (66%, 452/689 patients) and the conjunctiva (37%, 255/689 patients) were the most frequently involved anatomical structures. The 5-year, 10-year and 20-year disease-specific survival (DSS) were 96%, 91% and 90%, respectively. Stage IE patients treated with external beam radiation therapy (EBRT) as monotherapy (10-year DSS, 95%) were found to have a better DSS than stage IE patients treated with chemotherapy (10-year DSS, 86%). Stage IIIE/IVE patients treated with chemotherapy and rituximab had a better DSS (10-year DSS, 96%) than stage IIIE/IVE patients treated with chemotherapy without rituximab (10-year DSS, 63%). CONCLUSIONS AND RELEVANCE: EMZL is a slow-growing tumour with an excellent long-term survival. Low-dose EBRT as monotherapy should be considered in localised OA-EMZL. Rituximab-based chemotherapy should be chosen in those patients with disseminated disease.

Orbital Lymphoma-An International Multicenter Retrospective Study.

PURPOSE: To investigate and characterize the clinical features of subtype-specific orbital lymphoma. DESIGN: Retrospective, interventional case series. METHODS: The study included 7 international eye cancer centers. Patient data were collected from January 1, 1980 through December 31, 2017. A total of 797 patients with a histologically verified orbital lymphoma were included. The primary endpoints were overall survival, disease-specific survival, and progression-free survival. RESULTS: The median age was 64 years, and 51% of patients (n = 407) were male. The majority of lymphomas were of B-cell origin (98%, n = 779). Extranodal marginal zone B-cell lymphoma (EMZL) was the most frequent subtype (57%, n = 452), followed by diffuse large B-cell lymphoma (DLBCL) (15%, n = 118), follicular lymphoma (FL) (11%, n = 91), and mantle cell lymphoma (MCL) (8%, n = 66). Localized Ann Arbor stage IE EMZL and FL were frequently treated with external beam radiation therapy. DLBCL, MCL, and disseminated EMZL and FL were primarily treated with chemotherapy. EMZL and FL patients had a markedly better prognosis (10-year disease-specific survival of 92% and 71%, respectively) than DLBCL and MCL patients (10-year disease-specific survival of 41% and 32%, respectively). CONCLUSIONS: Four lymphoma subtypes were primarily found in patients with orbital lymphoma: EMZL, DLBCL, FL, and MCL. The histologic subtype was found to be the main predictor for outcome, with EMZL and FL patients having a markedly better prognosis than DLBCL and MCL.

Orbital tuberculosis: perspectives from Victoria, Australia.

PURPOSE: Orbital tuberculosis (TB) is a rare extra-pulmonary manifestation of tuberculosis and its clinical diagnosis poses unique challenges, with potential for destructive complications as well as social and public health implications. The aim of this study is to report our experience of patients presenting with orbital TB and to identify common aspects. METHODS: A systematic search for mandatory notifications of orbital tuberculosis between January 01, 1994 and December 12, 2016 was undertaken in the Victorian Tuberculosis database. In addition, members of the Australian and New Zealand Society of Ophthalmic Plastic Surgeons (ANZSOPS) were surveyed to identify cases of orbital tuberculosis diagnosed on biopsy in the past 20 years. Medical case notes of identified cases were reviewed retrospectively. RESULTS: Three cases were identified as having occurred in Victoria, aged 44-59 years old. All cases had emigrated from endemic countries with higher tuberculosis burden. Diagnosis of tuberculosis was often difficult due to few or non-viable acid fast bacilli and low yield of positive culture in paucicellular orbital specimens. CONCLUSIONS: Orbital TB is rare but remains an important differential diagnosis of orbital mass lesions. The diagnosis of orbital TB requires a high index of clinical suspicion and targeted investigations in patients originating from endemic areas. Diagnosis and treatment rely on effective collaboration between ophthalmologists, infectious disease physicians, and pathologists.

Bilateral facial nerve palsies secondary to chronic inflammatory demyelinating polyneuropathy following adalimumab treatment.

PURPOSE: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) presents uncommonly with cranial nerve involvement with ophthalmological implications. METHODS: We report the case of a 37year-old man who developed CIDP which manifested as progressive and relapsing bilateral facial nerve palsy with lagophthalmos and exposure keratopathy, in the setting of treatment of Crohn's disease with the anti-TNF-alpha agent adalimumab. RESULTS: Symptoms gradually improved over the course of several months following withdrawal of adalimumab and treatment with intravenous immunoglobulin (IVIg) and oral prednisolone. CONCLUSION: Bilateral facial nerve involvement occurs uncommonly as a feature of CIDP in its classic form. The prognosis is good for recovery of facial nerve function with discontinuation of anti-TNF-alpha therapy and concurrent use of steroid and intravenous immunoglobulin in this case.

Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort.

Importance: To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. Objective: To characterize the clinical features of OA-MCL. Design, Setting, and Participants: This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Main Outcomes and Measures: Overall survival, disease-specific survival, and progression-free survival were the primary end points. Results: Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region. Conclusions and Relevance: These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.

Lymphoma of the Eyelid - An International Multicenter Retrospective Study.

PURPOSE: To document subtype-specific clinical features of lymphoma of the eyelid, and their effect on patient outcome. DESIGN: Retrospective observational case series. METHODS: Patient data were collected from 7 international eye cancer centers from January 1, 1980 through December 31, 2015. The cases included primary and secondary lymphomas affecting the eyelid. Overall survival, disease-specific survival (DSS), and progression-free survival were the primary endpoints. RESULTS: Eighty-six patients were included. Mean age was 63 years and 47 (55%) were male. Non-Hodgkin B-cell lymphomas constituted 83% (n = 71) and T-cell lymphomas constituted 17% (n = 15). The most common subtypes were extranodal marginal-zone lymphoma (EMZL) (37% [n = 32]), follicular lymphoma (FL) (23% [n = 20]), diffuse large B-cell lymphoma (DLBCL) (10% [n = 9]), mantle cell lymphoma (MCL) (8% [n = 7]), and mycosis fungoides (MF) (9% [n = 8]). EMZL had a female predilection (69% [22 of 32]), whereas MCL (71% [5 of 7]) and MF (88% [7 of 8]) had a male predominance. MCL (57% [4 of 7]), DLBCL (56% [5 of 9]), and MF (88% [7 of 8]) were frequently secondary lymphomas. Localized EMZL and FL were mostly treated with external beam radiation therapy, whereas DLBCL, MCL, and high Ann Arbor stage EMZL and FL were frequently treated with chemotherapy. DLBCL and MCL had a poor prognosis (5-year DSS, 21% and 50%, respectively), whereas EMZL, FL, and MF had a good prognosis (5-year DSS, 88%, 88% and 86%, respectively). CONCLUSIONS: Lymphoma of the eyelid consists mainly of the lymphoma subtypes EMZL, FL, DLBCL, MCL, and MF. High-grade DLBCL and MCL, as well as MF, are frequently secondary eyelid lymphomas. The main predictor of outcome was the histologic subtype: EMZL, FL, and MF had a significantly better prognosis than MCL and DLBCL.

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

BACKGROUND: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. RESULTS: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10-8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10-4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. CONCLUSIONS: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.

Association of Polymorphisms in MACRO Domain Containing 2 With Thyroid-Associated Orbitopathy.

PURPOSE: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in individuals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. METHODS: Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in individual DNA samples from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. RESULTS: In the GWAS of pooled DNA samples, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6; rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on individual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5; odds ratio [OR] = 1.77; 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. CONCLUSIONS: In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.

Risk Factors for Graves' Orbitopathy; the Australian Thyroid-Associated Orbitopathy Research (ATOR) Study.

CONTEXT: Previous association studies suggest the development of Graves' orbitopathy (GO) is variably influenced by environmental risk factors. OBJECTIVE: To determine the risk factors and predict odds for developing GO in Graves' hyperthyroidism (GH). DESIGN: Case-control study. SETTING: Multi-centre Australian Thyroid-associated Orbitopathy Research group consisting of tertiary endocrinology and ophthalmology outpatients and related private practices. PATIENTS OR OTHER PARTICIPANTS: A total of 1042 participants with GH were designated as cases if they had GO (n = 604) and controls if they did not have GO (n = 438). MAIN OUTCOME MEASURES: Primary outcome was GO risk factors and secondary outcome was dysthyroid optic neuropathy (DON) with the effects of risk factors measured by odds ratio (OR) using multiple logistic regression, adjusted for known risk factors and exploratory variables. RESULTS: The odds of GO increased by 17% for each decade increase in the age of onset of GH (OR 1.17, confidence interval (CI): 1.06-1.29; P = .002) and by 7% for each year increase in the duration of GH (OR 1.07, CI: 1.05-1.10; P < .001). Smoking increased the odds for GO by 2.22 for current smoker and 2.07 for exsmoker (P < .001), compared with never smoking. The odds of GO are 86% less in Graves' patients using antithyroid medication than those not (OR 0.14, CI: 0.06-0.34; P < .001). Predictors for DON were older age, oculomotility restriction, strabismus, reduced palpebral aperture, and active GO. CONCLUSIONS: This study identified increase age of onset, duration of GH, and smoking as risk factors for GO. Usage of antithyroid medication was negatively related to GO. Older patients with restricted ocular motility, strabismus, and active GO are at higher risk of DON and may benefit from early medical intervention.

Pathogenesis of thyroid eye disease: review and update on molecular mechanisms.

Orbital changes in thyroid orbitopathy (TO) result from de novo adipogenesis, hyaluronan synthesis, interstitial oedema and enlargement of extraocular muscles. Cellular immunity, with predominantly CD4+ T cells expressing Th1 cytokines, and overexpression of macrophage-derived cytokines, perpetuate orbital inflammation. Orbital fibroblasts appear to be the major effector cells. Orbital fibroblasts express both thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R) at higher levels than normal fibroblasts. TSHR expression increases in adipogenesis; TSHR agonism enhances hyaluronan production. IGF-1R stimulation leads to adipogenesis, hyaluronan synthesis and production of the chemokines, interleukin (IL)-16 and Regulated on Activation, Normal T Cell Expression and Secreted, which facilitate lymphocyte trafficking into the orbit. Immune activation uses a specific CD40:CD154 molecular bridge to activate orbital fibroblasts, which secrete pro-inflammatory cytokines including IL-1ß, IL-1α, IL-6, IL-8, macrophage chemoattractant protein-1 and transforming growth factor-ß, to perpetuate orbital inflammation. Molecular pathways including adenylyl cyclase/cyclic adenosine monophosphate, phophoinositide 3 kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase are involved in TO. The emergence of a TO animal model and a new generation of TSHR antibody assays increasingly point towards TSHR as the primary autoantigen for extrathyroidal orbital involvement. Oxidative stress in TO resulting from imbalances of the oxidation-reduction state provides a framework of understanding for smoking prevention, achieving euthyroidism and the use of antioxidants such as selenium. Progress has been made in the understanding of the pathogenesis of TO, which should advance development of novel therapies targeting cellular immunity, specifically the CD40:CD40 ligand interaction, antibody-producing B cells, cytokines, TSHR and IGF-1R and its signalling pathways. Further studies in signalling networks and molecular triggers leading to burnout of TO will further our understanding of TO.

Differential Gene Expression Profiling of Orbital Adipose Tissue in Thyroid Orbitopathy.

PURPOSE: We aimed to determine differentially expressed genes relevant to orbital inflammation and orbital fat expansion in thyroid orbitopathy (TO) using microarray gene profiling in a case-control study. METHODS: Human orbital adipose samples were obtained from individuals with active TO (n = 12), inactive TO (n = 21), and normal controls (n = 21). Gene expression profiles were examined using microarray analysis and were compared between active and inactive TO, and between active TO and normal controls. Top ranked differentially expressed genes were validated by real-time RT-PCR in an additional eight active TO, 13 inactive TO, and 11 normal controls and correlated with gene set enrichment analysis (GSEA) and molecular pathways analysis. RESULTS: Seven hundred twenty-one probes (683 genes) and 806 probes (735 genes) were significantly differentially expressed in comparing active to inactive TO and in comparing active TO to healthy controls, respectively. All selected genes were confirmed to be differentially expressed by real-time RT-PCR. Multiple top ranked genes in active versus inactive TO comparison are overrepresented by immune and inflammatory response genes. They include defensins (DEFA1, DEFA1B, DEFA3), which were overexpressed by 3.05- to 4.14-fold and TIMD4 by 4.20-fold. Markers for adipogenesis were overexpressed including SCD, FADS1, and SCDP1. Gene set enrichment analysis revealed dysregulation of epigenetic signatures, T-cell activation, Th1 differentiation, defensin pathway, cell adhesion, cytoskeleton organization, apoptosis, cell cycling, and lipid metabolism in active TO. CONCLUSIONS: Active TO is characterized by upregulation of genes involved in cell-mediated immune, innate immune, and inflammatory response and enhanced orbital adipogenesis. TIMD4, DEFA1, DEFA1B, and DEFA3 genes may be involved in the innate immune-mediated orbital inflammation in TO. Epigenetic mechanisms may play a role in the pathogenesis of TO.

Ocular adnexal diffuse large B-cell lymphoma: a multicenter international study.

IMPORTANCE: The clinical features of diffuse large B-cell lymphoma (DLBCL) subtype of ocular adnexal lymphoma have not previously been evaluated in a large cohort to our knowledge. OBJECTIVE: To investigate the clinical features of ocular adnexal DLBCL (OA-DLBCL). DESIGN, SETTING, AND PARTICIPANTS: This retrospective international cooperative study involved 6 eye cancer centers. During 30 years, 106 patients with OA-DLBCL were identified, and 6 were excluded from the study. The median follow-up period was 52 months. MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific survival (DSS), and progression-free survival were the primary end points. RESULTS: One hundred patients with OA-DLBCL were included in the study (median age, 70 years), of whom 54 (54.0%) were female. The following 3 groups of patients with lymphoma could be identified: primary OA-DLBCL (57.0%), OA-DLBCL and concurrent systemic lymphoma (29.0%), and ocular adnexal lymphoma relapse of previous systemic lymphoma (14.0%). Of 57 patients with primary OA-DLBCL, 53 (93.0%) had Ann Arbor stage IE disease, and 4 (7.0%) had Ann Arbor stage IIE disease. According to the TNM staging system, 43 of 57 (75.4%) had T2 tumors. Among all patients, the most frequent treatments were external beam radiation therapy with or without surgery (31.0%) and rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone (CHOP) or rituximab-CHOP-like chemotherapy with or without external beam radiation therapy (21.0%). The 5-year overall survival among the entire cohort was 36.0% (median, 3.5 years; 95% CI, 2.5-4.5 years). Relapse occurred in 43.9% (25 of 57) of patients with primary OA-DLBCL. Increasing T category of the TNM staging system was predictive of DSS (P = .04) in primary OA-DLBCL, whereas the Ann Arbor staging system was not. However, when taking all 100 patients into account, Ann Arbor stage was able to predict DSS (P = .01). Women had a longer median DSS than men (9.8 years; 95% CI, 1.9-17.7 years vs 3.3 years; 95% CI, 1.6-5.0; P = .03). CONCLUSIONS AND RELEVANCE: Most patients with primary OA-DLBCL were seen with Ann Arbor stage IE and TNM T2 disease. The 5-year overall survival was between 2.5 and 4.5 years, which is the 95% CI around the median of 3.5 years in this cohort. Increasing T category appears to be associated with decreased DSS among patients with primary OA-DLBCL. When taking all patients into account, sex and Ann Arbor stage also seem to be DSS predictors.