Primary orbital melanoma: presentation, treatment and long-term outcomes for 13 patients

Background: Periocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest origin), conjunctiva or orbit (rarest primary site). Melanoma accounts for 5–10% of metastatic/secondary orbital malignancies, but only a tiny proportion of primary orbital neoplasia. Primary orbital melanoma (POM) is exceedingly rare, with approximately 50 cases reported to date. Methods: All patients seen in the orbital unit at a tertiary referral hospital (1991–2016) with a biopsy-proven diagnosis of POM were identified from a diagnostic database and were studied. The case notes, imaging, surgical approach, and histology were reviewed. Results: Thirteen patients (five male; 38%) presented with isolated malignant melanoma of the orbit, for which no other primary site was identified at presentation or during an average follow-up of 44 months (median 22; range 0–13 years). The patients presented between the ages of 40 and 84 years (mean 55.5; median 48 years) and typically gave a short history of rapidly increasing proptosis and eyelid swelling. On the basis of history, a malignant lesion was suspected in most patients and all underwent incisional biopsy, with debulking of the mass in 10 (77%) patients, and skin-sparing exenteration in 3/13 (23%). Ten patients underwent orbital radiotherapy and the survival to date ranged from 9 months to 14 years (mean 55 months; median 23 months); two patients received solely palliative care for widespread disease and one patient refused orbital radiotherapy. Five of the 13 (38%) patients died from the disease. Discussion: POM is a very rare malignancy, but clinical analysis of this cohort gives insight into disease presentation and prognosis. The tumor typically presents with a rapidly progressive, well-defined mass that is, in some cases, amenable to macroscopically intact excision. Unusual for malignant melanoma, some of these patients can show an unusually long period of quiescent disease after surgical debulking and radiotherapy

The Application of Infrared Imaging and Optical Coherence Tomography of the Lacrimal Punctum in Patients Undergoing Punctoplasty for Epiphora

Purpose To determine the application of imaging the stenotic lacrimal punctum with infrared photographs and optical coherence tomography (OCT) and to identify characteristics of the lacrimal punctum in patients who benefit from punctoplasty. Design Case-control study. Participants Twenty patients with epiphora who were listed for punctoplasty and 20 healthy controls. Methods Prospectively, 20 patients listed for punctoplasty were asked to rate their epiphora, using the Munk score, before and after punctoplasty. They also underwent preoperative OCT and infrared imaging of the affected punctum. They were divided into 2 groups, depending on whether the epiphora improved, and were compared with 20 healthy controls. Main Outcome Measures Measurements of puncta from infrared and OCT images were obtained along with Munk scores of patient epiphora. Results The infrared image measurements were significantly smaller in those patients whose epiphora improved compared with those whose did not in both the area of the punctal aperture and in the maximum punctal diameter. Additionally, those patients with improvement in epiphora had a significantly smaller preoperative punctal diameter at 100 μm depth on OCT compared with healthy controls; this was not observed in patients whose epiphora failed to improve. There was no significant difference in the punctum diameter among the 3 groups at the punctum surface entrance or at 500 μm depth. Patients with epiphora had a higher tear meniscus within the punctum compared with healthy controls. Conclusions Lacrimal punctum infrared and OCT imaging may be helpful in predicting patients more likely to benefit symptomatically from punctoplasty, with patients with smaller puncta having greater symptomatic improvement. However, the results suggest that inner punctum diameter (not readily measurable by slit-lamp examination), rather than the surface diameter, is correlated with outcome. Additionally, OCT measurements of the tear meniscus height within the punctum may be related to the degree of epiphora

Characterizing the Occluded Lacrimal Punctum Using Anterior Segment Optical Coherence Tomography.

PURPOSE: Epiphora is sometimes associated with an absent or occluded lacrimal drainage punctum (or puncta). This study uses noninvasive "enhanced depth" anterior segment optical coherence tomography (OCT) to give improved characterization and understanding of absent or fully occluded puncta and the underlying canaliculus. METHODS: Anterior segment spectral domain OCT images were collected prospectively from 9 lower puncta of 6 patients with epiphora and absent or fully occluded puncta, not amenable to dilation in clinic, to see if a canaliculus was visible on OCT imaging below the occluded punctum. RESULTS: An epithelial lined canalicular lumen was visible on OCT in 4 lower eyelid puncta from 2 patients and OCT identified 80% (4/5) of the canaliculi that were located on microscope-assisted punctal exploration. These lumens were seen within 580 μm depth from the eyelid margin surface. A half of the eyes in which a canaliculus was identified on OCT (the 2 eyes in a single patient) had resolution of epiphora following punctoplasty, and the other patient was found to have coexisting nasolacrimal duct stenosis and required later dacryocystorhinostomy. The positive predictive value for identifying a canaliculus on lower eyelid punctal exploration in acquired complete punctal occlusion (excluding the congenital case) was 1, with a negative predictive value of 1. CONCLUSIONS: This study demonstrates that canaliculi can be imaged with OCT where formal access is precluded by an occluded punctum. This noninvasive investigation might help predict the likelihood of successful retrieval of a canaliculus at surgical exploration

Feasibility and acceptability of postpartum voluntary counselling and testing (PPVCT) in a large tertiary hospital in the South African setting

Objective. To demonstrate the feasibility and acceptability of introducing postpartum voluntary counselling and testing (PPVCT) and the provision of post-exposure nevirapine prophylaxis (PEP) to HIV-exposed infants whose mothers did not receive any antiretroviral prophylaxis to prevent mother-to-child transmission (PMTCT) in a large, tertiary hospital in the South African setting. Design. Observational, interventional study. Setting. The programme was implemented at Chris Hani Baragwanath Hospital (tertiary referral centre) in Soweto, South Africa, following a study that established the efficacy of a postpartum regimen of PEP in PMTCT. Participants. From January 2003 to December 2004, 7 500 women who delivered at Chris Hani Baragwanath Hospital without a documented HIV-1 result were identified in the postnatal wards. PPVCT was offered to all eligible participants. Intervention. On-site HIV rapid tests were performed on all women who agreed to testing. For those women testing HIV-1 positive, a single dose of nevirapine syrup was offered to their infants as PEP within 72 hours after delivery. Infant feeding counselling, assistance with follow-up care and support programmes were also offered. Main outcome. From January 2003 to December 2004, 34 776 deliveries occurred at Chris Hani Baragwanath Hospital. Of these, 7 500 (21.5%) had no documented HIV status. After delivery 5 751 (76.7%) women were offered VCT, and of these 3 794 (66%) accepted testing. Of these women, 1 294 (34%) tested HIV positive and 1 243 (96%) women accepted the administration of single-dose nevirapine to their infants. Conclusions. The uptake of PPVCT is comparable to that seen in established antenatal VCT despite the numerous challenges PPVCT presents. This suggests that PPVCT is both an acceptable and a feasible option in a busy, resource-limited setting and remains an important strategy in PMTCT in untreated individuals. Southern African Journal of HIV Medicine Vol. 6 (2) 2005: pp. 8-1

Eyelid and Sternum Fibroblasts Differ in Their Contraction Potential and Responses to Inflammatory Cytokines

BACKGROUND: Adverse skin scarring varies by anatomical site with, for example, presternal skin showing a greater hypertrophic response when compared with eyelid; such differences have traditionally been attributed to regional variations in skin tension, thickness, and Langer's lines. Fibroblasts are the main cell implicated in fibrosis, and they too are known to show anatomical variation in their expression, differentiation, and intercellular interactions. We, therefore, investigated whether intrinsic differences in skin fibroblasts derived from separate locations might contribute to the observed discrepancies in clinical scarring. METHODS: Primary in vitro cultures were established using matched eyelid and presternal skin from 3 healthy donors undergoing blepharoplasty surgery. We used an in vitro collagen gel model of fibroblast-mediated tissue contraction to compare the properties of the dermal fibroblasts from each site. Cell contractile force and matrix stiffness were assessed in 3-dimensional tissue constructs using an automated high-throughput device. RESULTS: Dermal fibroblasts isolated from eyelid and sternum differ both in their ability to contract a gel matrix and in their response to cytokine stimulation; despite having lower intrinsic contractile force (P < 0.01) and resting stiffness (P < 0.02), the presternal cells were more contractile (P < 0.001) following stimulation with serum, or inflammatory cytokines transforming growth factor-β (P < 0.01) and interleukin-1β (P < 0.05). CONCLUSIONS: The propensity to cutaneous scarring may, at least in part, result from intrinsic differences in the local fibroblasts' ability to contract and their sensitivity to inflammatory cytokines. Improved understanding of the underlying molecular pathways should prove useful in identifying new therapeutic targets for altering surgical and other scarring

Mesenchymal Stem Cell–Like Properties of Orbital Fibroblasts in Graves’ Orbitopathy

PURPOSE. Graves’ orbitopathy (GO) is a sight-threatening autoimmune disorder causing extraocular muscle fibrosis, upper lid retraction and eye bulging due to orbital fat expansion. These clinical features are mediated by aspects of orbital fibroblasts differentiation, including adipogenesis and fibrosis. Our previous work suggested that this dual phenotype might be a manifestation of mixed cell populations, partially linked to the expression of mesenchymal stem cell (MSC) marker CD90. Thus, we set out to determine whether GO orbital fibroblasts displayed MSC properties. METHODS. Control and GO orbital fibroblasts previously characterized for CD90 and CD45 expression were analyzed by flow cytometry for classical MSC positive (CD73, CD105) and negative (CD14, CD19, HLA-DR, and CD34) markers. Graves’ orbitopathy fibroblasts were tested further for their ability to undergo lineage specific differentiation following standard protocols. RESULTS. Control and GO fibroblasts strongly expressed CD73 and CD105, with a higher percentage of positive cells and stronger expression levels in GO. Neither cell type expresses CD14, CD19, and HLA-DR. Protein CD34 was expressed at low levels by 45% to 70% of the cells, with its expression significantly lower in GO cells. Graves’ orbitopathy fibroblasts displayed features of osteogenesis (calcium deposits, and osteocalcin [BGLAP] and osteonectin [SPARC] expression), chondrogenesis (glycosaminoglycan production; SOX9 and aggrecan [ACAN] expression), myogenesis (α-smooth muscle actin expression), and neurogenesis (β-III tubulin expression) upon differentiation. CONCLUSIONS. Our findings suggest that orbital fibroblasts contain a population of cells that fulfil the criteria defining MSC. This subpopulation may be increased in GO, possibly underlying the complex differentiation phenotype of the diseas

Analysis of blink dynamics in patients with blepharoptosis

Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy

Determination of incommensurate modulated structure in Bi2Sr1.6La0.4CuO6+{\delta} by aberration-corrected transmission electron microscopy

Incommensurate modulated structure (IMS) in Bi2Sr1.6La0.4CuO6+{\delta} (BSLCO) has been studied by aberration corrected transmission electron microscopy in combination with high-dimensional (HD) space description. Two images in the negative Cs imaging (NCSI) and passive Cs imaging (PCSI) modes were deconvoluted, respectively. Similar results as to IMS have been obtained from two corresponding projected potential maps (PPMs), but meanwhile the size of dots representing atoms in the NCSI PPM is found to be smaller than that in PCSI one. Considering that size is one of influencing factors of precision, modulation functions for all unoverlapped atoms in BSLCO were determined based on the PPM obtained from the NCSI image in combination with HD space description

Macrophages promote a profibrotic phenotype in orbital fibroblasts through increased hyaluronic acid production and cell contractility

Graves’ orbitopathy (GO) is an autoimmune inflammatory disease affecting the orbit. Orbital fibroblasts are a key component in GO pathogenesis, which includes inflammation, adipogenesis, hyaluronic acid (HA) secretion, and fibrosis. Macrophages are thought to participate in the immunological stage of GO, but whether they can directly affect the fibroblasts phenotype and modulate disease progression is unknown. We previously showed that GO adipogenic and fibrotic phenotypes could be modelled in a pseudo-physiological 3D environment in vitro. Here, we introduced macrophages in this 3D culture model to investigate role for macrophages in modulating adipogenesis, HA production, and contractility in orbital fibroblasts. Macrophages had a minimal effect on lipid droplet formation in fibroblasts, but significantly increased HA production and cell contractility, suggesting that they may promote the fibrotic phenotype. This effect was found to be mediated at least in part through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation and linked to an increase in actin polymerization and protrusive activity in fibroblasts. Overall our work shows for the first time a direct role for macrophages in modulating the fibroblasts’ phenotype in GO, supporting a role for macrophages in the progression of the fibrotic phenotype through induction of HA production and stimulation of the contractile phenotype in orbital fibroblasts